From: Subject: Temozolomide and Treatment of Malignant Glioma -- Friedman et al. 6 (7): 2585 -- Clinical Cancer Research Date: Mon, 9 Feb 2009 10:16:04 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C98A9F.6A7B04D0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C98A9F.6A7B04D0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/cgi/content/full/6/7/2585 Temozolomide and Treatment of Malignant Glioma -- = Friedman et al. 6 (7): 2585 -- Clinical Cancer Research = 3D"Clinical = =20 =20
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Clinical Cancer Research Vol. 6, 2585-2597, July 2000
=A9 = 2000 American = Association for Cancer Research

Minireview

Temozolomide and Treatment of Malignant Glioma1=20

Henry S. Friedman2,=20 Tracy Kerby and Hilary Calvert

Departments of Surgery, Medicine, and Pediatrics [H. = S. F.] and=20 Department of Pathology [T. K.], Duke University, Durham, North Carolina = 27710,=20 and Division of Oncology, Newcastle General Hospital, Newcastle Upon = Tyne, NE4=20 6BE United Kingdom [H. C.]


3D"   =20 ABSTRACT
Top
3D"ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
M= alignant=20 gliomas (glioblastoma multiforme and anaplastic astrocytoma) = occur=20 more frequently than other types of primary central nervous = system=20 tumors, having a combined incidence of 5=968/100,000 = population. Even=20 with aggressive treatment using surgery, radiation, and = chemotherapy,=20 median reported survival is less than 1 year. Temozolomide, a = new=20 drug, has shown promise in treating malignant gliomas and = other=20 difficult-to-treat tumors.

Temozolomide, a p.o. imidazotetrazine second-generation alkylating=20 agent, is the leading compound in a new class of = chemotherapeutic=20 agents that enter the cerebrospinal fluid and do not require = hepatic=20 metabolism for activation. In vitro, temozolomide has=20 demonstrated schedule-dependent antitumor activity against = highly=20 resistant malignancies, including high-grade glioma. In = clinical=20 studies, temozolomide consistently demonstrates reproducible = linear=20 pharmacokinetics with approximately 100% p.o. = bioavailability,=20 noncumulative minimal myelosuppression that is rapidly = reversible,=20 and activity against a variety of solid tumors in both = children and=20 adults. Preclinical studies have evaluated the combination of = temozolomide with other alkylating agents and inhibitors of = the DNA=20 repair protein O6-alkylguanine = alkyltransferase to=20 overcome resistance to chemotherapy in malignant glioma and = malignant=20 metastatic melanoma. Temozolomide has recently been approved = in the=20 United States for the treatment of adult patients with = refractory=20 anaplastic astrocytoma and, in the European Union, for = treatment of=20 glioblastoma multiforme showing progression or recurrence = after=20 standard therapy. Predictable bioavailability and minimal = toxicity=20 make temozolomide a candidate for a wide range of clinical = testing to=20 evaluate the potential of combination treatments in different = tumor=20 types. An overview of the mechanism of action of temozolomide = and a=20 summary of results from clinical trials in malignant glioma = are=20 presented here.


3D"   =20 Introduction
Top
ABSTRACT
3D"Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
M= alignant=20 gliomas (glioblastoma multiforme and anaplastic astrocytoma) = occur=20 more frequently than other types of primary CNS tumors, = having a=20 combined incidence of 5=968/100,000 population. Even with = aggressive=20 treatment using surgery, radiation, and chemotherapy, median = reported=20 survival is less than 1 year (1)=20 . Temozolomide, a new drug, has shown promise in treating = malignant=20 gliomas and other difficult-to-treat tumors. Temozolomide=20 represents a new class of second-generation imidazotetrazine = prodrugs=20 that undergo spontaneous conversion under physiological=20 conditions to the active alkylating agent MTIC.3=20 Thus, temozolomide does not require hepatic metabolism for = activation=20 (2)=20 .

Interest in temozolomide as an antitumor agent derives from = its=20 broad-spectrum antitumor activity in tumor models in mice (3)=20 . In vitro, temozolomide has demonstrated = schedule-dependent=20 antitumor activity against a variety of malignancies, = including=20 glioma, metastatic melanoma, and other difficult-to-treat = cancers (3,=20 4,=20 5)=20 . In preclinical studies, temozolomide demonstrated distribution = to=20 all tissues, including penetration into the CNS; relatively = low=20 toxicity compared with its parent compound, mitozolomide; and = antitumor activity against a broad range of tumor types, = including=20 glioma, melanoma, mesothelioma, sarcoma, lymphoma, leukemia, = and=20 carcinoma of the colon and ovary (3,=20 4,=20 5,=20 6,=20 7,=20 8)=20 . Its demonstrated ability to cross the blood-brain barrier = is of=20 special interest with respect to its activity in CNS tumors = (9)=20 .

In Phase 1 and 2 clinical studies conducted by the CRC (London, = United=20 Kingdom), temozolomide was absorbed rapidly, exhibited 100% = p.o.=20 bioavailability within 1=962 h of administration, and demonstrated = antineoplastic activity in recurrent high-grade glioma, = melanoma, and=20 mycosis fungoides (10,=20 11,=20 12,=20 13)=20 . Results of these trials showed that when temozolomide is=20 administered p.o. once daily for 5 days in a 4-week cycle, it = is well=20 tolerated, producing mild-to-moderate toxicity that is both=20 predictable and easily managed. The results also confirmed = the=20 ability of temozolomide to penetrate the CNS and indicated = that=20 temozolomide has considerable potential in treating gliomas = and=20 improving the QOL of patients with glioma (12,=20 13,=20 14)=20 . Additional Phase 1 studies have confirmed these results and = have=20 extended these observations to pediatric patients (15=20 ,=20 16) .

Temozolomide has been evaluated in a number of Phase 2 and 3=20 clinical trials for the treatment of glioblastoma multiforme, = anaplastic astrocytoma, and malignant metastatic=20 melanoma=97malignancies for which there are no satisfactory = therapies.=20 On the basis of the results of these studies, temozolomide = has been=20 approved in the European Union for the treatment of patients = with=20 glioblastoma multiforme showing progression or recurrence = after=20 standard therapy. Recently, temozolomide received accelerated = approval from the FDA for treatment of adult patients with=20 anaplastic astrocytoma who have relapsed after treatment that = included a nitrosurea drug (BCNU or CCNU) and procarbazine. = Studies=20 are under way to evaluate the combination of temozolomide = with=20 other chemotherapeutic agents and biochemotherapy in the=20 treatment of malignant glioma and metastatic melanoma, = respectively.=20 This article reviews the mechanism of action of temozolomide = as=20 an anticancer agent and summarizes the most recent clinical=20 studies of temozolomide for the treatment of malignant = gliomas.=20


3D"   =20 Background
Top
ABSTRACT
Introduction
3D"Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
T= emozolomide=20 was synthesized at Aston University in the early 1980s as one = of a=20 series of novel imidazotetrazinones (17)=20 . These agents were structurally unique because they = contained=20 three adjacent nitrogen atoms that conferred unique=20 physicochemical properties and much greater antitumor = activity than=20 the previously synthesized bicyclic triazenes, which = contained only=20 two adjacent nitrogen atoms (17)=20 . The most potent antitumor compound of this class of = compounds,=20 mitozolomide, showed potent antitumor activity against a = large panel=20 of murine tumors (18)=20 . Mitozolomide is a prodrug that spontaneously decomposes to = a highly=20 reactive DNA-cross-linking metabolite without any need for=20 metabolic activation (19,=20 20,=20 21,=20 22,=20 23)=20 . Although Phase 1 clinical studies of mitozolomide revealed = some=20 activity against small-cell carcinoma of the lung and = malignant=20 melanoma, it also produced unpredictable and severe = thrombocytopenia=20 that limited its usefulness (24)=20 . These preliminary results precluded further clinical = development of=20 mitozolomide.

Temozolomide, a 3-methyl derivative of mitozolomide, was less=20 toxic than mitozolomide and exhibited comparable antitumor = activity=20 against various murine tumors (3)=20 . Additional characteristics that justified its further = development=20 for clinical evaluation in patients with cancer included wide = tissue=20 distribution with penetration into the intact mouse brain (25)=20 , 100% bioavailability after p.o. dosing, and no requirement = for=20 enzymatic conversion to the potent antitumor metabolite = MTIC.=20


3D"   =20 Mechanism of Action
Top
ABSTRACT
Introduction
Background
3D"Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
T= he=20 methylation of DNA seems to be the principal mechanism responsible=20 for the cytotoxicity of temozolomide to malignant cells. The=20 spontaneous conversion of temozolomide to the reactive methylating = agent MTIC is initiated by the effect of water at the highly=20 electropositive C4 position of temozolomide. This = activity=20 opens the ring, releases CO2, and generates MTIC = (Fig.=20 1) . The initial proposal was that this effect = of water=20 was catalyzed in the close environment of the major groove of = DNA (26=20 ,=20 27) , but confirming this mechanism has been difficult, = and it is=20 known that temozolomide converts readily to MTIC in free = solution in=20 the absence of DNA (2)=20 . MTIC degrades to the methyldiazonium cation, which = transfers=20 the methyl group to DNA and to the final degradation product, = AIC, which is excreted via the kidneys (28=20 ,=20 29) . The methyldiazonium cation can also react with RNA = and with=20 soluble and cellular protein (23)=20 . However, the methylation of RNA and the methylation or=20 carbamoylation of protein do not appear to have any known = significant=20 role in the antitumor activity of temozolomide. Additional = studies=20 are required to clarify the role of these targets in the = biochemical=20 mechanism of action of temozolomide.



View larger = version=20 (16K):
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  		Fig. 1. Chemical structure of=20 temozolomide. Adapted with permission from Stevens, M. F. G. = et=20 al. (3)=20 . =

 = ;
The=20 spontaneous conversion of temozolomide to MTIC is dependent = on pH.=20 Comparison of the half-life of temozolomide in phosphate = buffer [(pH=20 7.4) t1/2 =3D 1.83 h; Refs. 28=20 ,=20 29 ] with the mean plasma half-life observed in patients = after=20 i.v. and p.o. dosing (t1/2 =3D 1.81 h; = Refs. 10=20 ,=20 29 ) indicates that the conversion of temozolomide to = MTIC is a=20 chemically controlled reaction with little or no enzymatic = component.=20 The nonenzymatic conversion of temozolomide to MTIC may = contribute to=20 its highly reproducible PK in comparison with that of other=20 alkylating agents such as DTIC and procarbazine, which must = undergo=20 metabolic conversion in the liver and are, thus, subject to=20 interpatient variation in rates of conversion (27=20 ,=20 29) .

Among the lesions produced in DNA after treatment of cells with=20 temozolomide, the most common is methylation at the=20 N7 position of guanine, followed by = methylation at=20 the O3 position of adenine and the=20 O6 position of guanine (29)=20 . Although both the N7-methylguanine and=20 O3-methyladenine adducts probably contribute to the=20 antitumor activity of temozolomide in some if not all = sensitive=20 cells, their role is controversial (30,=20 31,=20 32)=20 . The O6-MG adduct (which accounts for 5% of the = total=20 adducts formed by temozolomide; Ref. 29=20 ) probably plays a critical role in the antitumor activity of = the=20 agent. This is supported by the correlation between the = sensitivity=20 of tumor cell lines to temozolomide and the activity of the = DNA=20 repair protein O6-alkylguanine alkyltransferase, = which=20 specifically removes alkyl groups at the O6 position = of=20 guanine. Cell lines that have low levels of AGT are sensitive = to the cytotoxicity of temozolomide, whereas cell lines that=20 have high levels of this repair protein are much more = resistant=20 to it (33,=20 34,=20 35)=20 . This correlation has also been observed in human = glioblastoma=20 xenograft models (4=20 ,=20 5 ,=20 8) . The preferential alkylation of guanine and adenine = and the=20 correlation of sensitivity to the drug with the ability to = repair the=20 O6-alkylguanine lesion also have been seen = with=20 triazine, DTIC, and the nitrosourea alkylating agents BCNU = and CCNU=20 (35,=20 36,=20 37)=20 .

The cytotoxic mechanism of temozolomide appears to be related = to=20 the failure of the DNA MMR system to find a complementary = base for=20 methylated guanine. This system involves the formation of a = complex=20 of proteins that recognize, bind to, and remove methylated = guanine (38,=20 39,=20 40)=20 . The proposed hypothesis is that when this repair process is = targeted to the DNA strand opposite the O6-MG, it = cannot=20 find a correct partner, thus resulting in long-lived nicks in = the DNA=20 (41)=20 . These nicks accumulate and persist into the subsequent cell = cycle,=20 where they ultimately inhibit initiation of replication in = the=20 daughter cells, blocking the cell cycle at the = G2-M=20 boundary (41,=20 42,=20 43,=20 44)=20 . In both murine (42)=20 and human (45)=20 leukemia cells, sensitivity to temozolomide correlates with = increased=20 fragmentation of DNA and apoptotic cell death. In addition to = causing=20 cell death, there is evidence from preclinical studies that = DNA=20 adducts formed by temozolomide and the subsequent alteration = of=20 specific genes and their cognate protein products may reduce = the=20 metastatic potential of tumor cells by altering the = immunogenicity of=20 the tumor cells (46,=20 47,=20 48)=20 . It has also been postulated that temozolomide-induced DNA = damage=20 and subsequent cell-cycle arrest may reduce the metastatic = properties=20 of some tumor cells (49,=20 50,=20 51)=20 .


3D"   =20 Mechanisms of Resistance
Top
ABSTRACT
Introduction
Background
Mechanism of Action
3D"Mechanisms of = Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
<= STRONG>AGT.
The=20 two primary mechanisms of resistance for temozolomide and = other=20 alkylating agents are the enzyme AGT (52=20 ,=20 53) and a deficiency in the MMR pathway. Of these two = mechanisms,=20 AGT plays a primary role in resistance to temozolomide by = removing=20 the alkyl groups from the O6 position of = guanine,=20 in effect reversing the cytotoxic lesion of temozolomide (54)=20 . The sensitivity of tumor cell lines to temozolomide and the = alkylating agents BCNU and DTIC can be correlated with AGT = levels (37=20 ,=20 45 ,=20 55, 56,=20 57,=20 58)=20 . Furthermore, retrovirusmediated transfer of human AGT gene = to=20 cells that are devoid of endogenous AGT activity confers a = high=20 level of resistance on temozolomide and other methylating and = chloroethylating agents (59)=20 .

MMR Pathway.
Although AGT is clearly important in = the=20 resistance of cells to temozolomide, some cell lines that = express low=20 levels of AGT are nevertheless resistant, which indicates = that other=20 mechanisms for resistance may be involved (60=20 ,=20 61) . A deficiency in the MMR pathway resulting from = mutations in=20 any one or more of the five or six protein complexes that = recognize=20 and repair DNA can render cells tolerant to methylation and = to the=20 cytotoxic effects of temozolomide. This deficiency in the MMR = pathway=20 results in a failure to recognize and repair the = O6-MG=20 adducts produced by temozolomide and other methylating agents = (33=20 ,=20 62 ,=20 63) . DNA replication continues past the O6-MG = adducts=20 without cell cycle arrest or apoptosis. Resistance in tumor = cells=20 that are deficient in MMR is unrelated to the level of AGT = and is,=20 therefore, unaffected by AGT inhibitors.

PARP.
Another possible mechanism of resistance = for=20 temozolomide is the base excision repair pathway. Studies = have shown=20 that treatment of human tumor cells with temozolomide induced = an=20 increase in the activity of PARP, which is believed to be = involved in=20 nucleotide excision repair (64=20 ,=20 65) , and the inhibition of PARP has been reported to = enhance the=20 cytotoxicity of methylating agents (66,=20 67,=20 68)=20 . Several studies with inhibitors of PARP and with cell lines = deficient in either MMR or excision repair have indicated a = role of=20 the repair of N7-methylguanine and=20 O3-methyladenine adducts in the resistance = to the=20 antitumor activity of temozolomide and other alkylating = agents (30=20 ,=20 33 ,=20 66 ,=20 67) . However, the importance of these adducts in the = antitumor=20 activity of the drug may be secondary to that of the = O6-MG=20 adduct, except in those tumors that are deficient in base = excision=20 repair (31=20 ,=20 32 ,=20 69) .


3D"   =20 Reducing Resistance to Temozolomide =
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
3D"Reducing Resistance = to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
<= STRONG>Alkylating=20 Agents.
Several preclinical studies have examined methods = for=20 reducing the resistance to alkylating agents such as = temozolomide.=20 Agents that deplete AGT levels or inhibit the activity of the = excision-repair pathway reduce resistance to temozolomide. = Other than=20 those mentioned above, few studies have investigated the use = of=20 agents that inhibit the excision-repair pathway, but various = studies=20 (5)=20 have used combinations of different alkylating agents to = deplete AGT=20 levels. Additive or more than additive antitumor effects and=20 complementary toxicity profiles characterized these = combinations.=20 Because it has a mild toxicity profile and the ability to = deplete=20 AGT, temozolomide has the potential to combine with other = alkylating=20 agents such as BCNU, assuming that overlapping toxicities are = manageable (5)=20 .

O6-BG.
O6-BG is a=20 low-molecular-weight substrate for AGT and a potent inhibitor = of=20 AGT-mediated resistance to DNA damage by chloroethylnitrosoureas = and=20 methylating agents (36=20 ,=20 70 ,=20 71) . Evidence from preclinical studies suggests a role = for=20 O6-BG in increasing the therapeutic index of = temozolomide.=20 Pretreatment with O6-BG enhances the activity of=20 temozolomide in vitro and in vivo in tumor cells = that=20 have high levels of AGT but has little effect on tumor cells = that=20 have low or undetectable levels of AGT (8=20 ,=20 33 ,=20 34 ,=20 56 ,=20 72) . However, in vivo enhancement of temozolomide=20 activity by O6-BG has been observed in a human glioma=20 xenograft derived from a low-AGT-producing cell line that is=20 refractory to O6-BG enhancement of temozolomide = activity=20 in vitro (73)=20 , which suggests that some in vivo metabolic = interaction with=20 O6-BG enhanced the activity of temozolomide. In = these=20 studies, extended treatments with O6-BG are more = effective=20 than single treatments (56=20 ,=20 73) . In a human melanoma xenograft model, a combination = of=20 O6-BG and temozolomide, given on a 5-day schedule, = resulted=20 in a greater antitumor effect than did an equitoxic dose of=20 temozolomide (8)=20 . The combination of temozolomide and O6-BG also = resulted=20 in a delay of tumor growth equivalent to that produced by a = 3-fold=20 greater dose of temozolomide on the same 5-day schedule. =

Other studies have shown that bone marrow cells are low in AGT = activity,=20 and AGT depletion with O6-BG substantially increased = the=20 sensitivity of these cells to O6-alkylating agents = including BCNU and temozolomide (74,=20 75,=20 76)=20 . It is, thus, possible that hematological toxicity may limit = the=20 doses of O6-BG and other inhibitors of DNA repair = used in=20 clinical practice. A study of the effect of O6-BG = pretreatment=20 on the toxic and clastogenic effects of temozolomide on = murine=20 hematopoietic cells in vivo has confirmed potentiation of = bone=20 marrow cell sensitivity (75)=20 . An increase in the frequency of formation of micronuclei in = the=20 bone marrow of mice pretreated with O6-BG observed = in this=20 study also suggests the possibility of an increased incidence = of=20 secondary leukemias.

Attempts to reduce the toxicity produced by this combination = have=20 focused on protection of normal hemopoietic tissue by transducing=20 hematopoietic progenitor cells with = O6-BG-resistant=20 methyltransferase genes (77=20 ,=20 78 ,=20 79) . Expression of a double-mutant form of AGT in murine = bone=20 marrow cells significantly reduced the toxicity produced by=20 temozolomide given in combination with O6-BG and led to = a=20 reduction in the frequency of combined=20 O6-BG/temozolomide-induced micronuclei in the bone = marrow=20 (78)=20 . Although transducing hematopoietic progenitor cells with=20 O6-BG-resistant methyltransferase genes protects = committed=20 murine hemopoietic progenitors against the toxicity of=20 O6-alkylating agents, a similar effect is not observed = with=20 primitive, multipotent spleen colony-forming cells (76)=20 . In a recent study, Chinnasamy et al. (76)=20 showed that transduction of primitive, multipotent spleen=20 colony-forming cells with a double mutant of AGT did not = result in a=20 significant protection against the toxicity produced by = combination=20 of BCNU and O6-BG. These results indicate that the = protective effect afforded by transducing hematopoietic = progenitor=20 cells with O6-BG-resistant methyltransferase genes = may be=20 highly specific to the cytotoxic agent and the cell type = involved (76)=20 . Thus, further investigation is needed to define the = potential=20 clinical benefit of this type of protective genetic = therapy.=20


3D"   =20 Clinical Experience with Temozolomide in Malignant Gliomas=20
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
3D"Clinical Experience = with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
<= STRONG>Initial=20 Phase 1 Studies.
The safety, PK, and antitumor activity of=20 temozolomide were initially evaluated in a Phase 1 trial = sponsored by=20 the CRC (10)=20 . In this study, 51 patients with advanced cancer received a = single=20 p.o. dose of temozolomide. The absolute bioavailability of=20 temozolomide was also studied in five of these patients. = Temozolomide=20 demonstrated approximately 100% p.o. bioavailability after = i.v.=20 versus p.o. administration. Peak plasma concentrations=20 occurred within 0.33=962 h after p.o. administration, and = the AUC=20 increased linearly with the dose. Elimination was equally = rapid, with=20 a plasma half-life ranging from 1.6 to 1.8 h and a whole-body = clearance of 12 liters/h. The PK of temozolomide was linear = and=20 reproducible, with little interpatient variation. PK = parameters did=20 not vary between the first and fifth dose, which indicated = that=20 temozolomide did not accumulate after multiple doses (10)=20 .

On the basis of the schedule-dependent antitumor activity = observed=20 with temozolomide in preclinical studies (3)=20 , an additional 42 patients were given a single p.o. dose of=20 temozolomide started at 150 mg/m2 and escalated to = 240=20 mg/m2 for 5 days in a 4-week cycle if no major=20 myelosuppression was detected. In this population, the DLT of = temozolomide was mild-to-moderate myelosuppression = (neutropenia and=20 thrombocytopenia), which was both predictable and easily = controlled.=20 The MTD was 200 mg/m2 per day (10)=20 . As a result, the recommended dosage for Phase 2 studies was = 150=20 mg/m2 for the first course and, in the absence of = any=20 major myelosuppression, escalation to 200 mg/m2 = for=20 subsequent courses. Nonhematological toxicity, mainly nausea = and=20 vomiting, was mild and controlled with standard antiemetic = agents. No=20 drug-related adverse CNS effects or alopecia occurred with=20 temozolomide (10)=20 .

Subsequent Phase 1 studies have been conducted to evaluate the=20 safety of a machine-filled capsule preparation of = temozolomide,=20 which differed from the hand-filled preparation used in the=20 initial CRC Phase 1 study (80=20 ,=20 81, 82,=20 83,=20 84)=20 .

These studies have confirmed the safety, tolerability, and PK = of=20 temozolomide reported by Newlands et al. (10)=20 .

Safety.
Consistent with the results of a Phase 1 = study,=20 hematological toxicity, specifically thrombocytopenia and=20 neutropenia, was dose limiting. Neutropenia or = thrombocytopenia=20 typically appeared 21=9628 days after the first dose of each = cycle and=20 recovered to grade 1 myelosuppression within 7=9614 days. = Grade 4=20 toxicity occurred at cumulative p.o. dosages of more than = 1000=20 mg/m2 over 5 days, but little other significant = toxicity=20 was seen. Grades 3 or 4 myelosuppression generally occurred = in=20 fewer than 10% of patients studied.

Prior treatment with chemotherapy, radiation, or both has a=20 significant effect on the MTD of temozolomide (83)=20 . Hammond et al. (80)=20 evaluated the effect of prior myelosuppressive therapy on = toxicity=20 and PK profile of temozolomide in 24 advanced cancer patients = who=20 were stratified according to prior exposure to chemotherapy = and=20 radiation. Patients in either category received a dosage of = 100=20 mg/m2/day temozolomide for 5 days, which was escalated = to=20 150 and 200 mg/m2/day in the absence of myelosuppression (80)=20 . The MTD for temozolomide was established as 150=20 mg/m2/day. Another similar Phase 1 study, reported = by the=20 National Cancer Institute, evaluated the safety of = temozolomide in=20 patients who were stratified on the basis of prior exposure = to=20 nitrosourea (83)=20 . The MTD for patients with prior exposure to nitrosourea was = 150=20 mg/m2/day, and the MTD for patients without such = prior=20 exposure was 250 mg/m2/day. An evaluation of the = PK of=20 temozolomide showed that clearance from the plasma was = significantly=20 less in patients with prior exposure to nitrosourea than it = was in=20 patients without such prior exposure (83)=20 . This may have contributed to the lower dosage of = temozolomide that=20 was tolerated by these patients and had a notable effect on = the=20 dosing recommendation for these patients.

The results of these studies indicate that a dosage of 200=20 mg/m2 of temozolomide given on a 5-day schedule = repeated=20 every 28 days is appropriate for patients who are not = pretreated=20 with radiation, chemotherapy, or both. Patients who are=20 pretreated with chemotherapy receive a lower starting dosage = of=20 temozolomide (i.e., 150 mg/m2), which can = be=20 escalated to 200 mg/m2 in subsequent courses in = the=20 absence of grade 3 or 4 myelosuppression (80)=20 . A summary of the administration schedule for temozolomide = and the=20 MTD that was observed in several completed Phase 1 trials is=20 presented in Table 1 .


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  		Table 1 Phase 1 trials of = temozolomide =

 = ;
PK.
PK=20 analysis of temozolomide has consistently shown that the PK = of=20 temozolomide are linear, with 100% bioavailability after p.o. = administration, and that there is no accumulation of drug on = day 5=20 after 5 days of dosing. Time to maximum plasma concentration=20 (tmax) is approximately 1 h. Elimination = half-life=20 (t1/2) is 1.6=961.8 h. A summary of the PK = properties=20 of temozolomide in adults is given in Table 2 .


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  		Table 2 PK parameters of = temozolomide=20 given once daily for 5 days =

 = ;
Studies=20 with p.o. 14C-temozolomide in patients with advanced=20 cancer (82)=20 indicate that the primary pathway for its clearance from = plasma is=20 degradation to MTIC with further degradation to AIC. In these = studies, temozolomide was eliminated primarily in the urine, = with 36%=20 of the dose excreted as the intact drug and AIC. The effect = of=20 gastric pH and ingestion of food on the PK properties and = p.o.=20 bioavailability of temozolomide has also been evaluated (85)=20 . Beale et al. (85)=20 evaluated the effect of an increase in gastric pH, through = the use of=20 ranitidine, on the p.o. bioavailability and plasma PK of = temozolomide=20 and MTIC. In this study, the p.o. bioavailability, maximum = plasma=20 concentration, and half-life of temozolomide were not = affected by an=20 increase in gastric pH of 1 to 2 units, resulting from the=20 administration of ranitidine every 12 h on either the first 2 = or the=20 last 2 days of the 5-day temozolomide dosing schedule (85)=20 . Administration of temozolomide after ingestion of food = results in a=20 small decrease in p.o. availability (84)=20 . When temozolomide was taken after a meal, a slight but=20 statistically significant reduction (9%) occurred in the rate = and=20 extent of absorption. Because AUC confidence limits were = within the=20 bioequivalence guidelines of 80=96125%, it is unlikely that = this=20 reduction has any clinical effect on the antitumor activity = of=20 temozolomide (84)=20 . Because bioavailability and 14C-temozolomide = metabolism=20 studies have shown that p.o. bioavailability is essentially = complete=20 (82)=20 , the p.o. formulation of the drug has been used for clinical = studies.

Pediatric Patients.
Phase 1 studies of = temozolomide were=20 expanded to include pediatric cancer patients (16)=20 . In a Phase 1 study conducted to define the multiple-dose PK = of=20 temozolomide, 20 patients between 3 and 17 years old were = given=20 temozolomide over a dosage range of 100=96240 mg/m2/day = (15)=20 . Patients were stratified according to prior craniospinal=20 irradiation or nitrosourea therapy. The MTD was 200 = mg/m2=20 for patients who had not received prior craniospinal = irradiation=20 or nitrosourea therapy but was not defined for children with=20 prior craniospinal irradiation because of the small number of = patients. Temozolomide was absorbed rapidly, had an AUC that=20 increased in a dosage-related manner, and showed no evidence = of=20 accumulation. The plasma half-life, whole-body clearance, and = volume=20 of distribution were independent of dosage (Table 3) . Compared with adult patients treated with 200=20 mg/m2/day, children seemed to have a higher AUC = (48.7=20 versus 34.5 =B5g=B7h/ml), most likely because children = have a=20 larger ratio of body surface area to volume (15)=20 . Despite higher concentrations at dosages equivalent to = those used=20 in adult patients, the bone marrow function in pediatric = patients=20 appears to allow greater exposure to the drug before bone = marrow DLT=20 develops.


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  		Table 3 PK parameters in = pediatric=20 patientsa =

 = ;
Antitumor=20 Activity.
As predicted by preclinical evaluations (5)=20 , Phase 1 studies have demonstrated the antitumor activity of = temozolomide in a number of difficult-to-treat cancers for = which=20 there is no satisfactory treatment. In the CRC Phase 1 study = (10)=20 , clinical responses were observed in patients with recurrent = high-grade glioma, melanoma, and mycosis fungoides. Similar = antitumor=20 activity has also been observed in subsequent Phase 1 trials=20 conducted with machine-filled capsules. In these studies,=20 temozolomide demonstrated clinical activity against = high-grade=20 gliomas in both adult and pediatric patients (84)=20 .


3D"    Phase=20 2 and 3 Clinical Experience
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
3D"Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
REFERENCES
 
<= STRONG>Rationale.
Adjuvant=20 chemotherapy with single-agent nitrosourea or combination therapy = for=20 the treatment of recurrent malignant glioma and malignant melanoma = is=20 far from satisfactory. This is primarily attributable to the = de=20 novo or acquired resistance to chemotherapeutic agents (86)=20 . Although alkylating agents such as procarbazine have = activity=20 in the treatment of malignant glioma, the use of these agents = has been associated with a high level of toxicity and only a=20 modest improvement in overall survival rate (87,=20 88,=20 89)=20 . As a result, there is a need for new agents that are = effective=20 and can be used in combination with other agents or radiation = to overcome resistance. The acceptable safety profile and = clinical=20 activity of temozolomide observed in patients with malignant = glioma=20 and recurrent astrocytoma prompted subsequent Phase 2 and 3 = studies=20 to confirm the activity of temozolomide in these malignancies. = The=20 CRC has conducted a number of these studies, in which the activity = of=20 temozolomide in recurrent and newly diagnosed gliomas was=20 established. A summary of Phase 2 and 3 trials is presented = in Table=20 4 .


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  		Table 4 Phase 2 and 3 trials of=20 temozolomide in malignant glioma =

 = ;
Primary=20 Brain Tumors.
O=92Reilly et al. (12)=20 treated 28 patients with primary brain tumors. The initial = dosage of=20 150 mg/m2/day of temozolomide was given p.o. once = daily=20 for 5 days; this dosage was increased to 200 = mg/m2/day=20 once daily for 5 days and repeated at 28-day intervals if the = patient=20 did not experience significant myelosuppression at day 22 of = the=20 first cycle. Treatment was well tolerated. Grade 3 leukopenia = occurred in only 3 (5%) of 57 courses, and grade 3 = thrombocytopenia=20 was reported in only 4 (7%) of 57 courses. Of the 10 = evaluable=20 patients with recurrent astrocytoma after radiation therapy, = 5 showed=20 major improvement on CT and complete resolution of clinical = signs and=20 symptoms that persisted for 3=966 months; 3 other patients = showed a=20 slight reduction or no change on CT, although their = neurological=20 condition improved (12)=20 . Major improvement on CT also was reported for two of nine = evaluable=20 patients treated with two courses of temozolomide before = cranial=20 irradiation for newly diagnosed high-grade astrocytomas; two = others=20 showed slight improvement. Three additional evaluable = patients=20 with primary brain tumors, including one with recurrent=20 medulloblastoma after chemotherapy and radiation therapy, = experienced=20 major improvement on CT that was maintained for 6 months (12)=20 .This study was extended to 75 patients=9748 with recurrent=20 disease and 27 with new diagnoses (90)=20 . Improvements on CT were seen in 12 (25%) of the patients = with=20 recurrent disease and in eight (30%) of the patients with new = diagnoses. Twenty-two % of patients with recurrences and 43% = of those=20 with newly diagnosed tumors survived to 1 year. Although = there was a=20 clear improvement in the QOL in responders who used the 5-day = schedule, no conclusions could be reached about the effect on = extended survival benefit in comparison with the overall = survival=20 data established by historical results (90)=20 . This study confirmed, however, the activity of temozolomide = against=20 gliomas in patients who have failed to respond to intensive = radiation=20 therapy.

Similar results were reported in a multicenter Phase 2 study=20 conducted by the CRC that evaluated temozolomide in patients=20 diagnosed with anaplastic astrocytoma, glioblastoma = multiforme=20 (grade 4), and unclassified high-grade astrocytoma (grades = 3=964;=20 13=20 ). In this study, objective responses, measured by improvement = in=20 neurological status, were seen in 11 (11%) of 103 patients = who=20 received temozolomide; 5 of these patients had improvement on = CT or=20 magnetic resonance imaging scans (13)=20 . An additional 47% of the patients in the study had stable = disease.=20 The median survival of all patients with measurable response = was 5.8=20 months, and 22% of the patients had no neurological or=20 radiological evidence of progressive disease at 6 months. The = results=20 of this study further confirmed the activity of temozolomide = in=20 patients with recurrent and progressive high-grade glioma. =

Recently, three open-label, multi-institutional studies have=20 evaluated the use of temozolomide in 525 patients with = malignant=20 glioma. These studies represent the largest evaluation of a=20 single agent in patients with recurrent malignant gliomas = that=20 were rigorously controlled with strict prospectively defined=20 criteria for assessment of tumor response, central review of=20 histology, and validated instruments to assess health-related = QOL. The first two trials evaluated the safety, efficacy, and = health-related QOL effects of temozolomide in patients with=20 glioblastoma multiforme at first relapse and were as follows:=20 (a) a pivotal multicenter Phase 2 study that compared = the PFS=20 at 6 months and the safety in patients treated with = temozolomide=20 with those in patients treated with procarbazine (91)=20 ; and (b) a second supportive trial in patients with = glioblastoma=20 multiforme to further examine the efficacy and health-related = QOL=20 aspects of temozolomide. In the pivotal Phase 2 study, 225=20 patients were randomized to receive either temozolomide = (n =3D=20 112) or procarbazine (n =3D 113; Ref. 91=20 ). The treatment arms were similar with respect to baseline = disease=20 characteristics and prior therapies. Objective responses (PR = or=20 stable disease) were seen in 46% of patients treated with=20 temozolomide and in 33% of patients treated with = procarbazine, with=20 PRs occurring in 5% of patients in both groups (91)=20 . Patients treated with temozolomide had significantly better = 6-month=20 PFS and overall survival than those treated with procarbazine = (21% in=20 the temozolomide group versus 9% in the procarbazine = group;=20 P =3D 0.008). Median PFS was also better for = temozolomide=20 compared with procarbazine (2.89 months for temozolomide=20 versus 1.97 months for procarbazine; hazard ratio of 1.47;=20 P =3D 0.0063; Ref. 91=20 . A difference in PFS in favor of temozolomide was observed = as early=20 as 1 month after randomization, and the difference was = maintained for=20 several months (Fig. 2) . Similar findings were observed in the = confirmatory=20 single-arm study that evaluated temozolomide in 138 = glioblastoma=20 multiforme patients. In this study, treatment with = temozolomide=20 resulted in a PFS of 19% (95% CI, 12=9626%; Table 5 ). These studies formed the basis for the = approval of=20 temozolomide in the European Union for the treatment of = patients with=20 glioblastoma multiforme showing progression or recurrence = after=20 standard therapy.



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  		Fig. 2. PFS for glioblastoma = multiforme=20 patients treated with temozolomide: intention to treat = population. =

 = ;

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  		Table 5 Progression-free = survival and=20 overall survival in GBMa patients treated = with=20 temozolomideb =

 = ;
The=20 third study evaluated the safety and efficacy of temozolomide = in=20 adult patients with malignant anaplastic astrocytoma at first = relapse=20 who had relapsed from their initial therapy (92)=20 . A total of 162 patients were enrolled in this trial. Of = these,=20 111 were confirmed to have had anaplastic astrocytoma or = anaplastic=20 mixed oligoastrocytoma. Patients who had not been previously=20 treated with chemotherapy received a starting dosage of 200=20 mg/m2 of p.o. temozolomide daily for 5 days on a = 28-day=20 cycle; patients with a history of chemotherapy received a = reduced=20 dose of 150 mg/m2/day, which was increased in = subsequent=20 cycles if no grade 3 or 4 hematological toxicities occurred.=20 Pathology confirmation of the diagnosis, including central = review of=20 histology, was required in all patients. In the = intent-to-treat=20 population, PFS at 6 months was 46%, and the median time to=20 progression was 5.4 months (Table 6) . The median overall survival was 13.6 months, = and the=20 6- and 12-month survival rates based on Kaplan-Meier estimates = were=20 75% (95% CI, 69=9683%) and 56% (95% CI, 50=9666%), respectively = (92)=20 . Central review of gadolinium-enhanced magnetic resonance = imaging=20 scans revealed a 35% objective response rate for the = intent-to-treat=20 population. When the stable disease population was included, = the=20 overall tumor response was 61% (92)=20 . In this study, maintenance of PFS and objective response = were=20 associated with health-related QOL benefits independent of = steroid=20 use. This study documents the efficacy, safety, and QOL = benefits=20 of temozolomide in patients with recurrent anaplastic = astrocytoma.=20 On the basis of these results, temozolomide received = accelerated=20 approval from the FDA for treatment of adult patients with = anaplastic=20 astrocytoma who have relapsed after treatment that included a = nitrosurea drug (BCNU or CCNU) and procarbazine.


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  		Table 6 Progression-free = survival and=20 overall survival in anaplastic astrocytoma patients treated = with=20 temozolomidea =

 = ;
The=20 use of temozolomide in the treatment of patients with newly = diagnosed=20 malignant glioma has also been evaluated (93)=20 . Thirty-three patients with newly diagnosed glioblastoma = multiforme=20 and five patients with anaplastic astrocytoma were treated = with a=20 starting dosage of 200 mg/m2 of p.o. temozolomide = daily=20 for 5 days on a 28-day cycle. Responses (complete and = partial) were=20 observed in 47% of the patients. Among the patients with = glioblastoma=20 multiforme, 3 achieved a CR and 14 achieved a PR. One patient = with=20 anaplastic astrocytoma had a PR. It is of interest that in 11 = tumors=20 that had 20% or more cells staining with anti-AGT antibody,=20 there were 1 patient with PR, 2 with stable disease, and 8 = with=20 disease progression. In 25 tumors that had fewer than 20%=20 AGT-positive cells, there were 3 CRs, 12 PRs, 4 patients with = stable=20 disease, and 6 patients with disease progression. = Temozolomide was=20 well tolerated, with grades 3 and 4 myelosuppression = occurring in=20 only 5% of the patients. Grade 3 nausea and constipation = occurred in=20 13% of the patients, and no grade 4 nonhematological toxicity = was=20 observed (93)=20 . These results suggest that temozolomide has activity in = newly=20 diagnosed malignant glioma, and that the evaluation of AGT = protein=20 expression may identify individuals who are more likely to = respond=20 to temozolomide therapy for malignant glioma.

Malignant Metastatic Melanoma.
The efficacy of=20 temozolomide was evaluated in a study of patients with = advanced=20 metastatic melanoma, including patients with brain metastases = (11)=20 . Fifty-six patients were given p.o. temozolomide 150=20 mg/m2 once daily for 5 days. If grade 2 or greater=20 myelosuppression did not occur by day 22, subsequent 5-day = courses=20 (200 mg/m2/day) were administered at 28-day = intervals.=20 Among the 56 patients (49 with evaluable lesions), CRs = occurred in 3,=20 all with lung metastases only, and PRs occurred in 9, which = yielded a=20 response rate of 21%. Stable disease was observed in an = additional=20 eight patients. The mean duration of response was 6 months=20 (range, 2.5=9618 months), and the median survival times were = 14.5=20 months in responding patients and 4.5 months in = nonresponders.=20 Leukopenia was the major toxicity; five cases of grade 4 = leukopenia,=20 two cases of grade 4 thrombocytopenia, and no other grade 4 = toxic=20 effects occurred in the 55 evaluable patients over 217 = courses of=20 treatment. These results confirmed the safety and efficacy of = temozolomide in malignant metastatic melanoma that were = observed in=20 the Phase 1 study (11)=20 .

A second Phase 2 trial in advanced malignant melanoma evaluated=20 the relationship between pretreatment AGT levels in biopsies = of=20 cutaneous tumors and involved lymph nodes and clinical response = to=20 treatment with temozolomide (94)=20 . Among the 50 evaluable patients, there were 3 CRs and 4 PRs = for an=20 overall response rate of 14%. Stable disease was observed in = an=20 additional six patients. Lymphocytopenia was the major = toxicity,=20 however, with only eight and nine cases of grade 3 or higher=20 neutropenia and thrombocytopenia, respectively. Analysis of = the=20 pretreatment AGT levels and clinical response to temozolomide = in 33=20 patients revealed that pretreatment levels of AGT are not=20 predictive of response to temozolomide in melanoma (94)=20 .

Recently, a Phase 3 trial compared the overall survival, PFS,=20 objective response, and safety of temozolomide and DTIC in = 305=20 patients with advanced metastatic melanoma (95)=20 . This study also assessed the health-related QOL and PK of = both=20 drugs and their metabolite, MTIC. In this study, patients = were=20 randomized to receive either p.o. temozolomide at a starting = dose of=20 200 mg/m2/day for 5 days every 28 days or i.v. = DTIC at a=20 starting dose of 250 mg/m2/day for 5 days every 21 = days.=20 Median survival in the intent-to-treat population was similar = for=20 patients treated with temozolomide or DTIC (7.7 and 6.4 = months for=20 temozolomide and DTIC, respectively; a hazard ratio of 1.18), = Median=20 PFS was significantly longer for temozolomide (1.9 months)=20 versus DTIC (1.5 months; P =3D 0.012; hazard = ratio =3D=20 1.37; CI, 1.07=961.75; Ref. 95=20 ). Temozolomide was associated with health-related QOL = benefit, with=20 more temozolomide-related patients demonstrating an = improvement or=20 maintenance in physical functioning at week 12 compared with = those=20 treated with DTIC. PK analysis revealed that systemic = exposure (AUC)=20 to the parent drug and the active metabolite MTIC was higher = after=20 p.o. temozolomide compared with i.v. DTIC. These results = indicate=20 that temozolomide demonstrates efficacy equal to that of DTIC = against=20 advanced metastatic melanoma.


3D"   =20 Overcoming Resistance
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
3D"Overcoming = Resistance
Summary and Conclusions
REFERENCES
 
C= ombining=20 two or more drugs that have different cytotoxic mechanisms or = are=20 subject to different mechanisms of resistance can produce = additive or=20 synergistic effects. The favorable safety profile of = temozolomide=20 allows it to be coadministered with various agents. The = antitumor=20 activity of temozolomide is dependent on the level of AGT = within the=20 tumor cell. Results from preclinical studies indicate that = inhibition=20 of AGT potentiates the activity of temozolomide in several = human=20 tumor cell lines (5)=20 . Several studies have investigated methods to deplete AGT = levels=20 further and increase the antitumor effect of temozolomide in=20 combination therapy with BCNU and different dosing = schedules.=20

Combination with Cisplatin.
Preclinical evidence=20 indicates that cisplatin enhances the antitumor activity of=20 temozolomide (96)=20 . On the basis of these data and complementary toxicity = profiles, a=20 Phase 1 trial of the combination was conducted in 15 patients = with=20 advanced cancer (97)=20 . In this study, cohorts of three patients received = temozolomide=20 daily for 5 days together with cisplatin on day 1 for 4 weeks = at the=20 following temozolomide (mg/m2/day) and cisplatin=20 (mg/m2) dose levels: 100/75; 120/75; 200/75; and = 200/100.=20 The DLT observed at the highest temozolomide/cisplatin dose = level was=20 myelosuppression (neutropenia and thrombocytopenia) and = vomiting. The=20 MTDs established in this trial were 200 mg/m2/day = for=20 temozolomide and 75 mg/m2 for cisplatin. This = combination=20 did not alter the PK or the MTD of temozolomide. The = principal=20 nonhematological toxicities consisted of nausea, vomiting, = and=20 hearing loss. PR was achieved in 2 of the 14 evaluable = patients,=20 one with untreated non-small cell lung cancer and the other=20 with squamous cell carcinoma.

Combination with BCNU.
In a Phase 1 study = evaluating the=20 combination of BCNU (75 mg/m2) given before or = after a=20 5-day course of temozolomide, no differences between the = regimens=20 were seen in the PK of temozolomide or the toxicity of the = drugs at=20 the doses used (98)=20 . One patient with glioblastoma had a PR that has been = maintained for=20 1 year, and two other patients (one with osteosarcoma and one = with=20 uterine carcinosarcoma) have had minor responses. This study = is=20 continuing so that the MTD for this combination can be = established (98)=20 .

Combination with IFN-3D{alpha}=20-2b.<= BR>Both=20 temozolomide and IFN-3D{alpha}=20-2b have = demonstrated=20 antitumor activity against melanoma. IFN-3D{alpha}=20-2b is = approved in the=20 United States for postsurgical adjuvant treatment of melanoma = with=20 high-risk metastases. It is approved in some European = countries for=20 use as monotherapy for the palliative treatment of melanoma. = In a=20 Phase 1 study to determine the MTD and DLT, patients with=20 histologically confirmed, surgically incurable metastatic = melanoma=20 were treated with 5-day courses of p.o. temozolomide in = dosages of=20 100 or 200 mg/m2/day with continuous s.c. = injections of=20 IFN-3D{alpha}=20-2b three = times a week=20 at escalating doses starting at 5 mU/m2 (99)=20 . In the cohort treated with 1000 mg/m2 of = temozolomide=20 and 5 mU/m2 of IFN-3D{alpha}=20-2b, two = patients=20 developed dose-limiting thrombocytopenia, and one patient = developed=20 grade 4 neutropenia. When higher doses of IFN-3D{alpha}=20-2b (7.5 and = 10.0=20 mU/m2) were combined with 150 mg/m2 of=20 temozolomide, grade 4 hematological toxicity was observed in = one of=20 six and one of three patients, respectively. No DLT occurred = in=20 patients treated with 750 mg/m2 of temozolomide = plus 5=20 mU/m2 of IFN-3D{alpha}=20-2b. The MTD = was=20 determined as temozolomide 150 mg/m2 and IFN-3D{alpha}-2b 7.5=20 mU/m2 (99)=20 . Antitumor responses were seen in 3 of 12 patients, and = stable=20 disease in 4 of 12 patients. These results indicate that this = combination when administered at the MTD is well tolerated, = and the=20 antitumor activity observed provides the basis for additional = studies.

Continuous Dosing Schedule.
Because AGT levels = may=20 recover within the 24-h interval between individual = temozolomide=20 doses in each 5-day cycle, dosing more frequently than once a = day for=20 5 days may improve the response to treatment. A Phase 1 study = of 24=20 patients with recurrent tumors, 17 of which were malignant = gliomas (81)=20 , examined continuous dosing of temozolomide over a 6- to = 7-week=20 period with dosages ranging from 50 to 100 = mg/m2/day. This=20 schedule produced a higher cumulative dose of drug than the = indicated=20 5-day schedule and increased the AUC by a factor of 2.1 = without=20 producing any hematological DLT. No major toxicity was = observed at=20 the dosage level of 75 mg/m2/day (81)=20 . Objective responses were reported in patients with = high-grade=20 glioma and melanoma, and the overall response rate for the = prolonged=20 schedule was 33%. Seven (41%) of 17 glioma patients = demonstrated=20 tumor responses. Six of the 17 glioma patients maintained = stable=20 disease (81)=20 .


3D"   =20 Summary and Conclusions
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
3D"Summary and = Conclusions
REFERENCES
 
T= emozolomide=20 is a new and effective p.o. administered anticancer agent = that=20 demonstrates a broad spectrum of activity in various solid tumors = and=20 distribution to all tissues, including the brain. It spontaneously=20 converts to an active methylating agent with activity against = a=20 number of refractory cancers, including malignant glioma, = metastatic=20 melanoma, and other solid tumors. Temozolomide is well = tolerated,=20 with minimal myelosuppression that is noncumulative and with=20 nonhematological toxicity that is easily managed with = standard=20 antiemetic agents.

Unique characteristics of stability and solubility allow temozolomide = to=20 be absorbed readily and distributed to all tissues with = approximately=20 100% bioavailability after p.o. administration. Thus, = temozolomide=20 does not require hepatic metabolism for activation and is = capable=20 of penetrating the blood-brain barrier. Temozolomide = demonstrates=20 dose-linear PK, is cleared rapidly, and does not accumulate=20 with repeat dosing. Its PK yields little intrasubject or = intersubject=20 variability, which is manifested by its predictable clinical=20 tolerance and mild side-effect profile.

Little success has been seen with BCNU, CCNU, or procarbazine = used=20 as single-agents or in combination chemotherapy for the = treatment of=20 high-grade gliomas; surgery and radiation therapy remain the=20 first-line treatments (87=20 ,=20 100) . These agents are severely cytotoxic or poorly = tolerated,=20 and resistance develops rapidly, which limits the minimal = benefits=20 offered by treatment with these drugs (87)=20 . Preliminary clinical studies conducted by the CRC = demonstrated that=20 temozolomide has meaningful efficacy and an acceptable safety = profile=20 in the treatment of patients with malignant glioma. The = results have=20 been confirmed in three open-label multi-institutional = studies that=20 represent the largest evaluation of a single agent in = patients with=20 recurrent malignant gliomas, using strict prospectively = defined=20 criteria for the assessment of tumor response, central review = of=20 histology, and validated instruments to assess health-related = QOL.=20 Temozolomide has also demonstrated activity in patients with = newly=20 diagnosed glioma. The tolerability and ease of administration = of=20 temozolomide have particular clinical value for the treatment = of=20 pediatric glioma, for which chemotherapy is often the primary = modality (87)=20 .

Although advanced melanoma is relatively resistant to therapy,=20 several biological response modifiers and cytotoxic agents = have=20 been reported to produce objective responses including DTIC,=20 IFN-3D{alpha}=20-2b, and = interleukin 2=20 (101)=20 . The objective response rate for DTIC is 15=9620%, and it = produces a=20 limited number of durable responses. Although various = combination=20 regimens of chemotherapy (e.g., DTIC, tamoxifen) and = cytokines=20 (e.g., interleukin 2, IFN-3D{alpha}=20-2b) have = increased the=20 rates of remission and improved response rates as much as = 50%, no=20 single agent has improved survival rates compared with those = obtained=20 with DTIC alone in patients with metastatic malignant disease = (101)=20 . Additionally, the chemotherapeutic regimens used to treat=20 metastatic malignant disease are ineffective in brain = metastases.=20 Thus, for long-term control of metastatic melanoma to be = achieved,=20 agents that are effective against CNS metastases must be = used.=20 Temozolomide demonstrates comparable activity to that of DTIC = against=20 advanced malignant melanoma and may offer an alternative = choice to=20 DTIC because of its ability to penetrate the blood-brain=20 barrier.

In summary, the unique pharmacological profile of temozolomide,=20 its availability as an oral agent, and its documented safety=20 and efficacy supports its potential in the treatment of = malignant=20 glioma and malignant melanoma. Future studies will focus on=20 various types of combination therapy, dose intensification, = and=20 dose-finding trials with new dosing schedules. Many tumors = including=20 sarcoma, colon, lung, and prostate are resistant to standard=20 chemotherapy, and synergistic or additive activity exhibited = by=20 temozolomide in combination with other chemotherapeutic = agents=20 (e.g., BCNU, cisplatin) or biologicalresponse modifiers=20 (e.g., IFN-3D{alpha}=20-2b) has been = documented in many of these chemoresistant tumor types. = Furthermore,=20 the potential for more predictable toxicity, increased = antitumor=20 activity, and activity in CNS metastasis may lead to improved = therapeutic index and health-related QOL.

Studies are ongoing in recurrent glioma to explore the standard=20 5-day temozolomide schedule with other cytotoxic agents including=20 6-thioguanine (Gliadel; BCNU) wafer as well as = cis-retinoic=20 acid. Studies in malignant metastatic melanoma are currently=20 exploring the use of the standard 5-day temozolomide schedule = in=20 combination with biochemotherapy regimens. Finally, = additional Phase=20 2 studies are planned to explore the antitumor activity of = the=20 standard 5-day temozolomide schedule in combination with=20 antimicrotubule agent taxanes (e.g., paclitaxel, = docetaxel);=20 topoisomerase I and II inhibitors (e.g., antitumor=20 antibiotics, camptothecin, topotecan); and the angiogenesis=20 inhibitor, thalidomide.


3D"   =20 FOOTNOTES
 
The costs of publication of this article were = defrayed=20 in part by the payment of page charges. This article must=20 therefore be hereby marked advertisement in accordance = with 18=20 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by a grant from = Schering-Plow Research Institute, Kenilworth, New = Jersey.=20

2 To whom requests for = reprints=20 should be addressed, at Duke Medical Center, Box 3624, = Durham, NC=20 27710. Phone: (919) 684-5301; Fax: (919) 681-1697. =

3 Abbreviations used: MTIC, = 5-(3-methyltriazen-1-yl)imidazole-4-carboximide; DTIC,=20 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide, or = dacarbazine;=20 CNS, central nervous system; CRC, Cancer Research Campaign; = BCNU,=20 carmustine; AIC, 5-aminoimidazole-4-carboxamide; = O6-MG,=20 O6-methylguanine; AGT, alkylguanine = alkyltransferase;=20 CCNU, lomustine; PARP, poly(ADP)-ribose polymerase; = O6-BG,=20 O6-benzylguanine; AUC, area under the=20 concentration-time curve; MTD, maximum tolerated dose/dosage; = CT,=20 computerized tomography; PK, pharmacokinetic(s); CR, complete=20 response; PR, partial response; QOL, quality of life. FDA, = United=20 States Food and Drug Administration; MMR, mismatch repair; DLT,=20 dose-limiting toxicity; PFS, progression-free survival; CI,=20 confidence interval.

Received 4/15/99; revised 3/29/00; accepted 3/30/00.


3D"   =20 REFERENCES
Top
ABSTRACT
Introduction
Background
Mechanism of Action
Mechanisms of Resistance
Reducing Resistance to...
Clinical Experience with...
Phase 2 and 3...
Overcoming Resistance
Summary and Conclusions
3D"REFERENCES
&nb= sp;

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A.=20 Benjelloun, J. Delavelle, F. Lazeyras, and P.-Y.=20 Dietrich
Possible efficacy of temozolomide in a patient = with=20 gliomatosis cerebri
Neurology, = November 27, 2001;=20 57(10): 1932 - 1932.
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J.=20 Ma, S. Pulfer, S. Li, J. Chu, K. Reed, and J. M.=20 Gallo
Pharmacodynamic-mediated Reduction of = Temozolomide Tumor=20 Concentrations by the Angiogenesis Inhibitor = TNP-470
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Synergy between Methionine Stress = and=20 Chemotherapy in the Treatment of Brain Tumor Xenografts in Athymic = Mice
Cancer Res., May 1, 2001; 61(10): 4017 = - 4023.=20
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V.=20 J. Patel, G. B. Elion, P. J. Houghton, S. Keir, A. E. Pegg, S. P. = Johnson,=20 M. E. Dolan, D. D. Bigner, and H. S.=20 Friedman
Schedule-dependent Activity of Temozolomide = plus=20 CPT-11 against a Human Central Nervous System Tumor-derived=20 Xenograft
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[Abstract]=20 [Full=20 Text]
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Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/javascript/ajax/xmlhttprequest.js /*=0A= =0A= Cross-Browser XMLHttpRequest v1.2=0A= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= Emulate Gecko 'XMLHttpRequest()' functionality in IE and Opera. Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0000_01C98A9F.6A7B04D0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name 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if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name 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if (name =3D=3D "margin-right") {=0A= e.style.marginRight =3D value;=0A= }=0A= else if (name =3D=3D "margin-top") {=0A= e.style.marginTop =3D value;=0A= }=0A= else if (name =3D=3D "min-height") {=0A= e.style.minHeight =3D value;=0A= }=0A= else if (name =3D=3D "overflow") {=0A= e.style.overflow =3D value;=0A= }=0A= else if (name =3D=3D "overflow-x") {=0A= e.style.overflowX =3D value;=0A= }=0A= else if (name =3D=3D "overflow-y") {=0A= e.style.overflowY =3D value;=0A= }=0A= else if (name =3D=3D "padding") {=0A= e.style.padding =3D value;=0A= }=0A= else if (name =3D=3D "padding-bottom") {=0A= e.style.paddingBottom =3D value;=0A= }=0A= else if (name =3D=3D "padding-left") {=0A= e.style.paddingLeft =3D value;=0A= }=0A= else if (name =3D=3D "padding-right") {=0A= e.style.paddingRight =3D value;=0A= }=0A= else if (name =3D=3D "padding-top") {=0A= e.style.paddingTop =3D value;=0A= }=0A= else if (name =3D=3D "page-break-after") {=0A= e.style.pageBreakAfter =3D value;=0A= }=0A= else if (name 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e.style.posTop =3D value;=0A= }=0A= else if (name =3D=3D "posWidth") {=0A= e.style.posWidth =3D value;=0A= }=0A= else if (name =3D=3D "right") {=0A= e.style.right =3D value;=0A= }=0A= else if (name =3D=3D "ruby-align") {=0A= e.style.rubyAlign =3D value;=0A= }=0A= else if (name =3D=3D "ruby-overhang") {=0A= e.style.rubyOverhang =3D value;=0A= }=0A= else if (name =3D=3D "ruby-position") {=0A= e.style.rubyPosition =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-3dlight-color") {=0A= e.style.scrollbar3dLightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-arrow-color") {=0A= e.style.scrollbarArrowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-base-color") {=0A= e.style.scrollbarBaseColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-darkshadow-color") {=0A= e.style.scrollbarDarkShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-face-color") {=0A= e.style.scrollbarFaceColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-highlight-color") {=0A= e.style.scrollbarHighlightColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-shadow-color") {=0A= e.style.scrollbarShadowColor =3D value;=0A= }=0A= else if (name =3D=3D "scrollbar-track-color") {=0A= e.style.scrollbarTrackColor =3D value;=0A= }=0A= else if (name =3D=3D "float") {=0A= e.style.styleFloat =3D value;=0A= }=0A= else if (name =3D=3D "table-layout") {=0A= e.style.tableLayout =3D value;=0A= }=0A= else if (name =3D=3D "text-align") {=0A= e.style.textAlign =3D value;=0A= }=0A= else if (name =3D=3D "text-align-last") {=0A= e.style.textAlignLast =3D value;=0A= }=0A= else if (name =3D=3D "text-autospace") {=0A= e.style.textAutospace =3D value;=0A= }=0A= else if (name =3D=3D "text-decoration") {=0A= e.style.textDecoration =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationBlink") {=0A= e.style.textDecorationBlink =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationLineThrough") {=0A= e.style.textDecorationLineThrough =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationNone") {=0A= e.style.textDecorationNone =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationOverline") {=0A= e.style.textDecorationOverline =3D value;=0A= }=0A= else if (name =3D=3D "textDecorationUnderline") {=0A= e.style.textDecorationUnderline =3D value;=0A= }=0A= else if (name =3D=3D "text-indent") {=0A= e.style.textIndent =3D value;=0A= }=0A= else if (name =3D=3D "text-justify") {=0A= e.style.textJustify =3D value;=0A= }=0A= else if (name =3D=3D "text-kashida-space") {=0A= e.style.textKashidaSpace =3D value;=0A= }=0A= else if (name =3D=3D "text-overflow") {=0A= e.style.textOverflow =3D value;=0A= }=0A= else if (name =3D=3D "text-transform") {=0A= e.style.textTransform =3D value;=0A= }=0A= else if (name =3D=3D "text-underline-position") {=0A= e.style.textUnderlinePosition =3D value;=0A= }=0A= else if (name =3D=3D "top") {=0A= e.style.top =3D value;=0A= }=0A= else if (name =3D=3D "unicode-bidi") {=0A= e.style.unicodeBidi =3D value;=0A= }=0A= else if (name =3D=3D "vertical-align") {=0A= e.style.verticalAlign =3D value;=0A= }=0A= else if (name =3D=3D "visibility") {=0A= e.style.visibility =3D value;=0A= }=0A= else if (name =3D=3D "white-space") {=0A= e.style.whiteSpace =3D value;=0A= }=0A= else if (name =3D=3D "width") {=0A= e.style.width =3D value;=0A= }=0A= else if (name =3D=3D "word-break") {=0A= e.style.wordBreak =3D value;=0A= }=0A= else if (name =3D=3D "word-spacing") {=0A= e.style.wordSpacing =3D value;=0A= }=0A= else if (name =3D=3D "word-wrap") {=0A= e.style.wordWrap =3D value;=0A= }=0A= else if (name =3D=3D "writing-mode") {=0A= e.style.writingMode =3D value;=0A= }=0A= else if (name =3D=3D "z-index") {=0A= e.style.zIndex =3D value;=0A= }=0A= else if (name =3D=3D "zoom") {=0A= e.style.zoom =3D value;=0A= }=0A= }=0A= catch (e) {=0A= /* ignore error on attempt to set e.style.[property] */=0A= }=0A= }=0A= }=0A= }=0A= ------=_NextPart_000_0000_01C98A9F.6A7B04D0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://clincancerres.aacrjournals.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_0000_01C98A9F.6A7B04D0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.google-analytics.com/urchin.js //-- Google Analytics Urchin Module=0A= //-- Copyright 2007 Google, All Rights Reserved.=0A= =0A= //-- Urchin On Demand Settings ONLY=0A= var _uacct=3D""; // set up the Urchin Account=0A= var _userv=3D1; // service mode (0=3Dlocal,1=3Dremote,2=3Dboth)=0A= =0A= //-- UTM User Settings=0A= var _ufsc=3D1; // set client info flag (1=3Don|0=3Doff)=0A= var _udn=3D"auto"; // (auto|none|domain) set the domain name for cookies=0A= var _uhash=3D"on"; // (on|off) unique domain hash for cookies=0A= var _utimeout=3D"1800"; // set the inactive session timeout in seconds=0A= var _ugifpath=3D"/__utm.gif"; // set the web path to the __utm.gif file=0A= var _utsp=3D"|"; // transaction field separator=0A= var _uflash=3D1; // set flash version detect option (1=3Don|0=3Doff)=0A= var _utitle=3D1; // set the document title detect option = (1=3Don|0=3Doff)=0A= var _ulink=3D0; // enable linker functionality (1=3Don|0=3Doff)=0A= var _uanchor=3D0; // enable use of anchors for campaign = (1=3Don|0=3Doff)=0A= var _utcp=3D"/"; // the cookie path for tracking=0A= var _usample=3D100; // The sampling % of visitors to track (1-100).=0A= =0A= //-- UTM Campaign Tracking Settings=0A= var _uctm=3D1; // set campaign tracking module (1=3Don|0=3Doff)=0A= var _ucto=3D"15768000"; // set timeout in seconds (6 month default)=0A= var _uccn=3D"utm_campaign"; // name=0A= var _ucmd=3D"utm_medium"; // medium (cpc|cpm|link|email|organic)=0A= var _ucsr=3D"utm_source"; // source=0A= var _uctr=3D"utm_term"; // term/keyword=0A= var _ucct=3D"utm_content"; // content=0A= var _ucid=3D"utm_id"; // id number=0A= var _ucno=3D"utm_nooverride"; 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