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Eradication of Human Medulloblastoma Tumor Xenografts with a Combination of O6-Benzyl-2'-deoxyguanosine
and 1,3-Bis(2-chloroethyl)-1-nitrosourea
Demetrius M. Kokkinakis, Robert C. Moschel, Anthony
E. Pegg and S. Clifford Schold
Department of Neurosurgery, University of Texas Southwestern
Medical Center at Dallas, Dallas, Texas 75235-8855 [D. M. K.]; National Cancer
Institute-Frederick Cancer Research and Development Center, Frederick, Maryland
21702-1201 [R. C. M.]; Departments of Cellular and Molecular Physiology and
Pharmacology, Pennsylvania State University, College of Medicine, The Milton
Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]; and Division of
Neurology, Duke University Medical Center, Durham, North Carolina 27710 [S. C.
S.]
[D. M. K.]: To whom requests for reprints should be addressed, at Department
of Neurosurgery, University of Texas Southwestern Medical Center, 5323
Harry Hines Boulevard, Dallas, TX 75235-8855. Phone: (214) 648-6314;
Fax: (214) 648-2265.
O6-Benzyl-2'-deoxyguanosine (dBG), a water-soluble
inhibitor of O6-methylguanine-DNA methyltransferase
(MGMT), potentiates the efficacy of
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against MGMT-positive,
BCNU-resistant Daoy human medulloblastoma tumor xenografts in athymic
mice (S. C. Schold et al., Cancer Res., 56:
2076–2081, 1996).
Such potentiation was comparable to that observed for O6-benzylguanine,
the prototype MGMT inhibitor that is currently undergoing clinical
trials.
In this study, we optimized the therapeutic effect of the dBG and
BCNU combination against brain tumor xenografts without inducing
substantial toxicity in the host by adjusting the doses of both
compounds.
dBG was escalated from 133 mg/m2 to 200 and 300 mg/m2,
whereas corresponding doses of BCNU were reduced from 25 mg/m2
to 17 and 11 mg/m2, respectively.
The growth delays of 30.2, 38.4, and 22.3 days, respectively,
observed for the above regimens suggest that the optimal drug
combination is not achieved with maximum doses of dBG.
In fact, the highest doses of dBG (300 mg/m2) contributed
to more frequent BCNU-related toxicities, despite the reduced BCNU
dosage, and a reduction of the therapeutic effect.
Toxicity was related to the depletion of MGMT activity in the gut of
host mice and was manifested by edema, inflammation, and hemorrhage
in the bowel wall by subsequent BCNU administration.
With additional dosage adjustments, we found that tumor suppression of
>90 days without toxicity was observed at 200 mg/m2 dBG and
23 mg/m2 BCNU.
At these doses, tumors were eradicated (regressed to an undetectable
size for >90 days) in 8 of 12 animals.
Thus, dBG is the first of the MGMT inhibitors to show a curative effect
in combination with BCNU against a human central nervous system tumor
xenograft in athymic mice.
© 1999 American Association for Cancer Research
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