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Oral administration of the PARP-1 inhibitor GPI 15427 increases
the anti-tumor activity of temozolomide against melanoma growing at the CNS site Lucio Tentori, Carlo Leonetti, Marco Scarsella, Weizheng Xu,
David C. Calvin, Lisa Morgan, Zhaocheng Tang, Krystyna M. Wozniak, Christina
Alemu, Randall Hoover, Rena G. Lapidus, Gabriella Zupi, Jie Zhang, Grazia
Graziani
University of Rome, Rome, Italy, Institute for Cancer
Research Regina Elena, Rome, Italy, Guilford Pharmaceutical Inc., Baltimore, MD,
University of Rome Tor Vergata, Rome, Italy. E-mail:
lapidusr@guilfordpharm.com
Temozolomide (TMZ) is a DNA methylating agent with high oral bioavailability and
ability to cross the blood brain barrier.
Recent clinical trials have shown that
TMZ improves progression-free survival and reduces the incidence of CNS relapse
in Stage IV melanoma patients in comparison to patients treated with
Dacarbazine, the standard care for this malignancy.
This is particularly
important for malignant melanoma in which brain metastases are common and can
lead to patient death in few months.
Unfortunately, resistance to TMZ occurs
relatively often and strongly affects the rate and durability of clinical
response.
However, recent studies have demonstrated that inhibition of poly
(ADP-ribose) polymerase-1 (PARP-1), an enzyme involved in the repair of
methylpurines, may represent a potential strategy to improve TMZ efficacy.
In this study we tested whether oral administration of a novel PARP-1
inhibitor GPI 15427 is able to enhance the anti-tumor efficacy of TMZ against
B16 melanoma growing at the CNS.
Pharmacokinetic studies revealed that GPI 15427
reached a Cmax of 4189 + 327 ng/ml in plasma after a single iv dose of 40 mg/kg
in rats.
When the same dose was given orally, the plasma Cmax was 1041 + 516
ng/ml, indicating a substantial oral bioavailability of the compound.
The brain
levels of GPI 15427 reached 1744 ng/g, 2301 ng/g at 0.5 and 1 h, respectively,
post oral dosing of 40 mg/kg rats, indicating that the compound readily
penetrates the blood brain barrier.
B16 melanoma cells (104) were injected intracranially into male
B6D2F1 mice.
Tumor bearing mice were treated when neoplastic infiltration of the
brain tissue was evident in histological sections.
GPI 15427 (10, 40, or 100
mg/kg/per os) was administered for three or five consecutive days 1 h before TMZ
(100 mg/Kg IP).
Efficacy of treatments was evaluated by comparing the survival
curves of untreated mice, mice treated with TMZ, or GPI 15427 alone to the
survival curves of mice treated with TMZ + GPI 15427.
At all doses tested, no drug-related deaths were observed.
Moreover, GPI
15427 + TMZ significantly increased life span of tumor bearing mice compared to
untreated mice, mice treated with GPI 15427 or with TMZ as single agents.
In
conclusion, these data indicate that oral administration of the PARP-1 inhibitor
GPI 15427 is well tolerated and induces significant enhancement of TMZ
anti-tumor efficacy against melanoma at the CNS site.
Copyright © 2004 American Association for Cancer Research.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=3725
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