Temozolomide

Temozolomide, an imidazotetrazine prodrug, is an alkylating agent that mediates its cytotoxic effects via O(6)-methylguanine adducts in DNA and their recognition and processing by the post-replication mismatch repair system. Temozolomide is similar to dacarbazine (DTIC) in that they share the same active metabolite; however, activation of the parent drug is spontaneous with temozolomide and not dependent on enzymatic activity, as is the case with dacarbazine. Temozolomide has excellent oral bioavailability with a single-agent MTD of 200215 mg/m2 day-1 when given to pediatric patients on a 5-day schedule in 28-day cycles, with the dose-limiting toxicity being neutropenia and thrombocytope-nia. Temozolomide readily crosses the blood-brain barrier, and has been proven to be active against a variety of brain tumors. Adult phase-II trials have shown response rates as high as 35-50% using temozolomide for recurrent high-grade glioma (Yung et al. 1999), leading to FDA approval for this indication. In addition to activity against brain tumors, temo-zolomide also appears to have modest activity against mouse models of non-CNS solid tumors, including neuroblastoma (Middlemas et al. 2000; Houghton et al. 2000). In a phase-II study recently reported in abstract form, 27 pediatric patients with refractory non-CNS solid tumors were treated with temozolomide 215 mg/m2 day-1 in 5-day courses. Although no objective imaging responses were observed, two isolated bone marrow responses were noted in 13 evaluable neuroblastoma patients, of whom 10 (77%) had stable disease lasting a median of 7 months (Donfrancesco et al. 2004).

In addition to the single-agent activity, the combination of temozolomide and irinotecan is attractive because of non-overlapping toxicities and the significant therapeutic synergy demonstrated by Houghton et al. (2000) in preclinical experiments. The combination of sub-therapeutic doses of each drug resulted in complete responses in four different xenograft models of neuroblastoma. The proposed mechanism of synergy is temozolomide-induced methylation causing localization and enhancement of topoisomerase I-DNA cleavage complexes, allow ing irinotecan to more effectively stabilize the DNAenzyme complex and cause cytotoxicity after collision with the advancing replication fork (Pourquier et al. 2001). Interestingly, the synergy seen in the mouse models appeared to be partly independent of the DNA repair phenotype of tumor tissue, including p53 status (Houghton et al. 2000). This observation is important in light of the frequency of acquired p53 mutations in neuroblastoma cell lines established at the time of relapse (Keshelava et al. 2000a). A recent phase-I study of the combination of intravenous irinotecan and temozolomide in pediatric solid tumors established the MTD as temozolomide 100 mg/m2day-1 daily for 5 days the first week, with irinotecan, 10mg/m2day-1 daily for 5 days x 2 consecutive weeks. Future studies may incorporate oral rather than intravenous irinotecan, and use an oral antibiotic to prevent the usual irinotecan-induced diarrhea (Takasuna et al. 1996; Cosetti et al. 2002; Furman et al. 2003).

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