tezacitabine and Glioblastoma

Antitumor and radiosensitizing effects of (E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide reductase, were evaluated on nude mice bearing s.c. human C33-A cervix cancer and U-87 MG glioblastoma xenografts. FMdC given once daily has a dose-dependent antitumor effect. The maximum tolerated dose in the mice was reached with 10 daily i.p. administrations of 10 mg/kg over 12 days. In the case of radiotherapy (RT) alone (10 fractions over 12 days), the radiation dose required to produce local tumor control in 50% of the treated C33-A xenografts was 51.0 Gy. When combined with FMdC, the radiation dose required to produce local tumor control was reduced to 41.4 and 38.2 Gy, at respective doses of 5 and 10 mg/kg given i.p. 1 h before each irradiation. The corresponding enhancement ratios (ERs) were 1.2 and 1.3, respectively. In U-87 MG xenografts, when 5-20 mg/kg FMdC combined with 30 or 40 Gy of RT, the combination treatment produced a significantly increased growth delay as compared with RT alone (P < or =0.002). The ERs of 5, 10, and 20 mg/kg FMdC at a dose of 30 Gy were 2.0, 1.4, and 1.8, respectively. At the 40-Gy level, ERs of 10 and 20 mg/kg FMdC were 1.4 and 1.7. When FMdC was combined with 50 Gy of RT, an increased long-term remission rate of 80-88.9% was observed, as compared with 25% for RT alone (P <0.05). FMdC produced moderate myelosuppression in the mice bearing cervix cancer, whereas leukocytosis occurred in the mice bearing glioblastoma at a low dose. Slightly increased skin toxicity (only with U-87 MG tumor) was observed, as compared with RT alone. In conclusion, FMdC is a potent cytotoxic agent and able to modify the radiation response of C33-A and U-87 MG xenografts.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Combined Modality Therapy; Deoxycytidine; Female; Glioblastoma; Humans; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Radiation-Sensitizing Agents; Transplantation, Heterologous; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

We examined the effects of MDL101731, a novel ribonucleoside reductase inhibitor, against human glioblastomas and neuroblastoma, both in vitro and in xenograft models, to determine its activity against malignant brain tumors. MDL101731 produced a concentration-dependent inhibition of both glioblastoma cell lines (HS683 and J889H) and neuroblastoma (SK-N-MC) in nanomolar concentrations (IC50, 30-90 nM). s.c. xenografts of human glioblastoma (D54) in athymic mice increased to five times their initial volume at a median of 7.4 days in control animals, while tumor regression occurred in 12 of 12 animals treated with MDL101731 (100 mg/kg, i.p., two times/week) during 22 days of treatment (P < 0.0001). Intracerebral implants of D54 carried a median survival of 20 days in control animals, whereas animals receiving MDL101731 (100 mg/kg, i.p., two times/week, days 10-35) had a median survival of 46.5 days (P < 0.0001). Intracerebral xenografts of SK-N-MC in athymic mice resulted in a median survival of 23 days in control animals and 26 days in animals treated with carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea 20 mg/kg/week, i.v. x 2; difference not significant). There was 90% survival in animals treated with MDL101731 (200 mg/kg, i.v., two times/week, days 7-35) up to 90 days after implant. These studies indicate that MDL101731 has potent antiproliferative activity against human malignant brain tumors.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Deoxycytidine; Enzyme Inhibitors; Glioblastoma; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Ribonucleoside Diphosphate Reductase; Transplantation, Heterologous