(E)-2'-deoxy-2'-(fluoromethylene) cytidine potentiates radioresponse of two human solid tumor xenografts.
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.
Sun
L Q
LQ
Department of Radiation Oncology, University Hospital of Lausanne (CHUV), Switzerland.
Li
Y X
YX
Guillou
L
L
Coucke
P A
PA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; C086432:tezacitabine