(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 reducÃase,
were evaluated on nude mice bearing s.c. human C33-A cervix cancer and
I -H7 MG glioblastoma xenografts. FMdC given once daily has a dosedependent
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. l h before each irradiation.
The corresponding enhancement ratios (ERs) were 1.2 and 1.3, respec
tively. 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 £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.