Sun L Q, Li Y X, Guillou L, Coucke P A
Department of Radiation Oncology, University Hospital of Lausanne (CHUV), Switzerland.
Cancer Res. 1998 Dec 1;58(23):5411-7.
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.
对新型核糖核苷酸还原酶抑制剂（E）-2'-脱氧-2'-(氟亚甲基)胞苷（FMdC）的抗肿瘤和放射增敏作用，在携带人C33 - A宫颈癌和U - 87 MG胶质母细胞瘤皮下异种移植瘤的裸鼠身上进行了评估。每日给药一次的FMdC具有剂量依赖性抗肿瘤作用。在12天内每天腹腔注射10 mg/kg，连续给药10次，达到了小鼠的最大耐受剂量。在单独进行放射治疗（RT）（12天内分10次）的情况下，使50%接受治疗的C33 - A异种移植瘤实现局部肿瘤控制所需的辐射剂量为51.0 Gy。当与FMdC联合使用时，在每次照射前1小时腹腔注射5和10 mg/kg的相应剂量，实现局部肿瘤控制所需的辐射剂量分别降至41.4和38.2 Gy。相应的增敏比（ERs）分别为1.2和1.3。在U - 87 MG异种移植瘤中，当5 - 20 mg/kg的FMdC与30或40 Gy的RT联合使用时，与单独放疗相比，联合治疗显著延长了肿瘤生长延迟时间（P≤0.002）。在30 Gy剂量下，5、10和20 mg/kg的FMdC的ERs分别为2.0、1.4和1.8。在40 Gy剂量水平，10和20 mg/kg的FMdC的ERs分别为1.4和1.7。当FMdC与50 Gy的RT联合使用时，观察到长期缓解率提高至80 - 88.9%，而单独放疗的长期缓解率为25%（P<0.05）。FMdC在携带宫颈癌的小鼠中产生了中度骨髓抑制，而在携带胶质母细胞瘤的小鼠中低剂量时出现白细胞增多。与单独放疗相比，观察到皮肤毒性略有增加（仅在U - 87 MG肿瘤中）。总之，FMdC是一种有效的细胞毒性药物，能够改变C33 - A和U - 87 MG异种移植瘤的放射反应。
