Additive action of gemcitabine (2',2'-difluorodeoxycytidine) and 2-chlorodeoxyadenosine on murine leukemias L1210 and P388.

The influence of 2-chlorodeoxyadenosine (2-CdA) and 2',2'-difluorodeoxycytidine (Gemcitabine, dFdC) on the survival time of mice bearing L1210 and P388 leukemias was investigated. Seventy-two male CD2F1 strain mice were used in the experiment. They were given 2-CdA (20 mg/kg) on days 1-5 after inoculation with leukemic cells (day 0) i.p. or dFdC (20 mg/kg) on days 1, 4, 7, and 10 i.p. The drugs were administered alone and in combination (sequential therapy) according to the following schedules: 2-CdA and dFdC at the same time at the doses given above; 2-CdA before dFdC, sequential therapy (2-CdA on days 1-5, then dFdC on days 6, 9, 12, 15); dFdC before 2-CdA, sequential therapy (dFdC on days 1, 4, 7, 10 and then 2-CdA on days 11-15). The animals were observed daily for survival for a minimum of 60 days. The efficacy of the therapy against leukemia (defined as the increase in lifespan, ILS) was assessed as the percentage of the median survival time (MST) of the treated group (T) to that of the control group (C): ILS = [(MSTc/MSTT-1] x 100. The survival time of mice bearing L1210 or P388 leukemia treated with dFdC before 2-CdA was significantly prolonged as compared with the animals receiving these agents separately. The prolongation of the survival time of the treated mice (ILS) compared with the untreated was 300% in case of L1210 and 241% in case of P388 leukemia. The combinations 2-CdA before dFdC and simultaneous injections of both drugs were not more effective than the treatment with dFdC alone. In case of L1210 leukemia, mice treated with these regimens showed a survival time similar to those treated with dFdC alone, although the survival time of mice bearing P388 leukemia treated with these regimens was shorter than that of mice given dFdC singly. Our study revealed that the most effective treatment schedule in both leukemias was dFdC given before 2-CdA. The results confirm the additive action of dFdC and 2-CdA.