Schedule-dependent antitumor effect of gemcitabine in in vivo model system

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC, LY188011) is a new deoxycytidine analog with preclinical antitumor activity in solid tumors from murine and human origin. Of particular importance is the fact that the therapeutic effects of gemcitabine at the maximum tolerated dose level are dependent on the administration schedule. This paper describes the sensitivity pattern of gemcitabine in human head and neck squamous cell carcinoma, ovarian carcinoma, and soft tissue sarcoma, all growing as xenografts in athymic nude mice. The drug was injected intraperitoneally in various schedules at equitoxic, maximum tolerated dose levels, resulting in a reversible weight loss that varied between 5% and 15%. Generally, it was found that treatment with 120 mg/kg gemcitabine, injected four times at 3-day intervals, was more effective than the schedules of daily (five times 2.5 to 3.5 mg/kg) or weekly (two times 240 mg/kg) injections. Other workers have shown that this 3-day interval schedule also was active in human pancreas and lung carcinoma xenografts. Additional experiments were performed on normal mice bearing the colon 26-10 murine colon carcinoma. The effect of a continuous intravenous infusion system was investigated by giving two injections of 15 mg/kg gemcitabine for 24 hours at a 7-day interval. Interestingly, the efficacy of treatment increased dramatically with this infusion schedule, producing complete remissions in most tumors. In conclusion, our data on the effect of gemcitabine in animal tumor models indicate that (1) the time interval between push injections is important when intermittent schedules are used and (2) continuous infusions over a 24-hour period can be very effective in in vivo models.