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The LD50 of intraperitoneally (ip) injected daunorubicin in nonleukemic mice (1.8 mg/kg, q4d times 3) can be increased several fold by the concomitant ip injection of ICRF-159. In addition, the survival of leukemic mice treated with daunorubicin and ICRF-159 on Days 1, 5, and 9 after ip inoculation of L1210 tumor cells was substantially greater than after treatment with either drug alone. This potentiation of survival with combination treatment usually occurred with doses of daunorubicin greater than the LD50 of daunorubicin alone. The LD50 of subcutaneously (sc) injected daunorubicin alone (14.0 mg/kg, q4d times 3) was not increased by concomitant ip treatment with ICRF-159. However, when leukemic mice were treated sc with daunorubicin and ip with ICRF-159 on Days 1, 5, and 9 after ip injection of L1210 leukemia cells, survival was greater than with treatment with either drug alone. The toxicity of ip injected adriamycin was not reduced by ICRF-159, but treatment of leukemic mice with this combination was more effective in prolonging survival than treatment with either drug alone. Combination treatment with daunorubicin plus ICRF-159 showed much less therapeutic enhancement against sc implanted L1210 leukemia than against the ip implanted tumor.

Treatment with cytosine arabinoside given intraperitoneally (ip) every 3 hours for 24 hours on every fourth day (Q3h/24h/4d) from 1 day after ip implantation of 10(6) or 10(7) leukemia L1210 cells in mice, was not observed to be superior to the same treatment after implantation of 10(5) cells. Similarly, when cytosine arabinoside therapy was delayed until Day 5 after 10(5) tumor cells were implanted, treatment Q3h/24h/4d did not provide a therapeutic advantage over treatment with a single injection every second or fourth day. A single treatment of the advanced disease with cyclophosphamide did not restore the sensitivity of the disease to the Q3h/24h/4d treatment schedule. Whether treatment with cytosine arabinoside was started on Days 1, 3, or 5, the optimal total dose per day for treatment given once every fourth day was 12-20 times greater than the optimal total dose per day for treatment given in eight equal injections every fourth day. Via the oral route, the Q3h/24h/4d treatment regimen was not superior to one treatment every fourth day from Day 1. The data clearly show that when the initial inoculum is high (10(6) or 10(7) cells) or when the disease is advanced, the response to cytosine arabinoside therapy does not display treatment-schedule dependency for the Q3h/24h/4d schedule.