Antitumor synergism occurs with two drugs in sequence when the second drug is given at the time of maximal regrowth of residual leukemia and peak humoral stimulatory activity (HSA). To determine if this enhancement relates to a host derived HSA, studies were conducted in Lewis x brown Norway F1 rats bearing brown Norway myelocytic leukemia. A significant cure rate was observed in rats treated initially with 1-beta-D-arabinofuranosylcytosine and then given injections of 10(6) leukemia cells and treated with a second 2-day course of 1-beta-D-arabinofuranosylcytosine in every-8-h s.c. injections in the 6-day period after the initial drug. No effect on survival of the initial drug or of the second drug given at intervals after day 6 was noted. This result is consistent with the efficacy of treatment at the time of peak HSA and tumor growth. The direct effect of HSA on tumor sensitivity to 1-beta-D-arabinofuranosylcytosine was evaluated by 18-h incubations of leukemia and HSA, followed by bioassay. Increased survival and high cure rates were observed when compared with cultured cells in normal serum. These studies support the notion that host derived factors operative during drug induced aplasia stimulate tumor growth and thereby, if the drugs are properly timed, increase sensitivity to cycle active agents.