A rationale for sequential high-dose chemotherapy of leukemia timed to coincide with induced tumor proliferation.

Studies in leukemic rats (LBN-ML) tested the hypothesis that an enhanced effect of drugs in sequence relates to temporally predictable induced tumor growth. As leukemia progresses, tumor labeling index (LI) declines in association with increasing tumor-associated inhibitory activity (TAIA) in serum. Graded initial doses of arabinofuranosyl cytosine (ara-C) (50-350 mg/kg every 8 hr x 6) produced relative increments of induced humoral stimulatory activity (HSA) and LI in vivo by day 6, while overcoming the antiproliferative effects of TAIA. Rats bearing late-stage tumor with high TAIA and low LI were treated with 50 or 100 mg/kg ara-C every 8 hr x 6 on days 0.1 and on other days in sequence (0.1-0,1 through 0.1-14.15). Serum, WBC and tumor LI were measured. With the 50 mg/kg initial dose, TAIA was not overcome, and the LI did not achieve levels above pretreatment. A second course of ara-C in sequence produced only additive survival, regardless of timing. In contrast, with the 100 mg/kg sequence, TAIA was overcome, the LI increased, and synergistic survival occurred in those treated with the second ara-C on days 6,7 (760% of controls) at the time of peak HSA and tumor LI. Survival times in other groups in sequence were only additive. Incremental doses of ara-C on day 6 produced linear prolongation of survival. These studies demonstrate that TAIA correlates with tumor LI and that the degree of resultant tumor growth relates to the initial drug dose, tumor kill, and TAIA reduction, and the amount of HSA induced. Survival relates directly to the dose of the second drug given at this predictable peak of maximal HSA and LI.