Enhanced tumor load reduction after chemotherapy induced recruitment and synchronization in a slowly growing rat leukemia model (BNML) for human acute myelocytic leukemia.

The cell cycle perturbation effect on leukemic cells of the Brown Norway myelocytic leukemia (BNML) after high dose Ara-C injection was used as the rationale for chemotherapy studies. A one log leukemic cell load reduction as determined by means of the leukemic colony forming units-spleen (LCFU-S) assay was observed when the second Ara-C injection was administered during a period of induced accumulation of cells in S phase. evidence was obtained that Ara-C was also cytotoxic for G1 phase cells. By comparing a continuous Ara-C infusion during 24 h with two Ara-C injections at the same total dosage given 12 h apart, it was found that the tumor load was significantly more reduced in the latter group. For the drug combination Ara-C/Adriamycin, maximal LCFU-S reduction of one log was observed when Adriamycin (7.7 mg/kg) was given 12 h after Ara-C. From the increase in survival time after the schedule of 6 X Ara-C plus 1 X Adriamycin (all injections given at 12 h intervals), it could be extrapolated that the tumor load was reduced by 6.7 logs; this was in agreement with the theoretically expected reduction of 6.2 logs based on the LCFU-S experiments. The schedule of 6 X Ara-C plus 1 X Adriamycin reduced the normal haemopoietic stem cell compartment by 2.5 logs. This therapeutic gain is attributed to the specific recruitment-synchronization inducing effect of Ara-C on leukemic cells in the G0 phase.