Enhanced tumor load reduction after chemotherapy induced recruitment and synchronization in a slowly growing rat leukemia model (BNML) for human acute myelocytic leukemia
article
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.
Topics
cytarabinedoxorubicinacute granulocytic leukemiaanimal cellanimal experimentblood and hemopoietic systemcancer chemotherapycancer combination chemotherapycell cyclechemotherapydrug administrationdrug cytotoxicitydrug efficacydrug interactiondrug mechanismerythropoietic stem cellintoxicationintravenous drug administrationmethodologymousenonhumanpriority journalratsynchronizationtherapyAnimalCell CycleCytarabineDoxorubicinHematopoietic Stem CellsLeukemia, Myelocytic, AcuteMiceMice, Inbred StrainsRatsRats, Inbred BNTumor Stem Cells
TNO Identifier
229731
ISSN
01452126
Source
Leukemia Research, 8(6), pp. 953-963.
Pages
953-963
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