Anthracyclines potentiate activity against murine leukemias L1210 and P388 in vivo and in vitro

Abstract

The interactions of 2-chlorodeoxyadenosine (2-CdA, cladribine) and three anthracyclines: doxorubicin (DOX), idarubicin (IDA) and mitoxantrone (MIT) were evaluated on murine leukemias P388 and L1210. Prolongation of survival time of animals receiving drugs in combination compared to mice treated with drugs in monotherapy was tested. We have also evaluated interactions of the cytostatics on murine leukemias in vitro by measuring their inhibitory effects on P388 and L1210 cell proliferation. We have observed a synergistic effect of MIT and IDA in combination with 2-CdA on P388 leukemia resulting in an increase of life span (ILS)=226% in case of MIT+2-CdA and ILS=126% in the case of IDA+2-CdA, whereas 2-CdA used as a sole drug resulted in an ILS=47%. The survival time of animals inoculated with P388 leukemic cells and treated with DOX+ 2-CdA was similar to ILS gained by DOX monotherapy (178% and 200% respectively). The mice bearing L1210 leukemia receiving combined chemotherapy lived significantly longer than the animals on single agent regimens. The animals treated with schedule 2-CdA+MIT lived significantly longer (P=0.004) as compared to the groups receiving drugs in monotherapy (ILS of 2-CdA+MIT group=60%, ILS of MIT group 33%, and 2-CdA group 33%). Finally, combination of DOX or IDA with 2-CdA resulted in ILS =73% (2-CdA+DOX regimen), and ILS=60% in case of 2-CdA+IDA regimen, which is significantly higher than ILS gained on monotherapy schedules. In vitro tests revealed that all tested anthracyclines enhance the antiproliferative activity of 2-CdA against L1210 and P388 leukemic cells (P<0.05). Our study has shown that all anthracyclines potentiate 2-CdA antileukemic activity, both in vivo and in vitro. It failed however to point the best one to be combined with cladribine. We suggests that further clinical trials with such combinations are needed.