Daunorubicin (DRB) and its two analogues containing a trisubstituted amidino group at the C-3' position of the daunosamine moiety have been compared regarding their cytotoxic activity, cellular uptake, subcellular localization and DNA damaging properties. An analogue containing in the amidino group a morpholine moiety (DRBM) as well as an analogue with a hexamethyleneimine moiety (DRBH), tested against cultured L1210 cells, exhibited lower cytotoxicity then DRB. The decrease of cytotoxic activity was not related to cellular uptake and subcellular localization of drugs. Although all tested drugs were active in the induction of DNA breaks and DNA-protein crosslinks, they differed in the mechanism of induction of DNA lesions. DRB produced DNA breaks mediated solely by topoisomerase II, whereas DRBM and DRBH induced two types of DNA breaks by two separate processes. The first is related to the inhibition of topoisomerase II and the second presumably reflects a covalent binding of drug metabolites to DNA. It is hypothesized that the replacement of the primary amino group (-NH(2)) at the C-3' position of the daunosamine moiety by a trisubstituted amidino group (-N=CH-NRR) may be a route to the synthesis of anthracycline derivatives with enhanced ability to form covalent adducts to DNA.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.