Identification of anthracycline analogues with enhanced cytotoxicity and lack of cross-resistance to adriamycin using a series of mammalian cell lines in vitro

Abstract

Clinical resistance to adriamycin (ADR) develops readily, and cardiotoxicity is a major dose-limiting side effect. A range of anthracycline derivatives have been synthesized recently, and a number reported to exhibit significantly reduced cardiotoxicity in experimental animals. Using NIL 8 Syrian hamster overy cells and two continuous human tumour cell lines derived from colon carcinomas we have screened a series of 11 anthracycline analogues, determining their in vitro cytotoxic effects by colony-forming assays. Five agents proved significantly more cytotoxic than ADR: dihydroxyanthraquinone (DHAQ), mitoxantrone (DHAD), 4-demethoxydaunorubicin (4-DNR), 4'-0-tetrahydropyranyl-adriamycin (THP-ADR), and 4'-deoxyadriamycin (4-ADR). We have also established in vitro a subline of the L5178Y murine lymphoma resistant to ADR and have used this model to identify derivatives with potential value for overcoming ADR resistance. We have observed three patterns of response: (i) complete cross-resistance with 4'-epiadriamycin and daunorubicin; (ii) slight cross-resistance with 4-DNR, THP-ADR, 7-con-O-methyl-nogarol and aclacinomycin A; and (iii) complete absence of cross-resistance with 4-ADR, 4'-O-methyladriamycin, DHAQ, DHAD, and methylhydroxyellipticinium. These straightforward preclinical screens thus identify three drugs which may merit clinical evaluation, since they not only show an increased level of cytotoxicity in vitro to ADR at equivalent concentrations but also overcome resistance to ADR in this murine model system.