C. Geroni, M. Sabatino, D. Ballinari
Apr 15, 2006
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Cancer Research
Abstract
3845 Nemorubicin is a potent antitumor agent currently in Phase II clinical studies for the treatment of primary hepatocellular carcinoma. Preclinical data showed that nemorubicin, although structurally related to doxorubicin, is not cardiotoxic, overcomes anthracyclines resistance and has a novel mechanism of action. We previously demonstrated that nemorubicin induces DNA strand breaks primarily through topoisomerase-I cleavage. As expected, nemorubicin is active in cells resistant to topoisomerase II inhibitors, whereas it is inactive against camptotecins resistant cells. In addition, we found that in vitro human hepatocytes or microsomes generate a nemorubicin metabolite (PNU-159682) that is hundred times more cytotoxic than the parent compound and that binds covalently to DNA. To further characterize the mechanism of action of nemorubicin, we generated a L1210 cell line resistant to nemorubicin. Since resistant L1210 cells were more sensitive than the parental cell line to UV irradiation and to platinum derivatives and alkylating agents, we reasoned that the nucleotide excision repair (NER) system might be involved in mediating the cytotoxic activity of nemorubicin. To test this hypothesis we used CHO cell lines proficient or deficient in excision repair cross-complementing (ERCC) genes, namely ERCC1 and ERCC6 genes. We found that nemorubicin is more cytotoxic in NER proficient than in deficient cells, suggesting that the NER system is involved in the induction of nemorubicin cytotoxicity. Comparable results were obtained testing PNU-159682 on NER proficient or deficient cells. In summary, nemorubicin, although structurally related to doxorubicin, has a novel mechanism of action that involves the NER system, providing the rationale for clinical combination studies of nemorubicin with platinum derivatives or alkylating agents.