DOXORUBICIN DISACCHARIDE ANALOG - APOPTOSIS-RELATED IMPROVEMENT OF EFFICACY IN-VIVO

Background: Although doxorubicin remains one of the most effective age nts for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical str uctures) that may have improved antitumor properties. We have synthesi zed a novel doxorubicin disaccharide analogue (MEN 10755) and have cha racterized some of its relevant biochemical, biologic, and pharmacolog ic properties. Methods: The antitumor activity of this compound (MEN 1 0755) was studied in a panel of human tumor xenografts, including xeno grafts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorub icin according to the optimal dose and schedule for each drug. The dru g's cytotoxic effects, induction of DNA damage, and intracellular accu mulation were studied in A2780 cells. DNA cleavage mediated by the enz yme topoisomerase II was investigated im vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug conce ntrations and analyzing the DNA cleavage-intensity patterns. Drug-indu ced apoptosis (programmed cell death) in tumors was determined with th e use of MX-1 and POVD tumor-bearing athymic Swiss nude mice. Results: MEN 10755 was more effective than doxorubicin as a topoisomerase II p oison and stimulated DNA fragmentation at lower intracellular concentr ations. In addition, MEN 10755 exhibited striking antitumor activity i n the treatment of human tumor xenografts, including those of the doxo rubicin-resistant breast carcinoma cell line MX-1. Conclusions: The hi gh antitumor activity of MEN 10755 in human tumor xenografts, includin g doxorubicin-resistant xenografts, and its unique pharmacologic and b iologic properties make this disaccharide analogue a promising candida te for clinical evaluation.