Mechanisms for Breast Cancer Cell Resistance to Doxorubicin and Solutions to Resistance and Side Effects

摘要

The anthracyclines, doxorubicin and epidoxorubicin, continue to be important drugs for the treatment of breast cancer. Recent studies refocus attention to anthracycline-alkylation and crosslinking of DNA as important toxic events triggering cell death. The long term goals of the proposed research are to establish the mechanism for the crosslinking, to produce new mechanism-based anthracycline derivatives which will be active against resistant breast cancer, and to develop a delivery vehicles for the improved drugs. New derivatives have been synthesized and characterized as the formaldehyde conjugates of doxorubicin and epidoxorubicin, doxoform and epidoxoform, respectively. The following results were obtained during the current year: (1) Sensitive but not resistant breast cancer cells show anthracycline induction of formaldehyde synthesis. (2) Apoptosis assays of drug-treated cells show similar patterns for doxorubicin and doxoform consistent with doxoform being a prodrug to the doxorubicin active metabolite. (3) Epidoxoform shows broad spectrum toxicity to human cancer cells including resistant cancer cells. (4) Epidoxoform can be formulated in DMSO/ cremaphor as a drug delivery vehicle. The new results continue to support a mechanism for drug toxicity which utilizes drug-induced formaldehyde synthesis and support epidoxoform as a new compound for the treatment of resistant breast cancer.