Mechanisms for Breast Cancer Cell Resistance to Doxorubicin and Solutions to Resistance and Side Effects (97 Breast)

摘要

Recent studies indicate that doxorubicin alkylates DNA through catalytic production of formaldehyde and utilization of formaldehyde for attaching itself to 0-bases. This discovery prompted the synthesis of anthracycline-formaldehyde conjugates as improved anti-tumor dmgs. The first conjugate, Doxoform, was equally toxic to both sensitive and resistant breast cancer cells but is predicted to be hydrolytically too unstable. The second conjugate, Epidoxoform, from reaction of epidoxorubicin with formaldehyde was synthesized and characterized and proved to be less toxic to breast cancer cells but more stable with respect to hydrolysis to epidoxorubicin. The following additional results with Doxoform and Epidoxoform were obtained during the first budget period: 1) The structure of epidoxombicin-aIkylated DNA, solved by x-ray crystallography, shows the epidoxombicin virtually crosslinking the DNA at NOC sites. 2) Flow cytometry measurements show drug- formaldehyde conjugates are taken up better by both sensitive and resistant breast cancer cells and retained longer than their clinical counterparts. 3) The nucleus of both sensitive and resistant cancer cells is the primary target for drug-formaldehyde conjugates. 4) Drug-formaldehyde conjugates are more toxic to breast cancer cells than confluent mammary epithelial cells.