Accession Number:

ADB281771

Title:

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

Descriptive Note:

Final rept. 15 Sep 1998-14 Sep 2001

Corporate Author:

TEXAS UNIV AT AUSTIN CIVIL ENGINEERING RESEARCH LAB

Personal Author(s):

Report Date:

2001-10-01

Pagination or Media Count:

67.0

Abstract:

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 grant period I The crystal structure of epidoxorubicin- alkylated DNA shows the epidoxorubicin virtually crosslinking the DNA at NGC 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. 5 Sensitive but not resistant breast cancer cells show anthracycline induction of formaldehyde synthesis. 6 Sensitive but not resistant breast cancer cells show measurable formaldehyde levels. 7 Apoptosis assays of drug-treated cells show similar patterns for doxorubicin and doxoform consistent with doxoform being a prodrug to the doxorubicin active metabolite. 8 Epidoxoform shows broad spectrum toxicity to human cancer cells including resistant cancer cells. 9 Epidoxoform can be formulated in DMSOCremaphor as a drug delivery vehicle. 10 Conjugation to glutathione is not a resistance mechanism for doxorubicin. 11 Peroxidation of unsaturated lip

Subject Categories:

  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE