NOVEL MECHANISM OF MULTIPLE DRUG RESISTANCE

DESCRIPTION: (Investigator's Abstract): CDDP is widely used in the treatment of ovarian cancer, lung cancer and testicular cancer. A variety of mechanisms of resistance to CDDP have been described including: 1) enhanced detoxification by glutathione (GSH) or metallothionein, and 2) increased DNA repair in CDDP-selected cell lines. Topotecan (TPT) is an investigational topoisomerase I (topo I)- directed agent that appears active in ovarian cancer and lung cancer. A variety of mechanisms of resistance to topo I-directed agents have been described including: 1) diminished drug accumulation; 2) quantitative or qualitative alterations in topo I; and 3) enhanced DNA repair. Preliminary studies from the applicant's laboratory indicate that previously unexposed human leukemia cell lines exhibit intrinsic differences in sensitivity to CDDP that are strongly correlated with their differences in sensitivity to TPT. These differences in drug sensitivity do not correlate with differences in topoisomerase levels, metallothionein expression, or GSH content. Instead, a strong correlation (R = 0.95, p = 0.0003) between IC(50) for CDDP and content of the metabolic intermediate NAD was observed. A similar correlation was demonstrated between NAD content and IC(50) for TPT. Studies presented in this application are designed to: 1) examine this correlation between NAD levels and sensitivity in additional tumor cell lines and in clinical samples; 2) examine the factors that control NAD levels; and 3) test the hypothesis that poly(ADP-ribose) polymerase, a DNA damage-recognition protein, is the pertinent NAD-metabolizing enzyme that is responsible for the observed correlation.