Analysis of comptothecin resistance in yeast: relevance to cancer therapy.

The budding yeast Saccharomyces cerevisiae is a well defined genetic system to investigate various aspects of camptothecin (Cpt)-induced cytotoxicity. This antineoplastic agent and its derivatives specifically poison eukaryotic DNA topoisomerase I, the product of the TOP1 gene, by stabilizing a covalent enzyme-DNA intermediate. Analyses of various yeast and human top1 mutants in yeast strains deleted for TOP1 (top1Delta) have defined amino acid residues critical for enzyme function and Cpt sensitivity.

Altered topoisomerase I and II activities in suramin-resistant lung fibrosarcoma cells.

To better understand the molecular basis for the cytotoxic effects of suramin, we have developed suramin-resistant DC-3F/SU 1000 cells by continuous exposure of fibrosarcoma cells to increasing concentrations of suramin. The suramin resistance (approximately 10-fold) is not associated with changes in uptake or intracellular distribution of the drug. The sensitivity to actinomycin D, cytarabine, aphidicolin, hydroxyurea, vincristine, and 5-fluorouracil is unaltered.

Aurintricarboxylic acid, a putative inhibitor of apoptosis, is a potent inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells.

Aurintricarboxylic acid (ATA) is a polyanionic, polyaromatic compound which has been shown to inhibit apoptotic cell death in various cell types induced by a variety of factors. Since ATA is known to be a general inhibitor of nuclease activities in vitro (ID50S ranging from 2 to 50 microM), the in vivo effects are usually attributed to inhibition of endogenous endonuclease activities. We show herein that ATA is a potent inhibitor of the nuclear enzyme DNA topoisomerase II.