Anguidine, a protein synthesis inhibitor, is the principle phytotoxic metabolite of the plant parasitic fungus Fusarum equiseti. Anguidine can preferentially induce a reversible cell cycle arrest in normal versus tumor cells. Such selective cell cycle arrest afforded preferential protection of the normal cells against the cytotoxicity of antineoplastic agents with S-phase activity like Adriamycin and 1-B-D-arabinofuranosyl- cytosine. In contrast to its protective effects with S-phase agents, anguidine can potentiate the cytotoxicity of DNA-reactive antineoplastic agents like cis-platinum, melphalan, and bleomycin. In view of the broad application of the DNA-reactive antineoplastic agents in clinical oncology and the fact that most patients with solid tumors are not cured by standard chemotherapeutic regimens with these agents, this project purposes to assess the potentiation by anguidine of DNA-reactive antineoplastic agents induced cytotoxicity in human transitional cell tumors of the urinary tract and normal cells. The sensitivity of the cells to the various drug treatments will be assessed in an antiproliferation assay, colormetric protein-based assay and a clonogenic assay. The long range goal of this project is to elucidate whether anguidine can be used as a synergistic agent with DNA-reactive antineoplastic drugs in clinical cancer chemotherapy. Such an approach would have clinical benefit in two ways: (1) it could improve the anticancer effect at a given dosage; and (2) it could allow for treatment with relatively lower doses or less frequent application of anticancer agents which are limited by local or systemic toxicities and thereby reduce the toxicity to normal tissues. The undergraduate student's knowledge will be enhanced in cell culture techniques, tumor cell biology, and the pharmacology of antitumor drugs.
