novobiocin and beta-lapachone

This study assessed the ability of 11 established and potential radiosensitizing agents to retard the repair of radiation-induced DNA damage with a view to enhancing the immunosuppressive effects of in vivo lymphoid irradiation. The capability of irradiated rat thymocytes to repair DNA damage was assessed by an adaptation of the fluorimetric unwinding method. Three compounds, 3-aminobenzamide (3-AB), novobiocin and flavone-8-acetic acid (FAA), inhibited repair significantly. We also report the effect of low-dose irradiation combined with repair inhibitors on the relationship between DNA strand breaks, fragmentation, cell viability and use of nicotinamide adenine dinucleotide (NAD). DNA fragmentation was increased by 1 mM/1 FAA, 1 mM/l novobiocin and 50 microM/l RS-61443 within 3 h of incubation. The latter two compounds also proved cytotoxic. All three drugs augmented the effect of ionizing radiation on the use of NAD. Of the agents investigated, FAA showed the most promise for augmenting the immunosuppressive action of irradiation at nontoxic, pharmacokinetically achievable concentrations.

Topics: Animals; Antineoplastic Agents; Aphidicolin; Benzamides; Cytarabine; DNA Damage; DNA Repair; Doxorubicin; Flavonoids; Gamma Rays; Kinetics; Naphthoquinones; Novobiocin; Radiation-Sensitizing Agents; Rats; Rats, Sprague-Dawley; T-Lymphocytes; Time Factors; Vidarabine

The in vitro interaction of modulators of topoisomerase I and II with cisplatin in human ovarian carcinoma cells might be synergistic. The interactions were evaluated by median effect analysis of survival data derived from continuous exposure to drug combinations for 10 days in colony-forming assays. The interaction between cisplatin and the topoisomerase I inhibitor camptothecin and the topoisomerase I activator beta-lapachone was additive, as was that between cisplatin and the topoisomerase II inhibitor novobiocin. Despite the clinical efficacy of the combination of etoposide (a topoisomerase II inhibitor) and cisplatin, the combination index at 50% cell kill indicated antagonism between these two drugs. Thus, biochemical synergism at the cellular level is not a prerequisite of improved therapeutic efficacy.

Topics: Antibiotics, Antineoplastic; Camptothecin; Cell Line; Cisplatin; DNA Topoisomerases, Type I; Drug Interactions; Etoposide; Female; Humans; Naphthoquinones; Novobiocin; Ovarian Neoplasms; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Tumor Cells, Cultured