The cytocidal and radiosensitizing effects of two newly developed 2-nitroimidazole derivatives (Ro 03-8799 and RSU-1164) were evaluated with the original compound, misonidazole, serving as a reference agent. More specifically, euoxic and hypoxic BP-8 murine sarcoma cells were exposed for up to 3 hours to various concentrations of the three nitroimidazole derivatives, with or without irradiation, and the resulting cell lethality was monitored with the $\sp{125}$IUdR prelabeling assay. When cell death was evaluated as a function of drug molarity, the three nitroimidazoles displayed widely different toxicities, but when expressed in terms of toxicity ratio between euoxic and hypoxic cells, all three drugs showed nearly identical toxicity differentials of 16 to 18 in 1 hour drug incubation experiments. Prolonging the treatment period to 3 hours with RSU-1164, the toxicity ratio was increased significantly from 16 to 73. This increase was attributed to the bifunctional action of RSU-1164 as a combined electron-affinic and alkylating agent, with the alkylation component of hypoxic cell killing becoming more pronounced after prolonged drug incubation. Combined administration of hyperthermia and nitroimidazoles increased drug-induced cell lethality for all three agents, but did not materially change the relative toxicity differential between euoxic and hypoxic cells. / The radiosensitizing effects of the three compounds were studied at sublethal drug doses, with the drug concentrations adjusted to provide equitoxic (isosurvival)treatment conditions. Under thse experimental conditions, all three drugs displayed equal radiosensitizing effects in short term drug exposures which measure mainly the so-called "oxygen-mimetic" component of radiosensitization. However, with longer drug incubation periods a second component of sensitization known as "preincubation effect" or "damage interaction" became apparent. The magnitude of this damage interaction effect at equitoxic doses for RSU-1164 produced significantly higher damage interaction than the other two agents. / In conclusion, based on cellular toxicity and radiosensitization data, Ro 03-8799 appears to offer no advantage over misonidazole as a selective cytocidal and radiosensitizing agent for hypoxic cells, but RSU-1164 does provide a moderate therapeutic advantage. Additional factors operating in intact animals could further enhance the potential of RSU-1164 and could also serve to make Ro 03-8799 more effective than misonidazole as an adjuvant to chemotherapy and radiotherapy of cancers. (Abstract shortened with permission of author.) / Source: Dissertation Abstracts International, Volume: 49-10, Section: B, page: 4126. / Major Professor: Kurt G. Holer. / Thesis (Ph.D.)--The Florida State University, 1988.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_77867 |
| Contributors | Lakkis, Maha M., Florida State University |
| Source Sets | Florida State University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | 90 p. |
| Rights | On campus use only. |
| Relation | Dissertation Abstracts International |
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