CYTOCIDAL AND RADIOSENSITIZING PROPERTIES OF TWO NEWLY DEVELOPED NITROIMIDAZOLE DRUGS : R0 03-8799 & RSU-1164

Maha  M. LAKKIS

The cytocidal and radiosensitizing effects of two newly developed 2‑‑nitroimidazole derivatives (Ro 03‑‑8799 and RSU‑1164) were evaluated at normal (37º C) and elevated (41.5º C) temperatures, 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 ¹²⁵IUdR 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 did not change the euoxic/hypoxic toxicity ratio for misonidazole and Ro 03‑8799, but with RSU‑1164 the toxicity ratio was increased significantly from 16 (at 1 hour) to 73 (at 3 hours) . 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 these 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 was the same for misonidazol and Ro 03‑8799, but 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 (e.g., enhanced drug accumulation in the tumor, reduced half‑‑life in the body, etc.) 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.