The chemosensitizing and cytotoxic effects of RSU 1164 and RSU 1165 in a murine tumor model

Abstract

RSU 1069, the lead compound in a series of nitroimidazoles containing an alkylating aziridine function, has been shown to be a potent radiosensitizer and chemopotentiator both in vitro and in vivo. However, this agent also demonstrates significant in situ toxicity. Recently it has been shown that less toxic analogues of RSU 1069 can be produced by the introduction of alkyl substituents to moderate the reactivity of the aziridine function. The present investigations were undertaken to evaluate the in vivo cytotoxicity and chemosensitizing efficacy of two such analogues, RSU 1164 and RSU 1165. All experiments were performed with KHT sarcomas grown intra-muscularly. In the cytotoxicity studies, a range of sensitizer doses was utilized whereas in the chemopotentiation investigations a fixed sensitizer exposure was combined simultaneously with a range of doses of the nitrosourea CCNU. In both studies, tumor cell survival was determined 22–24 hr after treatment using a soft agar clonogenic assay. Normal tissue toxicity in the chemopotentiation studies was assessed by bone marrow CFU-S assay. Both analogues were found to be significantly :less cytotoxic to KHT sarcoma cells than RSU 1169 (a factor of 4–6 in dose at 50% cell survival). Combining a 1.0 to 2.0 mmol/kg dose of RSU 1164 or RSU 1165 with a range of doses of CCNU increased tumor cell killing by a factor of 1.5–1.6 but did not enhance bone marrow stem cell toxicity. The addition of either sensitizer to CCNU treatment therefore led to a significant therapeutic benefit.