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Aerobic and Hypoxic Toxicity of a New Class of Mixed-Function Drugs Associating Nitroimidazoles and Chloroethylnitrosourea in Nitrosourea-sensitive (Mer^-) and -resistant (Mer⁺) Human Tumor Cells¹

Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53792 [R. T. M.] and Laboratoire de Chimie Bio-Organique, U. A. 488 au CNRS, U. S. T. L., Place Bataillon, 30460 Montpellier Cedex, France [A. C., J. L. B., J. L. I.]

The cytotoxicity of two series (A and B) of novel mixed-function compounds (NI-CENU) combining nitroimidazole (NI) and chloroethylnitrosourea (CENU) functions were examined in Mer^- HeLa-MR and Mer⁺ HeLa-S3 cells. Series A compounds differed from those in Series B by having a hydroxypropyl as opposed to an ethyl group linking the imidazole ring and the nitrosoureido function. Four analogues, including the imidazole and the 2-, 4-, and 5-NO₂ derivatives, were evaluated in each series. Cells were exposed to the various compounds for 4 h under aerobic and hypoxic conditions, and toxicity was assessed by clonogenic assay.

Corresponding analogues in Series A and B were equally toxic to HeLa-MR cells. Preferential hypoxic toxicity was observed only with the 2-NO₂ derivative in either series (I-278, Series A; I-282, Series B). For either compound a dose enhancement factor of 2.4 was observed for hypoxic exposures. The Mer⁺ HeLa-S3 cells were considerably more resistant to the NI-CENU than were their HeLa-MR counterparts. In further contrast to the HeLa-MR data, the Series B compounds were consistently more effective against the HeLa-S3 cells than were their corresponding Series A analogues. The enhanced effectiveness of the Series B compounds in HeLa-S3 cells may be related to the fact that these compounds express carbamoylating activity whereas Series A compounds lack this property. Again only I-278 and I-282 were preferentially toxic to hypoxic cells; however, the aerobic/hypoxic differential was dramatically reduced (dose enhancement factor = 1.3) as compared to that observed with the HeLa-MR cells. The enhanced hypoxic toxicity of the 2-NO₂ NI-CENUs was not due to direct hypoxic toxicity of the nitro moiety but presumably is the result of enhancement of CENU toxicity (i.e., chemosensitization). The data suggest that much lower concentrations of NI may be required to observe chemosensitization when the NI and chemotherapeutic agent are administered as a single mixed-function compound.

¹ Supported by Grant CA42325 from the National Cancer Institute, Department of Health and Human Services.

² To whom reprint requests should be addressed, at 600 Highland Avenue, K4/334, Madison, WI 53792.

Received 8/11/87. Revised 10/30/87. Accepted 11/11/87.