Abstract
Compounds containing two redox centers, both of which must be reduced for full expression of cytotoxicity by oxygen-inhibitable pathways (bis-bioreductive drugs), have potential as cytotoxins with high selectivity for hypoxic tumor cells. The bisnitroimidazole N-[2-(2-methyl-5-nitroimidazolyl)ethyl]-4-(2-nitroimidazolyl)butanamide (NNB, NSC 639862), in which a 2-nitroimidazole and 5-nitroimidazole moiety are joined via a carboxamide linker, is highly selective for hypoxic AA8 Chinese hamster cells (200-fold by 8 h) relative to mononitroimidazoles (5–25-fold). A bis-bioreductive mechanism is consistent with the marked increase in hypoxic potency and selectivity of NNB with time and the apparent requirement that the two nitro groups be present in the same molecule. NNB differed from mononitroimidazoles in inducing fewer DNA single strand breaks at equivalent toxicity, suggesting that a duplex DNA lesion (locally doubly damaged site) may be responsible for cell killing. Alkaline elution studies and the lack of hypersensitivity of the repair-defective UV4 cell line indicate that the cytotoxic lesion is not a DNA interstrand cross-link. NNB shows greater hypoxic selectivity than the alkylating 2-nitroimidazole RB 6145 against AA8 cells and is active in combination with radiation when administered in multiple doses against the MDAH-MCa-4 mouse mammary carcinoma.
Footnotes
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↵1 This work was supported by Contract NO1-CM-07321 from the National Cancer Institute. J. W. M. was the recipient of a scholarship from the Health Research Council of New Zealand.
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↵2 To whom requests for reprints should be addressed.
- Received July 21, 1994.
- Accepted November 29, 1994.
- ©1995 American Association for Cancer Research.
Volume 55, Issue 3
