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Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel [R. N., Z. B.-Z., E. M., R. A.]; National Human Genome Research Institute [F. C.] and Laboratory of Medicinal Chemistry [H. F., V. E. M., D. G. J.], Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland 21702; and Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892 [J. C. M.]

N-Methanocarbathymidine [(N)-MCT], a thymidine analogue incorporating a pseudosugar with a fixed Northern conformation, exhibits antiherpetic activity against both herpes simplex virus (HSV) HSV-1 and HSV-2, with a potency greater than that of the reference standard, ganciclovir (GCV). In the present study, we have assessed the cytotoxic activity in vitro of (N)-MCT in wild-type murine colon cancer cells (MC38) and in cells expressing the herpes simplex thymidine kinase gene (MC38/HSV-tk), and the antitumor activity of (N)-MCT in vivo against HSV-tk transduced and nontransduced MC38 murine tumors. In vitro, when assessed over a 48-h period, the growth-inhibitory activity (IC₅₀) of (N)-MCT toward MC38/HSV-tk cells was 2.9 µm In parallel studies, the cytostatic activity of the reference compound GCV in these tumor lines was 3.0 µm. In studies in vivo, both (N)-MCT and GCV (100 mg/kg) given twice daily for 7 days completely inhibited the growth of HSV-tk-transduced MC38 tumors while exhibiting no effect on nontransduced MC38 tumors in mice. In nontransduced cells both in vitro and in vivo, only low levels of (N)-MCT and its monophosphate could be detected after administration of the parent drug, whereas in HSV-tk-transduced cells (N)-MCT was phosphorylated to its respective mono-, di-, and triphosphates. Furthermore, data showed that (N)-MCT incorporated in high levels into cellular DNA whereas trace levels were measured into RNA. These observations indicate that (N)-MCT may be a useful candidate prodrug for HSV-tk suicide gene therapy of cancer.

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