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Antitumor activity and metabolic activation of N-methanocarbathymidine, a novel thymidine analogue with a pseudosugar rigidly fixed in the northern conformation, in murine colon cancer cells expressing herpes simplex thymidine kinase.

Abstract
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 microM. In parallel studies, the cytostatic activity of the reference compound GCV in these tumor lines was 3.0 microM. 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.
AuthorsRoy Noy, Zvi Ben-Zvi, Esther Manor, Fabio Candotti, John C Morris, Harry Ford Jr, Victor E Marquez, David G Johns, Riad Agbaria
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 8 Pg. 585-93 (Jun 2002) ISSN: 1535-7163 [Print] United States
PMID12479218 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Antiviral Agents
  • RNA
  • DNA
  • Thymidine Kinase
  • (north)-methanocarbathymidine
  • Thymidine
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Antiviral Agents (pharmacology)
  • Cell Division
  • Chromatography, High Pressure Liquid
  • DNA (metabolism)
  • Dose-Response Relationship, Drug
  • Genetic Therapy (methods)
  • Herpes Simplex (enzymology)
  • Hydrolysis
  • Inhibitory Concentration 50
  • Mice
  • Models, Chemical
  • Neoplasm Transplantation
  • Phosphorylation
  • RNA (metabolism)
  • Thymidine (analogs & derivatives, pharmacology)
  • Thymidine Kinase (metabolism)
  • Time Factors
  • Tumor Cells, Cultured

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