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.
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.
Noy
Roy
R
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Ben-Zvi
Zvi
Z
Manor
Esther
E
Candotti
Fabio
F
Morris
John C
JC
Ford
Harry
H
Marquez
Victor E
VE
Johns
David G
DG
Agbaria
Riad
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D002455:Cell Division; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D006561:Herpes Simplex / Q000201:enzymology; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D012313:RNA / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D012313:RNA; D004247:DNA; D013937:Thymidine Kinase; C469995:(north)-methanocarbathymidine; D013936:Thymidine