Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2 '-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), against tumor cells expressingeither the Varicella zoster or the Herpes simplex virus thymidine kinase

Citation
C. Grignet-debrus et al., Comparative in vitro and in vivo cytotoxic activity of (E)-5-(2-bromovinyl)-2 '-deoxyuridine (BVDU) and its arabinosyl derivative, (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), against tumor cells expressingeither the Varicella zoster or the Herpes simplex virus thymidine kinase, CANC GENE T, 7(2), 2000, pp. 215-223
Citations number
42
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER GENE THERAPY
ISSN journal
09291903 → ACNP
Volume
7
Issue
2
Year of publication
2000
Pages
215 - 223
Database
ISI
SICI code
0929-1903(200002)7:2<215:CIVAIV>2.0.ZU;2-0
Abstract
The inhibitory effects of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and i ts arabinosyl derivative (E)-5-(2-bromovinyl)-1-beta-D-arabinoruranosylurac il (BVaraU) on the growth of both MDA-MB-435 human breast carcinoma and 9L rat gliosarcoma cells expressing the thymidine kinase (tk)-encoding gene of the Varicella tester virus (VZV) or the Herpes simplex virus (HSV) were ev aluated. In vitro, BVDU and BVaraU effectively killed both cell types expre ssing VZVtk, with 50% inhibitory concentration values ranging from 0.06 to 0.4 mu M, whereas ganciclovir (GCV) lacked activity. On HSVtk(+) cells, BVD U had high cytotoxic activity, with 50% inhibitory concentration values tha t were similar to those of GCV, whereas BVaraU was inactive. In vivo, BVDU applied intraperitoneally caused a 50% tumor growth inhibition in nude mice inoculated subcutaneously with VZVtk(+) as well as HSVtk(+) mammary tumor cells. In mice and at variance with the in vitro results, BVaraU had very l ittle activity against the VZVtk+ mammary cells; GCV had the highest activi ty on the HSVtk(+) cells, resulting in a 50% eradication of the tumors. Wit h the 9L rat gliosarcoma model, the VZVtk/BVDU system completely failed to inhibit the development of VZVtk(+) glioma tumors induced subcutaneously in syngeneic rats, although BVDU had a similar 45-minute half-life in both ra ts and mice. Factors other than degradation of the prodrug and related to t he mode of action of these analogs are possibly involved in the observed di screpancies between the in vitro and in vivo results.