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
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
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.