Hydroxyurea significantly enhances tumor growth delay in vivo with herpes simplex virus thymidine kinase/ganciclovir gene therapy.
We have previously demonstrated with several cell lines in vitro that hydroxyurea (HU) synergistically enhances ganciclovir (GCV)-mediated cytotoxicity in bystander cells. In this study, we evaluated the role of DNA synthesis inhibition on enhanced bystander killing and assessed whether addition of HU would improve the efficacy of the HSV-TK/GCV system in vivo. Compared with GCV treatment alone, addition of HU resulted in increased DNA synthesis inhibition and delayed progression through S phase following removal of drug. In a xenograft tumor model, 1:10 and 1:1 mixtures of HSVtk- and LacZ-expressing SW620 cells were injected s.c. in the flanks of nude mice and treated i.p. (100 mg/kg GCV, 1500 mg/kg HU) daily for 5 days. Tumors from mice treated with GCV alone grew rapidly and increased to 10 times their initial size in 15.7 +/- 1.8 and 16.0 +/- 0.9 days for 1:10 and 1:1 mixtures, respectively. However, when both GCV and HU were administered in combination, a single complete tumor regression was observed in both the 1:10 and 1:1 groups. In the remaining mice treated with GCV/HU, it took 23.2 +/- 2.1 (1:10) and 26.4 +/- 3.8 days (1:1) to obtain a similar 10-fold increase in tumor size.
Boucher
P D
PD
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor 48109-0504, USA.
Ostruszka
L J
LJ
Murphy
P J M
PJ
Shewach
D S
DS
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D016590:Aphidicolin / Q000627:therapeutic use; D024201:Bystander Effect; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000628:therapy*; D004357:Drug Synergism; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics
D000963:Antimetabolites; D000998:Antiviral Agents; D016590:Aphidicolin; D013937:Thymidine Kinase; D015774:Ganciclovir; D006918:Hydroxyurea