Adenoviral-mediated herpes simplex virus-thymidine kinase gene transfer in vivo for treatment of experimental human melanoma.
To assess the efficacy of an in vivo adenoviral-mediated cytotoxic gene therapy, human melanomas were established in nude mice and transduced with herpes simplex virus-thymidine kinase (tk) followed by treatment with ganciclovir (GCV). In initial experiments, adenovirus (adv) containing the beta-galactosidase reporter gene was employed to determine melanoma cell infectivity in vitro. In comparison to murine melanoma cell lines B16 and K1735-M2, human A375-SM cells exhibited up to a 10-fold greater susceptibility to adenoviral transduction, similar to the degree of infectivity found for human epidermal HaCaT cells. In addition, human A375-SM melanoma cells exhibited a greater sensitivity in vitro to the cytotoxic effects of transduction with tk-adv and treatment with GCV, which was mediated by a strong bystander effect. In vivo, intratumoral injection of relatively large human melanomas (160 mm3) with 1.2 X 109 pfu of tk-adv, followed by intraperitoneal GCV treatment (60 mg/kg twice daily) over 4 days, typically resulted in a 50% reduction in melanoma growth rate compared to mock or untreated controls. Moreover, histometrical analysis employing a rigorous computerized imaging system revealed that the residual viable tumor area in the tk-adv/GCV-treated group was only one-fifth that of solvent controls. These data show that adv is a highly efficient in vivo gene delivery system to treat experimental human melanomas. In comparison to a previous murine melanoma study, human melanomas appeared to exhibit a greater sensitivity to this cytotoxic treatment in vivo, which may hold significant promise for development of effective gene therapy modalities to treat melanoma in humans.
Bonnekoh
B
B
Department of Cell Biology, Baylor College of Medicine, Houston Texas, USA.
Greenhalgh
D A
DA
Bundman
D S
DS
Kosai
K
K
Chen
S H
SH
Finegold
M J
MJ
Krieg
T
T
Woo
S L
SL
Roop
R
R
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015774:Ganciclovir / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007274:Injections, Intraperitoneal; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase / Q000235:genetics
D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir