title: A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma.
abstract: One major problem associated with application of gene therapy to treatment of tumors is poor transgene expression. Although suicide gene therapy with the herpes simplex virus-thymidine kinase gene (HSV-tk) followed by administration of ganciclovir (GCV) was effective in the treatment of melanoma, it was still difficult to induce complete remission to cancer. A novel histone deacetylase inhibitor drug FR901229 was found to enhance transgene expression in tumor cells both in vitro and in vivo. Combination therapy with HSV-tklGCV and FR901228 by direct injection into tumor enhanced antimelanoma effects. The number of apoptotic cells in melanoma tumors was increased significantly (P<.05) after combined suicide gene therapy and FR901228. Six times injection of HSV-tk/GCV and FR901228 prolonged mice survival compared to that of HSV-tk/GCV injection alone (P=.021). In total, 56% (10 of 18) of the mice survived 120 days after combined suicide gene therapy and FR901228 treatment, and no new tumors appeared in the surviving mice. However, only 19% (3 of 16) of the mice survived when treated with suicide gene therapy alone. This novel strategy may be applicable as a therapeutic regimen for the treatment of aggressive types of cancers.
authors.affiliation: Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Tomoki
authors.initials: T
authors.lastname: Yamano
authors.forename: Maki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
authors.forename: Sonshin
authors.initials: S
authors.lastname: Takao
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Takashi
authors.initials: T
authors.lastname: Aikou
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D015552:Injections, Intralesional; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D013937:Thymidine Kinase / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008081:Liposomes; D010456:Peptides, Cyclic; C087123:romidepsin; D013937:Thymidine Kinase; D001616:beta-Galactosidase; D015774:Ganciclovir