A novel combination of suicide gene therapy and histone deacetylase inhibitor for treatment of malignant melanoma.
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.
Yamamoto
Seiji
S
Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan.
Yamano
Tomoki
T
Tanaka
Maki
M
Hoon
Dave S B
DS
Takao
Sonshin
S
Morishita
Ryuichi
R
Aikou
Takashi
T
Kaneda
Yasufumi
Y
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
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