Mutant SV40 large T antigen as a therapeutic agent for HER-2/neu-overexpressing ovarian cancer.
The HER-2/neu gene is frequently amplified and/or its protein product, p185, is overexpressed in a number of human cancers. Overexpression of p185 correlates with poor prognosis and low survival rates in ovarian cancer patients. We previously found that the K1 mutant of SV40 large T antigen inhibits rat neu promoter and suppresses mutation-activated rat neu transformation in mouse fibroblasts. We show here that K1 also inhibits human HER-2/neu promoter in human ovarian cancer cells. To investigate whether K1 can suppress HER-2/neu transformation and thus is a potential therapeutic agent, we used an orthotopic ovarian cancer model in which mice were injected intraperitoneally with HER-2/neu-overexpressing human ovarian cancer cells to induce tumor development. The tumor-bearing mice were then treated with K1-liposome complex weekly. We found that liposome-mediated K1 gene transfer decreased the p185 protein level by K1 expression in these cancer cells and significantly prolonged mice survival; about 40% of these treated mice were alive for more than 1 year without any tumor development. On the other hand, the animals from control groups that did not receive this gene therapy all developed tumors and died within 7 months. The results indicate that liposome-mediated K1 gene transfer is able to suppress tumor development from HER-2/neu-overexpressing ovarian cancer cells in mice.
Xing
X
X
Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Matin
A
A
Yu
D
D
Xia
W
W
Sorgi
F
F
Huang
L
L
Hung
M C
MC
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis*; D017931:DNA Primers; D018572:Disease-Free Survival; D004337:Drug Carriers; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D013539:Simian virus 40 / Q000276:immunology*; D015996:Survival Rate; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection / Q000379:methods
D000957:Antigens, Viral, Tumor; D017931:DNA Primers; D004337:Drug Carriers; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins