Intratumoral administration of an adenovirus expressing a kinase dead form of ErbB-2 inhibits tumor growth.
ErbB-2 is amplified or overexpressed in a number of different cancers including breast, ovarian, lung, prostate and stomach. This overexpression leads to enhanced receptor dimer formation and stabilization allowing the receptor to remain in an active state. The clinical consequences of ErbB-2 overexpression include increased tumor aggressiveness, poor prognosis, decreased patient survival and resistance to chemotherapy. As a result, a variety of different strategies are being examined to inhibit its function or expression. In this study, we explored the efficacy of a type 5 recombinant adenovirus encoding a kinase dead form of ErbB-2, AderbB-2 Delta tk, as a potential therapeutic agent for breast cancer using a murine breast model expressing constitutively active ErbB-2. Co-expression in tumor cells of the kinase dead form of ErbB-2 inhibits receptor activity and induces the death of cells expressing constitutively active ErbB-2. In addition, AderbB-2 Delta tk exhibits antitumor activity in both immune-competent and immune-deficient animals with increased antitumor activity in the immune-competent animals. The results suggest both immune and non-immune mechanisms contribute to the antitumor efficacy of this vector.
Palmer
K
K
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Sharan
N
N
Emtage
P
P
Gauldie
J
J
Muller
W J
WJ
Wan
Y
Y
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D015870:Gene Expression; D018734:Genes, erbB-2; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D015552:Injections, Intralesional; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D023421:Models, Animal; D010770:Phosphotransferases; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000276:immunology
D017252:CD3 Complex; D010770:Phosphotransferases; D018719:Erb-b2 Receptor Tyrosine Kinases