Tissue-targeted antisense c-fos retroviral vector inhibits established breast cancer xenografts in nude mice.
The c-fos proto-oncogene has been implicated as a regulator of estrogen-mediated cell proliferation. We have tested the tissue specificity and antitumor efficacy of a mouse mammary tumor virus-regulated antisense c-fos retroviral vector. Systemically administered vector could be detected in several tissues but was only expressed in breast epithelium, thus supporting targeting to mouse mammary tumor virus-regulated tissues. Ex vivo transduction of 30-70% of MCF-7 human breast cancer cells produced expression of antifos RNA, decreased expression of the c-fos target mRNA, induction of differentiation, and inhibition of s.c. tumor growth and invasiveness. In vivo transduction of established i.p. MCF-7 tumors with a single injection of XM6:antifos inhibited tumor growth in athymic mice with a corresponding inhibition of c-fos, transforming growth factor beta1 and transforming growth factor alpha expression. Four daily injections with the antifos RNA induced a much larger MCF-7 i.p. tumor inhibition, with a marked prolongation of survival in the absence of any host tissue toxicity. These results indicate that inhibition of key nuclear genes such as c-fos may lead to disruption of paracrine factors and an antitumor effect, providing a strategy for cancer gene therapy.
Arteaga
C L
CL
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Holt
J T
JT
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D002455:Cell Division; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D000090063:Proto-Oncogene Mas; D016372:RNA, Antisense / Q000235:genetics / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016372:RNA, Antisense