Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element.
We have isolated 462 bp of sequence termed ovarian-specific promoter 1 (OSP-1) that is part of a retrovirus-like element specifically expressed in the rat ovary. We have evaluated the ability of OSP-1 to activate gene expression in normal and neoplastic cell lines derived from the ovaries of rats and women. We have found that there was marked specificity in the ability of OSP-1 to drive reporter gene expression in an ovarian epithelial cell lineage manner. The expression of herpes simplex virus thymidine kinase (HSV-TK) under OSP-1 control was sufficiently ovarian cancer cell line specific to render ganciclovir approximately 50-fold more toxic in the A2780 human ovarian cancer cell line compared with clones of the HCT-116 and HT-29 colon cancer cell lines. Furthermore, ganciclovir had marked antitumor efficacy in vivo in severe combined immunodeficient mice bearing A2780OSP-1-HSV-TK as a s.c. xenograft. We suggest that these data support the use of OSP-1 as a tool to provide specificity to the gene therapy of ovarian cancer and to drive ovarian-specific oncogene expression for the creation of transgenic mouse models of ovarian cancer.
Ovarian Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
M
M
Selvakumaran
R
R
Bao
A P
AP
Crijns
D C
DC
Connolly
J K
JK
Weinstein
T C
TC
Hamilton
D000818:Animals; D001483:Base Sequence; D001711:Biotransformation; D019070:Cell Lineage / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000493:pharmacokinetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D018626:Retroelements / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D011355:Prodrugs; D018626:Retroelements; D013937:Thymidine Kinase; D015774:Ganciclovir