The therapeutic potential of hepatocyte growth factor to sensitize ovarian cancer cells to cisplatin and paclitaxel in vivo.
OBJECTIVE
Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance. We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics.


METHODS
Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses.


RESULTS
In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own.


CONCLUSIONS
These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.
Bardella
Chiara
C
Laboratory of Cancer Genetics and Division of Molecular Oncology of the Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Turin, Italy.
Dettori
Daniela
D
Olivero
Martina
M
Coltella
Nadia
N
Mazzone
Massimiliano
M
Di Renzo
Maria Flavia
MF
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes
D017228:Hepatocyte Growth Factor; D017239:Paclitaxel; D002945:Cisplatin