IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro.
OBJECTIVE
The purpose of this study was to compare in vitro and in vivo responses of primary human tumor cells to IFN-gamma.


METHODS
IFN-gamma may have therapeutic activity in patients with ovarian cancer. We showed previously that this cytokine had direct antiproliferative activity against human ovarian cancer cell lines and xenografts in nude mice. To further understand the role of IFN-gamma in ovarian cancer, we compared its action on 8 ovarian cancer cell lines with the response of 14 primary cultures of ovarian tumor cells isolated from patients with ascitic disease. A pilot clinical study was then conducted to see whether IFN-gamma would also induce apoptosis in human tumor cells in vivo. Six patients with ascites and advanced disease were given IFN-gamma by i.p. injection, and sequential samples of ascites were analyzed.


RESULTS
IFN-gamma had antiproliferative activity in 8 of 8 ovarian cancer cell lines and 11 of 14 primary cultures. This activity was dose related, and cleaved poly(ADP-ribose) polymerase in protein isolates provided evidence of apoptosis. In the clinical study, there was a 3 log(10) pharmacokinetic advantage in peritoneal compared with plasma levels of IFN-gamma. In two of six patients, there was a 90% reduction in tumor cells in ascites after IFN-gamma treatment, and this was related to clinical benefit as assessed by intervals between paracentesis. In all six patients, there were increased amounts of cleaved poly(ADP-ribose) polymerase in protein extracts of ascitic cells sampled during IFN-gamma treatment.


CONCLUSIONS
IFN-gamma induces apoptosis in vitro and in vivo in human epithelial ovarian cancer.
Wall
Lucy
L
Cancer Research UK, University Department of Oncology, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
Burke
Frances
F
Barton
Caroline
C
Smyth
John
J
Balkwill
Fran
F
D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D017209:Apoptosis; D001201:Ascites / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005840:Gentian Violet / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D000097382:CD68 Molecule
D000891:Anti-Infective Agents, Local; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005840:Gentian Violet; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D011065:Poly(ADP-ribose) Polymerases; D011994:Recombinant Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule