Interferon gamma induces cell cycle arrest and apoptosis in a model of ovarian cancer: enhancement of effect by batimastat.
Locoregional human IFN-gamma may have activity against refractory ovarian cancer. We investigated this further in an ovarian cancer xenograft model. Administered at clinically relevant doses, intraperitoneal IFN-gamma prolonged the survival of mice bearing multiple established peritoneal tumours, with optimal treatment giving a 3-6-fold increase in median survival time. Daily dosing, which was superior to intermittent treatment, decreased DNA synthesis and induced apoptosis in tumour cells with maximal effects after 7-21 days treatment. This was preceded by an increase in p53 protein at 48 h. The effect of IFN-gamma was not enhanced by sequential treatment with carboplatin. However, the matrix metalloprotease inhibitor, batimastat, further increased mouse survival when given after IFN-gamma. Thus IFN-gamma is cytotoxic to ovarian epithelial cells in vivo and intensive locoregional dosing over short periods is effective. Sequential administration of novel agents that perturb the host/tumour relationship may be of benefit.
Burke
F
F
Biological Therapy Laboratory, Imperial Cancer Research Fund, London, U.K.
East
N
N
Upton
C
C
Patel
K
K
Balkwill
F R
FR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D016190:Carboplatin / Q000008:administration & dosage; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D013876:Thiophenes / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D010649:Phenylalanine; D007371:Interferon-gamma; D016190:Carboplatin; C080985:batimastat; D008666:Metalloendopeptidases