Abstract
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.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Apoptosis / drug effects*
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Carboplatin / administration & dosage
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Cell Division / drug effects
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Cystadenocarcinoma, Serous / drug therapy*
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Cystadenocarcinoma, Serous / pathology
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Cystadenocarcinoma, Serous / ultrastructure
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Drug Screening Assays, Antitumor
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Drug Synergism
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Female
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Humans
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Interferon-gamma / administration & dosage
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Interferon-gamma / pharmacology
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Metalloendopeptidases / antagonists & inhibitors
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Mice
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Mice, Nude
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / pathology
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Ovarian Neoplasms / ultrastructure
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Phenylalanine / administration & dosage
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Phenylalanine / analogs & derivatives
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Survival Rate
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Thiophenes / administration & dosage
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Transplantation, Heterologous
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Tumor Suppressor Protein p53 / metabolism
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Thiophenes
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Tumor Suppressor Protein p53
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Phenylalanine
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Interferon-gamma
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Carboplatin
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batimastat
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Metalloendopeptidases