In vitro tumor cell growth inhibitory and cytotoxic synergisms between a novel amphibian oocytic ribonuclease (ONCONASE)(ONC) and tamoxifen (TMX), lovastatin (LVT) and cisplatin (CDDP), have been observed in the human, estrogen and androgen receptor positive, chemotherapy-resistant NIH-OVCAR-3 ovarian carcinoma cell line. In view of the fact that the resistance to the available systemic chemotherapy represents one of the most important causes of treatment failure in patients with advanced ovarian cancer, the observed various forms of combination therapy synergisms suggest that these regimens could be tested in vivo, including human clinical trials. Particularly important are findings of significant synergistic tumor cell growth inhibitory and cytotoxic activities exerted by the combination of ONC with CDDP; NIH-OVCAR-3 cells are reportedly resistant to the latter. Of specific interest are the observed synergisms between ONC and TMX and between ONC and LVT, an inhibitor of the 3-hydroxy-3- methyl-glutaryl-CoA reductase which is a rate-limiting enzyme in the mevalonate/cholesterol synthesis pathway. A facilitation of apoptosis-induction by the drug combinations presently studied is discussed as a possible mechanism of the observed synergisms.

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