ABSTRACT
The effect of a mixture of naturally occurring aversectin C and avermectin B(1) on the growth of ascites and solid experimental tumors of mice was studied. It was shown for the first time that avermectins possess a pronounced antitumor action. When added at nontoxic doses, they significantly suppressed the growth of ascites Ehrlich carcinoma and P388 lympholeukemia and solid Ehrlich and 755 carcinomata. With some administration regimens, avermectins suppressed the tumor growth by 70-80%. Avermectins were most effective when injected intraperitoneally. It was also shown that avermectins enhanced the vincristine-induced suppression of the growth of Ehrlich carcinoma, melanoma B16, and P388 lympholeukemia. Avermectins produced this effect only when injected after vincristine.
Subject(s)
Antineoplastic Agents/therapeutic use , Ivermectin/analogs & derivatives , Ivermectin/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Carcinoma, Ehrlich Tumor/drug therapy , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Ivermectin/pharmacology , Leukemia P388/drug therapy , Male , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Mice, Inbred DBAABSTRACT
The modification of the sensitivity of Hep-2 and P388 tumor cells to taxol and vincristine, substrates of multidrug resistance proteins, by naturally occurring avermectins and the effect of avermectins on the accumulation of calcein in cells and the efflux of rhodamine 123 were studied. While avermectins did not affect the sensitivity of tumor cells to hydrogen peroxide and cisplatin, they significantly enhanced the sensitivity of cells of both wild-type and resistant strains to taxol and vincristine. The coefficients of modification for resistant strains were substantially higher. Avermectins suppressed the efflux of rhodamine 123 from cells and increased the accumulation of calcein in cells. The relative inhibitory activity of avermectins depended on the cell type and on the substrate of multidrug resistance proteins whose transport they suppressed (vincristine, taxol, rhodamine 123, calcein acetoxymethyl ester). The least active was avermectin B1 or ivermectin; the most active avermectins varied depending on the substrate and the cell type. In the case of vincristine transport, the most active avermectin was almost by one order of magnitude more effective than the traditional inhibitor of multidrug resistance cyclosporin A. This property of avermectins can be used in tumor therapy by combining application of avermectins with antitumor preparations, the substrates of multidrug resistance proteins.
Subject(s)
Cell Line, Tumor , Drug Resistance, Multiple/drug effects , Drug Resistance, Multiple/physiology , Ivermectin/analogs & derivatives , Ivermectin/pharmacology , Animals , Cell Division/drug effects , Cell Survival/drug effects , Cyclosporine/pharmacology , Dose-Response Relationship, Drug , Drug Combinations , Drug Evaluation, Preclinical/methods , Drug Synergism , Fluoresceins/metabolism , Fluorescence , Humans , Ivermectin/chemistry , Leukemia P388/pathology , Male , Mice , Paclitaxel/pharmacology , Rhodamine 123/metabolism , Rhodamine 123/pharmacology , Russia , Vincristine/pharmacologyABSTRACT
BACKGROUND: Taxanes have been widely used against advanced non-small cell lung cancer (NSCLC), alone and in combination with platinum agents. In order to develop a tolerable palliative regimen, we combined carboplatin with low dose docetaxel. PATIENTS AND METHODS: Chemotherapy-naive patients, with Stage IIIB or IV NSCLC and an ECOG performance status < or = 2, were enrolled. Treatment consisted of docetaxel 60 mg/m2 and carboplatin AUC 6 every 21 days. Therapy continued for 1 year or 6 months beyond best response, whichever was greater. RESULTS: Twenty-five patients were enrolled. Most patients (80%) had Stage IV disease. The partial response rate was 16%. Response duration ranged from 6 to 115 weeks. Median survival was 55 weeks. Toxicity was generally limited to grade 3 or 4 neutropenia. There was 1 septic death. CONCLUSION: Survival compared favorably to other similar trials employing higher doses of docetaxel. Additionally, a hematologic toxicity advantage was seen compared to regimens containing higher doses of docetaxel.