| Clinical resistance to chemotherapeutic drugs is a major problem in the treatment of cancer. Multidrug resistance (MDR) is defined as the ability of cells that after exposed to a single drug can develop resistance to a broad range of functionally and structurally unrelated drugs. Many investigators have focused on the pharmacological overcoming of MDR. There may be two pharmacological pathways by which to overcome MDR: (1) finding new compounds that could reverse MDR; (2) searching for new anticancer drugs that are sensitive to MDR cells. A variety of compounds, including Ca2+ channel blocker, cyclosporins, noncytotoxic anthracycline, et al, are able to reverse the MDR in vitro. But there is limited successful agents for use in the clinic. It i.s necessary to discover unique methods by which to reverse or circumvent MDR. In this study, the new nucleoside transport inhibitor have been used to reverse MDR, and its mechanism has been explored. In addition, three new drugs which are sensitive to MDR cells have been found.Antibiotic C3368-B (CB) , identified as 3,9-dihydroxy-1-methoxy-7-methylanthraquione, is produced by a fungus strain from a soil sample collected in Antarctica. E6 is a plant-derived compound from Uvaria grantiflora. CB and E6 markedly inhibits [3H] labeled thymidine and uridine transport in mouse Ehrlich carcinoma cells. For [3H]-thymidine transport, the IC50 value of CB and E6 are 5.8 uM and 4. 7uM ; and those for [3H]-Uridine transport are 7.9 uM and 5.6 uM respectively. In this studies, CB and E6 are used for reversing the MDR in vitro. By MTT assay, combined with CB (20 uM) , the IC50 of Adriamycin (ADM) for the multidrug resistant human breast cancer cells (MCF-7/ADM) is reduced from 14.5uM to 4.0uM; and by clonogenic assay, the IC50 is from 4.0uM to 0.7uM; CB at 20uM partly reverses the VCR in human oral epidermoid cancer KB/VCR cells. Determined by MTT assay, the IC50 values are reduced by 6.1-hold (1.25uM/0.19uM) . E6 is effective in reversing MDR, too.
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