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Megha Barot, Mitan R. Gokulgandhi, Dhananjay Pal, Ashim K. Mitra; Moxifloxacin: A Valuable New Addition To Chemotherapeutic Armamentarium For The Treatment Of Retinoblstoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):467.
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Multidrug resistance (MDR) proteins (P-gp and MRPs) mediated chemoresistance have been considered as a major cause of treatment failure in the management of retinoblastoma (RB) with systemic chemotherapy. Here, we have examined an interaction of fluoroquinolone moxifloxacin (MFX) with three anticancer drugs (Topotecan, Etoposide, Vinblastine) for the treatment of RB. We hypothesized that in such interactions, MFX will not only modulate the bioavailability of anticancer agent at the ocular site such as retina (due to competitive inhibition at efflux sites) but it will also synergize antiproliferative activity of anticancer agent.
Time dependent uptake and transport of three anticancer drugs was performed in presence of MFX across model cell lines (MDCK-MDR1 and MDCK-MRP2). Modulation of time dependent cell cytotoxicity and caspase-3 enzyme activity of anticancer drugs in presence of MFX was evaluated using retinoblastoma (Y-79) cells. IC-50 value of anticancer drugs alone and in presence of MFX was also determined.
2-2.5 fold increased uptake of all three anticancer drugs was observed in presence of MFX across MDCK-MDR1 and MDCK-MRP2 cells suggesting MFX mediated evasion of efflux pumps. Significant reduction in efflux ratio (B-A/A-B permeability) of three anticancer drugs was also observed in presence of MFX indicating MFX mediated improved transport. Following cytotoxicity study, tenfold reduction in IC-50 value of Topotecan and Etoposide and twofold reduction in IC-50 value of Vinblastine was observed in combination with MFX. Significant enhancement in caspase-3 enzyme activity of three anticancer drugs was observed in combination with MFX on Y-79 cells.
Strategy of utilizing efflux pump inhibitors (which is yet not clinically approved) for improving ocular bioavailability of anticancer agent has its own limitations in terms of little or no improvement in toxicity of chemotoxic agents. However, ocular cells have shown good tolerability against MFX, which is a clinically well accepted drug even at higher dose level. Our results suggest that MFX may be a valuable new addition to chemotherapeutic armamentarium, concurrently improving cytotoxic activity while evading MDR mediated chemoresistance of various anticancer drugs currently used for the treatment of RB. These novel drug interactions will provide dual benefit in terms of overcoming chemoresistance and synergistic cytotoxic effect will help reducing chemotherapeutic dose which eventually reduces probability of dose-limiting toxicity.
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