Effect of SILA-409, a New Organosilicon Multidrug Resistance Modifier, on Human Pancreatic Cancer Xenografts

Abstract

Background: Failure of cancer chemotherapy is largely caused by multidrug resistance in tumor cells, mediated by ABC transporters that pump many cytostatics out from the cells. Thus, inhibition of the activity of P-glycoprotein efflux pumps can improve the therapeutic results. Disiloxanes are synthetic resistance modifiers that suppressed not only the multidrug resistance gene but also MRP in various cancer cell lines. Among these compounds, SILA-409 [1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis(3-morpholino-propyl)-disiloxane-dihydro chloride] showed a remarkable antiproliferative effect and markedly inhibited the P-glycoprotein-mediated efflux mechanism in vitro. The efficacy of this organosilicon drug was investigated in vivo, in a xenograft system. Materials and Methods: Human pancreatic cancer xenografts (PZX-40/19G) were treated s.c. with 10 mg/kg b.w. SILA-409 every second day for 34 days. Tumor volume changes were recorded every week. At the end of the experiment, a complete autopsy was performed and all the vital organs were evaluated histologically. The apoptotic and mitotic rates were counted and evaluated by morphometric methods, and the immunohistochemical expression of P-glycoprotein was determined using a monoclonal anti-p170 antibody. Results: This large dose of the organosilicon compound did not result in histologically observable toxic effects, and some tumor growth delay was noted. SILA-409 did not affect the mitotic activity, but the number of apoptotic cells per mm² was significantly increased. In the untreated tumors, 60% of the cells displayed p170-positivity, while in the treated group, P-glycoprotein was expressed in just 26% of the carcinoma cells. Conclusion: The multidrug reversal effect of SILA-409 was demonstrated in vivo without any apparent toxicity. In addition, it increased the apoptotic activity, exhibited some tumor growth delay, but did not affect the mitotic rate. This new organosilicon compound deserves further attention with a combination of multidrug-resistant substrate chemotherapeutic agents, especially in multidrug-resistant tumors.