Multidrug resistance (MDR) is a phenomenon by which
tumor cells develop reduced sensitivity to anticancer drugs, which often leads to the failure of
cancer chemotherapy. A prominent mechanism of MDR is the overexpression of the multidrug efflux pump,
P-glycoprotein (P-gp), that decreases the intracellular accumulation of many anticancer drugs, leading to increased
tumor growth. Intensive efforts are under way to develop clinically useful MDR modulators that inhibit the function of P-gp for use in combination with established anticancer drugs. Our goal was to develop an improved in vivo solid
tumor model utilizing immunocompetent animals to examine the efficacy of P-gp-specific MDR modulators. Using in vitro cytotoxicity and
drug accumulation assays, two transformed murine cell lines, JC and TIB-75, were found to demonstrate the P-gp-mediated MDR phenotype. In contrast, two similar lines did not express functional P-gp. Western blot analyses confirmed the expression of P-gp and the lack of expression of the closely related
drug efflux
protein MRP1 in the JC and TIB-75 cell lines. The JC cell line displayed excellent tumorigenicity and consistent growth kinetics when implanted into immune-competent Balb/c mice. Animals treated with a combination of a known MDR modulator,
cyclosporin A, and a cytotoxic
drug,
doxorubicin, exhibited significantly reduced
tumor growth compared with untreated controls or animals treated with either
cyclosporin A or
doxorubicin alone. Similarly, a novel P-gp-specific MDR modulator,
PGP-4008, in combination with
doxorubicin showed inhibition of
tumor growth. However, in contrast with the significant loss of
body weight observed in the animals treated with the combination of
cyclosporin A and
doxorubicin, those treated with
PGP-4008 plus
doxorubicin did not experience
weight loss. Therefore, this syngeneic solid
tumor model provides a new in vivo system that can be used to evaluate the efficacy of P-gp inhibitors in an immune-competent host. This should allow improved prediction of the clinical utility of these compounds.