Overcoming MDR by ultrasound-induced hyperthermia and P-glycoprotein modulation

We assessed the effects of combining ultrasound-induced hyperthermia (USHT) with the P-glycoprotein modulator PSC 833 on cellular retention and cytoto xicity of rhodamine 123 (R123) and doxorubicin in the parent and multidrug resistance (MDR) variants of two human cancer lines. USHT significantly inc reased cellular uptake of R123 and doxorubicin. Without PSC 833, release of R123 and doxorubicin from both USHT-treated and untreated cells was rapid. As expected, PSC 833 (0.5 muM) only slowed their release into the MDR line s. Interestingly, despite the differences in their starting amounts, PSC 83 3 was effective in prolonging R123 and doxorubicin release from both USHT-t reated and untreated MDR cells. PSC 833 did not augment the cytotoxicity of doxorubicin in parent lines but did cause a significant increase in cytoto xicity of doxorubicin in the MDR lines. However, the combined effect of USH T and PSC 833 on cytotoxicity of doxorubicin far exceeded that produced by USHT or PSC 833 alone. (C) 2001 Academic Press.