A variety of chemotherapies are available to oncologists and these generally reduce the rate of tumor progression. However intrinsic or acquired tumor-mediated drug resistance is a major clinical obstacle that can result in the lack of tumor responsiveness in patients undergoing treatment. Drug resistance is in part due to active efflux transporters such as p-glycoprotein. More recently data has suggested that p-glycoprotein is also involved in the passage of molecules across the blood brain barrier, and in inducing apoptosis in peripheral blood mononuclear cells. The development of substrates or inhibitors of this protein therefore represents an active area of the pharmaceutical industry. Indeed over 15 molecules are in development, over half of which are in preclinical phases of evaluation. One of the more advanced p-glycoprotein inhibitors is Ontogen’s ONT-093 (formerly OC-144-093). ONT-093 reversed multi-drug resistance to doxorubicin, paclitaxel and vinblastine in human lymphoma, breast, ovarian, uterine and colorectal carcinoma cell lines expressing P-glycoprotein. Furthermore it enhanced the antinociceptive effect of loperamide in the mouse hotplate test. Studies are ongoing to investigate whether ONT-093 can increase the brain penetration of HIV protease inhibitors. As a result of preclinical data, ONT-093 was advanced into phase I trials in 1999. A phase II trial in breast cancer patients is planned for 2003. Licensing opportunities are being sought to develop ONT-093 as an adjunct to analgesic or anti-viral therapies.

January, 2003

Adapted from Mistry & Folkes, Curr Opin Investig Drugs 2002 Nov;3(11):1666-71