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. Multidrug resistance (MDR) is in part due to active efflux transporters such as p-glycoprotein. For example, p-glycoprotein is over-expressed in about 30–40%of primary and more than 50% of metastatic breast cancer patient samples. 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.

Clinical trials have been conducted to evaluate the efficacy of MDR-reversing agents such as verapamil, quinidine and cyclosporin A. Results have been mixed: in some cases serum levels of reversing agents needed to block p-glycoprotein could not be achieved; in other cases, p-glycoprotein could be blocked but the levels of chemotherapeutic drugs had to be reduced in order to prevent excessive toxicity. However, some small-scale studies showed that incorporation of verapamil or cyclosporin in chemotherapy significantly improved overall survival. New, more potent p-glycoprotein inhibitors such as PSC388, GF120918, dexverapamil and XR9576 are also currently being evaluated in clinical trials, and preliminary results to date indicate that at minimum it is possible to obtain serum levels of reversing agents sufficient to block p-glycoprotein.

As p-glycoprotein is also expressed in certain normal tissues, blockade of p-glycoprotein in vivo by reversal drugs inevitably changes drug distribution and metabolism, thus altering the pharmacokinetics of chemotherapeutic agents. As a result, increased accumulation of the drugs in plasma or tissue can cause increased toxicity. Doxorubicin, one of the most potent chemotherapeutic agents for treating hematological malignancies and solid tumors, has dose-limiting cardiotoxicity both in animal models and in cancer patients. In one study, coadministration of cyclosporin and doxorubicin resulted in 55%and 350%increase in area-under-the-curve (AUC) of doxorubicin and its metabolite doxorubicinol, respectively. PSC388, when used in combination with doxorubicin, increases the AUC of doxorubicin tenfold. Using a murine model, the combination of verapamil and doxorubicin has been shown to increases peak doxorubicin concentrations in heart tissue by about 40% compared to doxorubicin alone. This increased tissue doxorubicin levels led to severe heart damage and a significantly lower survival rate.

Ketotifen is a first-generation antihistamine that can sensitize MDR human breast cancer cells to doxorubicin. In a recent study Zhang and Berger have evaluated the efficacy of MDR-reversing agents In MCF-7 and multidrug-resistant variant MCF-7/adr cells. The authors found that the sensitivity of MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine was returned to control levels by ketotifen or verapamil. As observed with verapamil, pretreatment of mice with ketotifen significantly increased doxorubicin accumulation in the heart indicating that, like verapamil, ketotifen causes a buildup of doxorubicin in tissue, likely due to inhibition of normal drug clearance mechanisms. Importantly however, ketotifen pretreatment conferred protection against rather than an exacerbation of doxorubicin-cardiotoxicity. Mice treated with doxorubicin alone demonstrated well-known pathological changes including dilation of capillaries, myocyte degeneration and vacuolization in left ventricular tissue. Addition of verapamil enhanced cardiac damage caused by doxorubicin however ketotifen administration 30 min prior to doxorubicin decreased the extent of cardiotoxicity. This translated to a survival advantage both in comparison to mice receiving doxorubicin alone and to those receiving both doxorubicin and verapamil.

Although the mechanism of action of ketotifen is unclear its unique ability to decrease the cardiotoxic effects of doxorubicin while increasing the uptake of this common chemotherapeutic by p-glycoprotein expressing cancer cells suggests that the development of ketotifen or its novel analogues may produce a highly effective adjuvant treatment of various malignancies.

Entry date Tuesday, June 03, 2003

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