Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

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ABSTRACT:The rhesus monkey (Macaca mulatta) is a primate species used extensively as a preclinical safety species in drug development. In this report, we describe the cloning, expression, and characterization of CYP3A64 (AY334551), a CYP3A4 homolog expressed in rhesus liver. The deduced amino acid sequence was found to be 93% similar to human CYP3A4, 83% similar to human CYP3A5, and identical to the previously reported cynomolgus monkey CYP3A8 Cytochromes P450 (P450s) are a superfamily of enzymes involved in the elimination of a wide variety of chemical xenobiotics including pharmaceuticals, carcinogens, and environmental pollutants (Wrighton and Stevens, 1992). CYP3A4 is the most abundant of these enzymes in humans and is responsible for the biotransformation of nearly 50% of all pharmaceuticals (Guengerich, 1995). Substrates for CYP3A4 include such structurally distinct molecules as testosterone, nifedipine, lidocaine, lovastatin, erythromycin, cyclosporine, diazepam, midazolam, and coumarins.Rhesus monkeys (Macaca mulatta) and cynomolgus monkeys (Macaca fascicularis) are widely used throughout the pharmaceutical industry as preclinical safety species. Much emphasis is placed on the overall drug safety profile and the extrapolated CYP3A metabolic activities of monkeys to corresponding human drug metabolism variables, even though very little information is known about monkey CYP3A enzymes or their metabolic capabilities. There are relatively few reports, compared with rat and human, regarding the specific activity of rhesus and cynomolgus monkey CYP3A enzyme activities, and most of these reports are from purified regenerated systems or liver homogenates and not from recombinantly expressed enzyme systems (Ohta et al., 1989;Ohmori et al., 1993;Ramana and Kohli, 1999;Matsunaga et al., 2002). Although it is believed that monkey CYP3A metabolic capabilities should be similar to those of human CYP3A, there has not been an in-depth investigation of the enzymatic properties of the individual monkey CYP3A isoforms. Therefore, we sought to clone, express, and characterize the major CYP3A4-like drug-metabolizing enzyme from rhesus monkey liver.Based on its predicted homology to human CYP3A4, we cloned the CYP3A4 homolog from rhesus monkeys. The cloned cDNA was expressed using a commonly used insect cell expression system and characterized with multiple probe substrates. Insect cells offer several advantages over other expression systems: 1) they do not require alteration of the P450 coding sequence for expression, 2) they lack endogenous cytochromes P450, and 3) they can be used to make microsomes or coexpressed with NADPH-P450 oxidoreductase (OR) to produce Supersomes (Gonzalez and Korzekwa, 1995;Crespi and Miller, 1999).It is valuable to understand the metabolic capabilities of preclinical animal models to accurately predict safety and clearance profiles of pharmaceutical candidates in development. Therefore, in addition to the evaluation of the rhesus CYP3A64 enzyme activity in relationship Article, publication date, ...