Targeting P-glycoprotein for effective oral anti-cancer chemotherapeutics.
Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life. Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance. P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies. This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.
Bebawy
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The Faculty of Pharmacy, The University of Sydney NSW 2006, Building A15, Science Road, NSW 2006, Australia. maryb@pharm.usyd.edu
Sze
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DM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents