carotid-artery-infusions-for-pharmacokinetic-pharmacodynamic-analysis

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

When proposing the use of a drug, drug combination, or drug delivery into a novel system, one must assess the pharmacokinetics of the drug in the study ...

Fox Chase Cancer Center

Much effort has been devoted to development of cancer therapies targeting EGFR, based on its role in regulating cell growth. Small-molecule and antibody EGFR inhibitors have clinical roles based on their efficacy in a subset of cancers, generally as components of combination therapies. Many cancers are either initially resistant to EGFR inhibitors or become resistant during treatment, limiting the efficacy of these reagents.

Mechanisms of tumor resistance to EGFR-targeted therapies.

In recent years, oncologists have begun to conclude that chemotherapy has reached a plateau of efficacy as a primary treatment modality, even if toxicity can be effectively controlled. Emerging specific inhibitors of signaling and metabolic pathways (i.e., targeted agents) contrast with traditional chemotherapy drugs in that the latter primarily interfere with the DNA biosynthesis and the cell replication machinery. In an attempt to improve on the efficacy, combination of targeted drugs with conventional chemotherapeutics has become a routine way of testing multiple new agents in early phase clinical trials. This review discusses the recent advances including integrative systematic biology and RNAi approaches to counteract the chemotherapy resistance and to buttress the selectivity, efficacy and personalization of anti-cancer drug therapy.

Chemotherapy and signaling: How can targeted therapies supercharge cytotoxic agents?

Recently, we reported that the ATP-binding cassette transporter 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7), is able to confer resistance to a variety of anticancer agents, including taxanes. However, the in vivo functions of the pump have not been determined to any extent. In this study, we generated and analyzed Abcc10(-/-) mice to investigate the ability of Abcc10 to function as an endogenous resistance factor. Mouse embryo fibroblasts derived from Abcc10(-/-) mice were hypersensitive to docetaxel, paclitaxel, vincristine, and cytarabine (Ara-C) and exhibited increased cellular drug accumulation, relative to wild-type controls. Abcc10(-/-) null mice treated with paclitaxel exhibited increased lethality associated with neutropenia and marked bone marrow toxicity. In addition, toxicity in spleen and thymus was evident. These findings indicate that Abcc10 is dispensable for health and viability and that it is an endogenous resistance factor for taxanes, other natural product agents, and nucleoside analogues. This is the first demonstration that an ATP-binding cassette transporter other than P-glycoprotein can affect in vivo tissue sensitivity toward taxanes.

Contribution of Abcc10 (Mrp7) to in vivo paclitaxel resistance as assessed in Abcc10(-/-) mice.

The cell surface molecule ABCC10 is a broad-acting transporter of xenobiotics, including cancer drugs, such as taxanes, epothilone B, and modulators of the estrogen pathway. Abcc10(-/-) mice exhibit increased tissue sensitivity and lethality resulting from paclitaxel exposure compared with wild-type counterparts, arguing ABCC10 functions as a major determinant of taxane sensitivity in mice. To better understand the mechanistic basis of ABCC10 action, we characterized the biochemical and vectorial transport properties of this protein. Using crude membranes in an ABCC10 overexpression system, we found that the ABCC10 transport substrates estrogen estradiol-glucuronide (E(2)17βG) and leukotriene C4 (LTC(4)) significantly stimulated ABCC10 beryllium fluoride (BeFx)-sensitive ATPase activity. We also defined the E(2)17βG antagonist, tamoxifen, as a novel substrate and stimulator of ABCC10. In addition, a number of cytotoxic substrates, including docetaxel, paclitaxel, and Ara-C, increased the ABCC10 basal ATPase activity. We determined that ABCC10 localizes to the basolateral cell surface, using transepithelial well assays to establish that ABCC10-overexpressing LLC-PK1 cells exported [(3)H]-docetaxel from the apical to the basolateral side. Importantly, we found that the clinically valuable multikinase inhibitor sorafenib, and a natural alkaloid, cepharanthine, inhibited ABCC10 docetaxel transport activity. Thus, concomitant use of these agents might restore the intracellular accumulation and potency of ABCC10-exported cytotoxic drugs, such as paclitaxel. Overall, our work could seed future efforts to identify inhibitors and other physiologic substrates of ABCC10.

Elizabeth A. Hopper-Borge

Program in Developmental Therapeutics

Fox Chase Cancer Center

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

Elizabeth A. Hopper-Borge

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Fox Chase Cancer Center

Carotid Artery Infusions for Pharmacokinetic and Pharmacodynamic Analysis of Taxanes in Mice

Program in Developmental Therapeutics