UCSF

ABSTRACT

TARGETING DRUG TRANSPORTERS AS A NOVEL APPROACH FOR PLATINUM-BASED ANTICANCER THERAPY

Shuanglian Li

Tissue specific targeting by design and development of influx transporter targeted compounds represents one effective approach for increasing efficacy and reducing toxicity of drugs. The overall goal of this dissertation research was to test the hypothesis that organic cation transporter 1 (OCT1) can be used as a target to deliver platinum-based chemotherapeutics to tumors with the goal of enhancing the efficacy and reducing the toxicity of these agents.

As a first step in evaluating the potential of OCT1 as a valid drug delivery target we determined the effect of OCT1 on the disposition of pyroplatin (a potent OCT1 substrate) under normal physiological OCT1 expression level in vitro and in vivo. Studies in primary hepatocytes and Oct1 knockout mice demonstrated that Oct1 plays a role in mediating the transport of pyroplatin into the Oct1 expressing tissues and accordingly its pharmacokinetics.

The goal of the second part of this dissertation was to determine the role of OCT1 in response to pyroplatin. In particular the role of OCT1 in the toxicity and antitumor effect of pyroplatin was intensively investigated using genetically modified mice. The data supported the concept that by targeting drug influx transporters, off-target toxicities can be greatly spared. Although OCT1 mediated the accumulation of pyroplatin in hepatocellular carcinoma, a benefit on overall survival of the mice was not observed. Further investigation is needed to elucidate the mechanisms of resistance of hepatocellular carcinoma to pyroplatin and other platinum based chemotherapies.

In the final part of this dissertation, the role of OCT1 in the disposition and drug action of oxaliplatin (a moderate substrate of OCT1) was explored. The minor effects of OCT1 on the pharmacokinetics and tissue accumulation suggested that the Oct1-mediated transport of oxaliplatin is not sufficiently high to remarkably affect its disposition in vivo. The increased hepatic platinum levels after multiple dosing in Oct1+/+ mice did not result in obvious liver toxicity, indicating that the hepatic toxicity of oxaliplatin observed in humans was not observed under the conditions used in this study and a clear role for Oct1 in oxaliplatin-induced hepatotoxicity could not be established.