Pharmacogenomics of New Generation Platinums in Lung Cancer
Initial Award Abstract
Currently, platinum based therapies are among the most effective in the treatment of non-small cells lung cancer (NSCLC). In fact, the use of a platinum-containing regimen is the standard treatment for advanced NSCLC. Although cisplatin and carboplatin are active; both are associated with profound dose-limiting toxicities including kidney toxicity and neutropenia. Choice of a cisplatin or carboplatin based therapy is often empirical, with no rationale. Clearly, the development and optimization of therapy with newer platinum analogs with distinct anti-tumor and toxicity profiles could greatly improve the treatment outcome of NSCLC.
In recent preliminary studies, we observed that the cytotoxicity of third and fourth generation platinum drugs, oxaliplatin and picoplatin, respectively, is enhanced approximately 10-fold in cells over-expressing the human organic cation transporter, OCT1, in comparison to those not expressing the transporter or expressing it at low levels. Our data also indicated that OCT1 enhanced the influx of the drugs into the cells and was associated with greater amounts of platinum-DNA adducts in the cells. The OCT1-mediated enhanced potency was specific for oxaliplatin and picoplatin and was not observed with cisplatin or carboplatin. Collectively these preliminary data suggest that oxaliplatin and picoplatin may be exceptionally potent in tumors that express OCT1. Preliminary data in our laboratory demonstrate that OCT1 is highly expressed in lung cancer tumor samples and provide strong support for the proposed research focused on NSCLC.
In the proposed studies, we will test the hypothesis that OCT1 is a major determinant of response to oxaliplatin and picoplatin in OCT1-transfected cells and in lung cancer cell lines and importantly, in mouse models of lung cancer. Further, we will test the hypothesis that genetic variants of OCT1 modulate response to these agents. |
|Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue
|Periodical: Molecular Cancer Therapeutics
|Authors: More, SS; Li, S; Yee, SW; Chen, L; Xu, Z; Jablons, DM; Giacomini, KM