Download Enhancing Tumor-Specific Uptake of the Anticancer Drug Cisplatin

Enhancing Tumor-Specific Uptake of the Anticancer Drug Cisplatin with a Copper Chelator
Seiko Ishida, Frank McCormick, Karen Smith-McCune, and Douglas Hanahan
Cancer Cell 17(6):574-83, 2010
Presenter: Hsin-Yi Pan
Commentator: Dr. Jang-Yang Chang and Dr. Ching-Chuan Kuo
Date/Time: 2011/3/21 17:10-18:00
Place: 602, College of Medicine
Background:
Cervical and ovarian cancers are the common cause of cancer-related death among women
worldwide. Cisplatin exerts its cytotoxic effect by forming an intrastrand crosslink on DNA, and has
been one of the most active single agents and a component of combined-agent chemotherapy
regimens for patients with advanced such kind of cancers. However, inefficient drug delivery and
attendant toxicity represent impediments to successful platinum-based chemotherapy.
Objective:
Since uptake of the anticancer drug cisplatin is mediated by the copper transporter CTR1 in cultured
cells, thus, the objective of this study could be divided into the following parts: (1) to evaluate
whether copper transporter CTR1 correlate with clinical response to platinum drugs; (2) to elucidate
whether a copper chelator, tetrathiomolybdate (TM), selectively increases cisplatin uptake and killing
of tumor cells without affecting normal organs.
Result:
In this paper, the authors elucidated the relative association of CTR1 levels with the therapeutic
efficacy of cisplatin-based treatment by Q-PCR analysis. The result showed in human ovarian tumors
that low levels of CTR1 mRNA are associated with poor clinical response to platinum-based therapy.
To more address the issue, HPV16/E2 mice develop progress to invasive squamous cell carcinoma
was used in this paper. The result demonstrated that combined treatment with TM and cisplatin
increases cisplatin-DNA adduct levels in cancerous but not in normal tissues, impairs angiogenesis,
and improves therapeutic efficacy. Of notes, TM could also enhance the sensitivity of cisplatin to
several cervical and ovarian human cancer cells. Furthermore, isogenic mouse embryonic fibroblasts
that are either wild-type or homozygous for a knockout allele of CTR1 were used, and found that TM
increases cisplatin sensitivity is a CTR1-dependent manner.
Conclusion:
Taken together, this study identify the copper transporter as a therapeutic target, which can be
manipulated with copper chelating drugs to selectively enhance the benefits of platinum-containing
chemotherapeutic agents.
Reference:
1.
Ishida S.et al. 2002. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in
yeast and mammals. Proc Natl Acad Sci U S A. 99(22):14298-302.
2.
Safaei R.2006. Role of copper transporters in the uptake and efflux of platinum containing drugs. Cancer
Lett. 234(1):34-9.