Editors' ChoiceCancer

Precious Metals

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Science Translational Medicine  14 Jul 2010:
Vol. 2, Issue 40, pp. 40ec110
DOI: 10.1126/scitranslmed.3001466

Platinum brings to mind a medley of images—a top-selling album, rapper-style bling, the ideal setting for a perfect diamond. But platinum also plays a central role in a more serious realm: the treatment of cancer. Platinum-based chemotherapy kills cancer cells by causing crosslinking of its DNA and inciting programmed cell death. But the development of resistance by cancers to platinum-based agents is common and often caused by poor drug uptake into the cells. The copper transporter CTR1, which carries platinum into cells, is degraded when exposed to high concentrations of copper, and pretreatment of cells in culture with this metal prevents platinum uptake, resulting in CTR1-dependent resistance to platinum chemotherapy. However, CTR1’s role in platinum-based drug resistance in cancer patients and the safety and efficacy of copper chelation for platinum sensitization in vivo were unknown. Now, new work by Ishida et al. addresses both of these questions.

First, the authors found that high CTR1 mRNA concentrations in ovarian cancer patients were associated with sensitivity to the platinum-based drug cisplatin. Furthermore, high amounts of CTR1 mRNA, detected in a separate in silico analysis of gene expression profiles in ovarian cancer cells taken from patients treated with platinum chemotherapy, directly correlated with increased disease-free survival. Using a mouse model of human cervical cancer, which is commonly treated with platinum chemotherapy, the researchers also showed that exposure of these animals to the copper chelator tetrathiomolybdate (TM)—a drug used to treat Wilson’s disease, a copper-overload disorder—before cisplatin treatment lowered plasma copper concentrations, increased cisplatin adduct levels in a cancer-specific manner, and reduced cervical tumor volumes better than cisplatin alone. In order to control for possible antiangiogenic effects of TM, which had been demonstrated previously, the authors treated cervical and ovarian cancer cells in vitro and again demonstrated cisplatin sensitization with TM treatment.

Several steps remain before these results are implemented in clinical practice. First, the correlation between CTR1 expression and platinum-based drug sensitivity should be validated in larger patient cohort. And although the combination of TM with platinum chemotherapy appears promising, phase I clinical trials will be necessary to assess the safety of this approach in patients. However, this mechanism-based work clearly demonstrates that when it comes to treating cancer, copper may make platinum even more precious.

S. Ishida et al., Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 17, 574–583 (2010). [Abstract]

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