Research ArticlePharmacology

Quinone Oxidoreductase-2–Mediated Prodrug Cancer Therapy

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Science Translational Medicine  14 Jul 2010:
Vol. 2, Issue 40, pp. 40ra50
DOI: 10.1126/scitranslmed.3000615

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A Lethal Combination for Liver Cancer?

Undergoing chemotherapy to treat cancer is a dreaded—and often grueling—experience. Many chemotherapeutic drugs are double-edged swords: Used with the aim of destroying rapidly dividing cancer cells, they also kill normal cells that exhibit this behavior, sometimes resulting in debilitating side effects. For example, destruction of the quickly multiplying cells that line the gastrointestinal tract can lead to painful ulcerations; loss of proliferating bone marrow cells reduces immune system function and can cause anemia. Ideally, chemotherapeutic drugs display greater specificity toward cancer cells, thus reducing toxicity to healthy tissue. Now, Middleton and colleagues describe their work on a chemotherapy regime that shows promise for specifically destroying liver cancer.

The system in question is based on the weak alkylating agent CB1954. Monofunctional alkylating agents such as CB1954 react with a single DNA residue, whereas the more potent bifunctional alkylating agents can react with two residues on different DNA strands, cross-linking them and preventing the strands from uncoiling during replication. Rapidly proliferating cells that duplicate their DNA frequently are more sensitive than others to such damage. CB1954 can be converted to a far more cytotoxic bifunctional agent by the oxidoreductase enzyme NQO2—which is ubiquitously expressed in human tissues—but only in the presence of a cofactor.

Middleton and co-workers investigated how this chemotherapy system might be used most effectively. Using structural data, they modeled how CB1954 and a synthetic cofactor bind to NQO2, which indicated that the cofactor should saturate NQO2 before CB1954 is added to maximize conversion of CB1954 to its cytotoxic form. On the basis of these data, a phase I clinical study was performed, during which first the cofactor and then CB1954 were administered to patients with several types of cancer, and a maximum tolerated dose for the drug combination was determined. As predicted, DNA cross-links were observed in tumors after treatment. The researchers also compared the fates of the cofactor and CB1954 when they were administered separately or in combination, and saw a striking interaction: The plasma concentration of CB1954 dropped much more sharply in the presence than in the absence of the cofactor, indirectly indicating activation of NQO2 by the cofactor. However, side effects from the drug combination were similar to those caused by CB1954 alone. NQO2 activity was generally elevated in tumors and was low in bone marrow, blood cells, and epithelial cells from the colon, providing an explanation for the lack of additional side effects caused by use of the cofactor. NQO2 activity in liver cancer was higher than in other cancers by a factor of 6, suggesting that the CB1954-cofactor drug combination might be especially effective for treating liver cancer. Moreover, normal liver cells are relatively resistant to the effects of DNA cross-links, probably because of their low rates of cell division. Thus, the authors propose that a phase II efficacy trial for liver cancer patients is in order for this chemotherapeutic agent.

Footnotes

  • Citation: M. R. Middleton, R. Knox, E. Cattell, U. Oppermann, R. Midgley, R. Ali, T. Auton, R. Agarwal, D. Anderson, D. Sarker, I. Judson, T. Osawa, V. J. Spanswick, S. Davies, J. A. Hartley, D. J. Kerr, Quinone oxidoreductase-2–mediated prodrug cancer therapy.Sci. Transl. Med. 2, 40ra50 (2010).

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