Cation Transporters Increase Effectiveness of Certain Anticancer Drugs

Cancer researchers have found that a positively charged analogue of the anticancer drug cisplatin may be selectively taken up by colorectal cells and therefore cause fewer side effects than the currently used drug, oxaliplatin.

Oxaliplatin was approved by the [U.S.] Food and Drugs Administration in 2004 and is usually the first therapeutic line of defense against colorectal cancer. However, it is readily taken up by most cell types, which can result in serious damage to normal body tissues.

Investigators at the Massachusetts Institute of Technology (Cambridge, MA, USA) decided to revisit a compound called cDPCP (cis-diammine(pyridine)chloroplatinum(II), cis-[Pt(NH3)2(py)Cl]+) that had been known for over twenty years as having significant anticancer activity in a mouse tumor model. However, this drug had not been tested in humans, as its positive charge would normally prevent it from passing through the membranes of cancer cells.

Data published in the June 25, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that colorectal cancer cells possess an abundant supply of two cation transporters (OCTs) embedded in the cell membrane that actively transport positively charged molecules into the cell. Although cDPCP would affect other cells in the body, uptake by the transporters would focus its activity towards colorectal cancer cells. Thus, dosages could be reduced, and the drug would cause fewer and milder side effects.

"This compound, the anti-tumor properties of which were established in mice over 20 years ago, emerged in our search for platinum anticancer drug candidates with cellular uptake properties analogous or superior to those of oxaliplatin,” explained senior author Dr. Stephen Lippard, professor of chemistry at the Massachusetts Institute of Technology.


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