Wednesday, November 6, 2013

Masked cytotoxic agents could provide selective killing of cancer cells.

The goal of all cancer treatments is to eradicate the diseased cells while leaving the normal cells unharmed. The reality is that all current cancer treatment options come with a price, damage to normal cells that results in the undesirable side-effects associated with the treatment.

A current article in the journal Nature Communications provides some real hope that there may be a way to selectively target cancer cells. This article, entitled "Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease" describes work done by scientists at Stony Brook University in New York. These scientists found that all the cancer cells that they tested had high levels of two enzymes, histone deacetylase (HDAC) and a protease called cathepsin L (CTSL).

Space-filling model of puromycin, an antibiotic
by Jynto
The team wondered if they could take advantage of the high levels of HDAC and CTSL. Their approach was to modify a known cytotoxic agent in such a way that it would be masked in the absence of HDAC and CTSL activity. They modified puromycin, a protein synthesis inhibitor, with a tag that consisted of an acetylated lysine. This modified puromycin will not have cytotoxic effects until the acetylated lysine is removed. Unmasking of puromycin is accomplished by the sequential activity of HDAC removing the acetyl group and the CTSL removing the lysine. Proof of concept experiments in cancer cells and mice afflicted with human tumors point to the powerful inhibition of growth using this approach.

A similar approach could revive other compounds that were deemed too cytotoxic for clinical use.