Targeting cancer to improve drug delivery

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Selectively targeting only cancer cells could help to avoid healthy cells and side effects from treatments. New research has investigated two enzymes, histone deacetylase (HDAC) and cathepsin L (CTSL), which have very high activity in cancer cells. The researchers, based at Stony Brook University, in Stony Brook, New York, have sought to develop drugs to target those two enzymes.

The research team developed a prodrug, a precursor for the intended drug that improves the efficacy of the primary drug and enhances how selectively it interacts with nontargeted cells.

Their prodrug used a substrate as a chemical tag. The substrate is a modification cleaved, or removed, by the two enzymes, HDAC and CTSL, that the researchers found to have very high activity in cancer cells. Attaching this chemical tag to the cancer drugs protects normal cells because only cancer cells have the enzymes needed to cleave the masked prodrug and release the medication.

“This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development, and could be applied to many other cytotoxic agents,” said Nobuhide Ueki, PhD, of Stony Brook.

The team tested their strategy in human cancer cell lines with high activity of the HDAC and CTSL enzymes. They found that their prodrug selectively killed these cells. They also used the prodrug in mice bearing human xenografts, where they found tumor growth was inhibited. The study was published in Nature Communications (2013; doi:10.1038/ncomms3735).

Ueki and his team hope their effort will attract the attention of pharmaceutical companies and other researchers, motivating them to make their own compounds using this technique.

“Sometimes drug companies give up on a drug because it is so toxic,” Ueki said. “If they can use this technique, they might be able to use their drug again. The more new drugs are developed, the more chances of successful treatment are increased. That's our purpose.”

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