Chemically Basic Drugs Are Better Anti-Cancer Agents

Cancer researchers have found that chemotherapeutic drugs that are chemically basic rather than neutral are better able to destroy tumor cells while causing less damage to surrounding normal tissues.

Investigators at the University of Kansas (Lawrence, USA) exploited previous findings showing the existence of differential intracellular pH gradients between normal and cancer cells.

Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation, and survival. In the current study published in the June 2006 edition of ACS Chemical Biology, the investigators evaluated five Hsp90 chaperone inhibitors containing basic or neutral properties in anti-proliferation assays using cells with variable lysosomal pH. Inhibitors with basic functionalities had reduced activity in cells with normal (low) lysosomal pH but showed significantly greater activity in cells with abnormally elevated lysosomal pH (similar to what has been recorded in many types of cancer cells). Conversely, such selectivity enhancement was not observed for neutral inhibitors.

"The results of our studies should lead to the development of rationally designed molecules that are more selective and produce fewer side effects,” explained senior author Dr. Jeffrey P. Krise, professor of pharmaceutical chemistry at the University of Kansas. "Importantly, this technology can also be used to modify existing drugs and increase their selectivity. It could allow cancer patients to tolerate higher and more effective doses of chemotherapy before normal cells are damaged to an extent that causes serious side effects and cessation of therapy. The approach is completely different from previous attempts that were designed to deliver drugs only to cancer cells and not normal cells.”



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