A Novel Method to Enhance the Activity of Routinely Used Anticancer Agents
Dartmouth researchers have discovered a new methodology that can enhance the activity of routinely used anticancer agents. In particular, this method appears to be selective for tumors that are defective in the p53 tumor suppressor gene, and thereby should spare any additional toxicity to the non-tumor tissue.
Much of the past success in cancer therapy has involved the use of cytotoxic anticancer drugs, including many that directly damage the cells DNA (for example, cisplatin, mitomycin C, topotecan, etoposide). However, the use of all these agents is limited by the toxicity to the patient. Dartmouth researchers made the important observation that an indolocarbazole known as 7-hydroxystaurosporine (or UCN-01) could selectively enhance the cytotoxicity of these DNA damaging agents only in cells defective for the p53 tumor suppressor protein. Considering that more than 50% of tumors exhibit this defect, while normal cells do not, the combination of DNA damaging agents and UCN-01 has the potential to significantly improve therapeutic outcome.
Unfortunately, there are several limitations to the use of UCN-01 in humans, most notably its ability to bind very strongly to plasma proteins such that it does not penetrate the tumor. UCN-01 is also not selective for the critical protein target and more specific drugs are being sought. Dartmouth scientists continue studying various analogs that exhibit greater specificity for the intended target, that enhance the cytotoxicity of DNA damaging agents, and do this only when p53 is defective. In addition, the analogs appear to have reduced binding to plasma proteins such that they would be expected to better penetrate the tumor tissue. Following more extensive analysis, lead compounds will be selected for further testing, and hopefully clinical development.
This technology is claimed in the issued United States Patent No. 6,472,385. We are seeking an industrial partner interested in its commercialization. (Ref: J7)
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