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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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