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Flavopiridol (NSC 649890)1992 Flavopiridol (NSC 649890) is an important experimental semisynthetic flavonoid derived from the indigenous Indian plant Dysoxylum binectariferum, and it was the first cyclin-dependent kinase (CDK) inhibitor to be tested in clinical trials. In 1992, it was identified as a potent anti-cancer agent in an empirical screening program when it was found to directly inhibit CDKs 1, 2, and 4 as a competitive ATP site antagonist. Cancer cells often overproduce CDKs, which appear to be involved in the ability of cancer cells to circumvent the various checkpoints in the cell cycle. In a variety of experiments, flavopiridol emerged as a potent CDK inhibitor; moreover, preclinical studies demonstrated the capacity of flavopiridol to rapidly induce programmed cell death, promote differentiation, inhibit angiogenic processes, and modulate transcriptional events. 1994 Clinical trials began in 1994 and have now shown that concentrations sufficient to inhibit cell proliferation and CDK activity in vitro can be safely achieved in humans. Testing in early clinical human trials with infused flavopiridol showed activity in non-Hodgkin lymphoma and renal, prostate, colon, and gastric carcinomas. The main side effects were secretory diarrhea and a pro-inflammatory syndrome associated with hypotension. Biologically active plasma concentrations of flavopiridol (approximately 300–500 nM) can be easily achieved. Phase II trials involving administration of infusional flavopiridol for several tumor types, with other schedules, and in combination with standard chemotherapies, are being assessed. Although important questions remain to be answered, the positive results obtained with flavopiridol will likely stimulate the development of novel CDK modulators for cancer therapy. 1 Interview with Dr. David Newman. Palladian Partners. April 2005. Link:
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Michael Grever, M.D. Flavopiridol is derived from a medicinal plant from India that has been used for centuries in indigenous medicine. The drug is under investigation for the treatment of various solid tumors as well as hematological cancers.1
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