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Peripheral white blood cell toxicity induced by broad spectrum cyclin‐dependent kinase inhibitors
Author(s) -
Jessen Bart A.,
Lee Leo,
Koudriakova Tatiana,
Haines Morgan,
Lundgren Karen,
Price Sharon,
omiya Jim,
Lewis Cristina,
Stevens Gregory J.
Publication year - 2007
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1177
Subject(s) - cyclin dependent kinase , toxicity , pharmacology , cdk inhibitor , bone marrow , cytotoxic t cell , biology , cancer research , immunology , cancer , medicine , cell cycle , biochemistry , in vitro
Cyclin‐dependent kinases (CDKs) have been pursued for more than a decade for the treatment of cancer. CDK inhibitors are expected to slow the rate of cell division and potentially increase the apoptotic fraction of rapidly dividing cells. Although CDK activity is often increased in tumors, normal dividing tissues are also susceptible to the cytostatic and cytotoxic effects of CDK inhibitor action. Therefore the typical toxicity profile associated with cytotoxic anti‐cancer therapy, bone marrow suppression and gastrointestinal toxicity, is expected with CDK inhibitors. Bone marrow toxicity and the ensuing delayed peripheral leukocyte suppression often limit the therapeutic application of cytotoxic anticancer drugs. Here we characterize an unusual bone marrow‐independent acute toxicity toward leukocytes from broad spectrum CDK inhibitors in monkeys and rodents. The potential combination of both acute and delayed immunosuppression would likely further restrict the application of these particular compounds. Since the cells targeted were non‐proliferating, it was assumed that the toxicity was not driven by the intended pharmacological mechanism thereby facilitating the development of a testing strategy to identify compounds with a reduced potential for acute leukocyte toxicity. This testing strategy resulted in a CDK inhibitor void of bone marrow‐independent leukocyte toxicity that is currently undergoing clinical testing. Copyright © 2007 John Wiley & Sons, Ltd.

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