Peripheral white blood cell toxicity induced by broad spectrum cyclin-dependent kinase inhibitors.
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.
Jessen
Bart A
BA
Pfizer Global Research and Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA 92121, USA. bart.jessen@pfizer.com
Lee
Leo
L
Koudriakova
Tatiana
T
Haines
Morgan
M
Lundgren
Karen
K
Price
Sharon
S
Nonomiya
Jim
J
Lewis
Cristina
C
Stevens
Gregory J
GJ
D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000633:toxicity
C512484:AG-012986; D001549:Benzamides; D004791:Enzyme Inhibitors; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases