Peripheral white blood cell toxicity induced by broad spectrum cyclin‐dependent kinase inhibitors

Abstract

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.

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

“…These off-target kinase interactions and the non-selective inhibition of CDKs have detrimental effects on normal cells and likely explain the appearance of numerous side effects seen in clinical trials. 18,19 In the last ten years the use of multiplexed biomarkers and phenotypic assays (e.g. cell cycle arrest concomitant to target engagement) has led to the identification of more specific CDK inhibitors, particularly for CDK4, CDK6 and CDK7/9.…”

Anaemia in Cancer Patients Undergoing Radiotherapy and Chemotherapy at the National Hospital, Abuja

“…The above observation helped to strengthen our earlier report that Chemotherapy had greatest impact on Hb level during therapy. This assertion was supported by three different studies elsewhere Ludwig et al, Grossi et al and Jassen et al which showed that Chemotherapy is a well-known bone marrow depressant and acute cytotoxic agent [3,27,28], To reduce a lot of confounding factors which will likely influence the results of this study, patients that had World Health Organization (WHO), performance status of 0 and 1 were selected. Out of 201 patients studied, 54% (108) had WHO performance status of 0 while 46% (93) had WHO performance status of 1.…”

ATP‐Noncompetitive Inhibitors of CDK–Cyclin Complexes

“…In fact these off-target kinase interactions could explain the appearance of numerous side effects during treatment. [22] For example, flavopiridol provokes the appearance of the hyperacute tumor lysis syndrome which determines the dose limitation of the drug, [23] and the histopathological analysis of monkey-treated eyes showed specific cellular damage in the photoreceptor layer. [24] Additionally in combination with docetaxel, flavopiridol induces neutropenia in patients with metastatic breast cancer.…”