Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer

Abstract

Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma. Experimental Design: Patients with treatment-naI« ve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation. Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclinT. Conclusions: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.

R-roscovitine Reduces Lung Inflammation Induced by Lipoteichoic Acid and Streptococcus pneumoniae

“…This step indicates that there is a possible role for CDK inhibition in infectious diseases: where antibiotics eradicate bacteria, R-roscovitine will likely diminish the severity of lung injury driven by microbial components as well as host inflammatory mediators. Despite being well tolerated by humans (45,46), clinical use of R-roscovitine to reduce lung injury is still far away. Further research is warranted to dissect the effects of R-roscovitine and CDK inhibition on pulmonary inflammation in the setting of infectious and noninfectious disease.…”

Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma

“…Roscovitine, a kinase inhibitor with potent activity against CDK1 and CDK2, is currently in trials for treatment of solid tumors (16)(17)(18). Like PIK-75, roscovitine induced p-Erk (Fig.…”

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…Tumour biopsies were taken at day 1 (just prior to dosing) and on day 13 (after dosing had ceased). Fifty percent of the 14 evaluable patients showed signs of a reduction in tumour volume and were associated with increases in levels of apoptosis, necrosis, and reductions in plasma EBV DNA levels following dosing [170]. It was promising that this short treatment with CYC202 had such apparently positive outcome at the lower dosing schedule and no limiting toxicities.…”