Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Schwartz, Gary K.; O’Reilly, Eileen M.; Ilson, David H.; Saltz, Leonard B.; Sharma, Sunil; Tong, William P.; Maslak, Peter; Stoltz, M.; Eden, Larry; Perkins, Pam; Endres, Sandra; Barazzoul, John; Spriggs, David R.; Kelsen, David P.

doi:10.1200/jco.2002.08.080

Cited by 143 publications

(87 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that flavopridol, an inhibitor of cyclindependent kinases, significantly enhances paclitaxel-induced apoptosis when paclitaxel precedes flavopridol (Schwartz et al, 2002). Since vinorelbine, but not paclitaxel, was able to induce p21 expression in AI cells, we postulated that the sequential exposure of AD and AI cells to paclitaxel followed by vinorelbine might produce synergistic outcomes.…”

Section: Synergistic Combination Of Paclitaxel and Vinorelbinementioning

confidence: 90%

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

View full text Add to dashboard Cite

To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21 WAFl/CIP1 (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

show abstract

Section: Synergistic Combination Of Paclitaxel and Vinorelbinementioning

confidence: 90%

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

View full text Add to dashboard Cite

show abstract

“…The most effective antitumor combination is PTX on day 1 followed by FL on day 2. 45 FL increases cytotoxicity of PTX, when it is added after paclitaxel. Antagonism and synergism between FL and PTX are sequence dependent.…”

Section: Discussionmentioning

confidence: 99%

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

Blagosklonny¹,

Darzynkiewicz²,

Figg³

2002

Cancer Biology & Therapy

View full text Add to dashboard Cite

Resting cells are relatively resistant to microtubule-active drugs including paclitaxel (PTX). By causing p53-mediated arrest, pretreatment with low concentrations of doxorubicin (DOX) protected HCT116 cells from the cytotoxicity caused by PTX. Unlike DOX, flavopiridol (FL) did not protect HCT116 cells. Low concentrations of FL (50 nM) induced p21 but not p53. High concentrations of FL (500 nM) decreased levels of p21 and Mdm-2 but dramatically induced p53. Thus, FL reciprocally affects p21 and p53. In LNCaP, a prostate cancer cell line which is highly sensitive to p21-induced growth arrest (p21-sensitive), low concentrations of FL (50 nM) induced p21 (without induction of p53) and caused G1 and G2 arrest. This precluded mitotic arrest, Bcl-2 and Raf-1 phosphorylation, and diminished cell death caused by PTX. In contrast, FL did not protect PC3M, arrest-resitant and highly aggressive prostate cancer cells. Like LNCaP, HL60 and SKBr3 cells are known to be p21-sensitive. As predicted, low concentrations of FL antagonized PTX-mediated cytotoxicity in HL60 and SKBr3 cell lines. In summary, only low concentrations of FL can induce p21, and, in turn, only p21-sensitive cells are protected from PTX.

show abstract

“…Secretory diarrhea, neutropenia, nausea, vomiting and proinXammatory syndrome were reported as main drug adverse eVects (DAE). Another phase I clinical study of sequential paclitaxel and Xavopiridol showed clinical activity in patients with esophagus, lung and prostate cancer including patients who had not (Schwartz et al 2002). The combination of Xavopiridol and docetaxel has been shown to be quite promising in several phase I clinical studies (Fornier et al 2007;El-Rayes et al 2006;Tan et al 2004).…”

Section: Broad-range Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

213

172

View full text Add to dashboard Cite

Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

show abstract

Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Cited by 143 publications

References 16 publications

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

The CDK inhibitors in cancer research and therapy

Contact Info

Product

Resources

About

Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid Tumors

Cited by 143 publications

References 16 publications

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Flavopiridol Inversely Affects p21WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel

The CDK inhibitors in cancer research and therapy

Contact Info

Product

Resources

About

Flavopiridol Inversely Affects p21^WAF1/CIP1and p53 and Protects p21-Sensitive Cells from Paclitaxel