Phase I Dose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors

Fornier, Monica; Rathkopf, Dana E.; Shah, Manisha H.; Patil, Shekar; O’Reilly, Eileen M.; Tse, Archie; Hudis, C.; Lefkowitz, Robert A.; Kelsen, David P.; Schwartz, Gary K.

doi:10.1158/1078-0432.ccr-07-1218

Cited by 86 publications

(62 citation statements)

References 14 publications

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“…Indeed, we have previously reported that inhibition of CDK-1 by its inhibitor, flavopiridol enhanced PBOX-induced apoptosis in CML cells by accelerating exit from G 2 /M (32). Sequential treatment with flavopiridol is also reported to enhance effects of docetaxel in patients with advanced solid tumours (33). Therefore, we decided to investigate if flavopiridol was capable of enhancing PBOX-induced apoptosis in PC3 cells.…”

Section: Discussionmentioning

confidence: 99%

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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Abstract. Advanced hormone-refractory prostate cancer is associated with poor prognosis and limited treatment options. Members of the pyrrolo-1,5-benzoxazepine (PBOX) family of compounds exhibit anti-cancer properties in cancer cell lines (including multi-drug resistant cells), ex vivo patient samples and in vivo mouse tumour models with minimal toxicity to normal cells. Recently, they have also been found to possess anti-angiogenic properties in vitro. However, both the apoptotic pathways and the overall extent of the apoptotic response induced by PBOX compounds tend to be cell-type specific. Since the effect of the PBOX compounds on prostate cancer has not yet been elucidated, the purpose of this study was to investigate if PBOX compounds induce antiproliferative effects on hormone-refractory prostate cancer cells. We examined the effect of two representative PBOX compounds, PBOX-6 and PBOX-15, on the androgen-independent human prostate adenocarcinoma cell line, PC3. PBOX-6 and -15 displayed anti-proliferative effects on PC3 cells, mediated initially through a sustained G 2 /M arrest. G 2 /M arrest, illustrated as DNA tetraploidy, was accompanied by microtubule depolymerisation and phosphorylation of antiapoptotic proteins Bcl-2 and Bcl-x L and the mitotic spindle checkpoint protein BubR1. Phosphorylation of BubR1 is indicative of an active mitotic checkpoint and results in maintenance of cell cycle arrest. G 2 /M arrest was followed by apoptosis illustrated by DNA hypoploidy and PARP cleavage and was accompanied by degradation of BubR1, Bcl-2 and Bcl-x L . Furthermore, sequential treatment with the CDK1-inhibitor, flavopiridol, synergistically enhanced PBOXinduced apoptosis. In summary, this in vitro study indicates that PBOX compounds may be useful alone or in combination with other agents in the treatment of hormone-refractory prostate cancer. IntroductionProstate cancer is the leading cause of cancer and the second leading cause of cancer-related deaths among men in Europe and the USA (1). Early diagnosis following widespread PSA screening has resulted in most patients presenting with localized tumours. These patients generally exhibit good survival rates following radiotherapy or surgery. However, a number of patients still progress to or are diagnosed with locally advanced or metastatic tumours. While androgendeprivation therapy can slow the development of advanced metastatic prostate cancer, most tumours will still progress within a few years to an androgen-independent state (2). At this stage, treatment options become limited. The current treatment of choice for patients with advanced hormonerefractory prostate cancer is docetaxel-based chemotherapy. While these treatments significantly improve the overall survival of patients (3,4), the prognosis still remains poor for patients presenting with advanced stage prostate cancer. Therefore, the development of improved treatments and combinations are required.Our research group have established that some members of the pyrrolo-1,5-benzoxazepine (PBOX) famil...

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Section: Discussionmentioning

confidence: 99%

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Nathwani

Cloonan²,

Stronach³

et al. 2010

Oncol Rep

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“…The best response was an extraordinary complete response in pancreatic cancer. Four prs were observed in various tumours 46 .…”

Section: Flavopiridolmentioning

confidence: 96%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

196

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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“…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). The combinations of Xavopiridol with gemcitabine and irinotecan (Fekrazad et al 2010), vorinostat (Dickson et al 2010), oxaliplatin and Xuorouracil/leucovorin (Rathkopf et al 2009), paclitaxel and carboplatin (George et al 2008), cisplatin and carboplatin ) and irinotecan (Shah et al 2005) were also assessed in various solid tumors in phase I clinical trials.…”

Section: Broad-range Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

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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.

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Phase I Dose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors

Cited by 86 publications

References 14 publications

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Novel microtubule-targeting agents, pyrrolo-1,5-benzoxazepines, induce cell cycle arrest and apoptosis in prostate cancer cells

Development of Cell-Cycle Inhibitors for Cancer Therapy

The CDK inhibitors in cancer research and therapy

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