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Checkpoint Responses in Cancer Therapy



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Author: Wei Dai

Publisher: Humana Press

Genres:

Publish Date: June 6, 2008

ISBN-10: 1588299309

Pages: 314

File Type: PDF

Language: English

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Book Preface

The cell cycle is tightly regulated by a number of molecular entities that maintain the genetic integrity of the cell and ensure that genetic information is passed correctly to the daughter cells. Starting in the 1980s, extensive research efforts have revealed the existence of evolutionarily conserved surveillance mechanisms—commonly referred to as checkpoints—that regulate the cell cycle by monitoring specific cellcycle processes and block progression through the cell cycle until these  processes have been completed accurately. If any of the molecular events underlying these processes are impaired, the cell cycle stops to allow the cell time for repair. If the cell is damaged beyond repair, it will commit suicide by activating apoptotic processes. The loss of checkpoint function often results in infidelity of DNA replication, chromosome mis-segregation, or both, thereby predisposing the cell to genetic instability and neoplastic transformation.

Cancer frequently results from damage to multiple genes controlling cell division. Existing evidence indicates that cancer cells are frequently defective in regulating one cell-cycle checkpoint, which makes them very susceptible to insults to a second checkpoint, resulting in apoptosis. Based on their mechanism of action, current antitumor drugs that target the cell cycle can generally be divided into three categories: inhibition of DNA synthesis, induction of DNA damage, and disruption of mitotic processes. Most cancer drugs used in clinical settings kill cancer cells by altering the DNA structure and inhibiting DNA replication. Such events inevitably lead to activation of the DNA replication or the DNA damage checkpoint. Since the 1980s, much effort has also been directed to the discovery of mitotic targets or processes, which, if altered, can lead to a mitotic catastrophe (a specialized case of apoptosis). It is known that mitotic processes are closely monitored by several surveillance mechanisms, including the G2/M transition checkpoint, the prophase stress checkpoint, and the spindle checkpoint. A defect in the regulation of any mitotic checkpoint often results in genomic instability, which predisposes the cell to malignant transformation. By characterizing the molecular components of cell-cycle checkpoint mechanisms and exploring differences in the checkpoint status between normal cells and malignant cells, we may be able to facilitate the discovery and development of chemotherapeutic compounds that are more effective and more specific for tumor cells.

Contents
Preface …………………………………………………………………………… v
Contributors ……………………………………………………………………. xi
1 RB-Pathway: Cell Cycle Control and Cancer Therapy….. 1
Erik S. Knudsen and Wesley A. Braden

2 Targeting the p53/MDM2 Pathway for Cancer Therapy … 19
Christian Klein and Lyubomir T. Vassilev

3 DNA Topoisomerases as Targets for the Chemotherapeutic Treatment of Cancer
Ryan P. Bender and Neil Osheroff

4 Targeting ATM/ATR in the DNA Damage Checkpoint…. 93
Joseph M. Ackermann and Wafik S. El-Deiry

5 Compounds that Abrogate the G2 Checkpoint………………. 117
Takumi Kawabe

6 CDK Inhibitors as Anticancer Agents ………………………….. 135
Timothy A. Yap, L. Rhoda Molife, and Johann S. de Bono

7 CHFR as a Potential Anticancer Target ……………………….. 163
Minoru Toyota, Lisa Kashima, and Takashi Tokino

8 Antimicrotubule Agents ……………………………………………… 177
Miguel A. Villalona-Calero, Larry Schaaf, and Robert Turowski

9 Kinesin Motor Inhibitors as Effective Anticancer Drugs……
Vasiliki Sarli and Athanassios Giannis

10 Targeting the Spindle Checkpoint in Cancer Chemotherapy…..227
Jungseog Kang and Hongtao Yu

11 Antiproliferation Inhibitors Targeting Aurora Kinases …… 243
Kishore Shakalya and Daruka Mahadevan

12 Plks as Novel Targets for Cancer Drug Design …………….. 271
Wei Dai, Yali Yang, and Ning Jiang

13 Do Histone Deacetylase Inhibitors Target Cell Cycle Checkpoints that Monitor Heterochromatin Structure?…291
Brian Gabrielli, Frankie Stevens, and Heather Beamish
Index ……………………………………………………………………………… 311


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