Introduction and Overview of DNA Repair Targets: From Bench to Clinic - DNA Repair in Cancer Therapy - page 16

inhibitors and other types of inhibitors that capitalize
on specific biochemical processes altered in cancer cells
e and turn them into synthetic lethalities. Figure 1.8
summarizes the types of inhibitors that target various
aspects of tumorigenesis.
This textbook focuses onDNA repair processes, poten-
tial biomarkers for repair pathways, and the possibility of
developing corresponding inhibitors based on that
research. At least one chapter is dedicated to describing
how each DNA repair pathway works and preclinical
or clinical drug development that is in progress as
a result. Some DNA repair pathways lend themselves
more to exploiting synthetic lethality than others; the
reasons for that are discussed in the following chapters
as well. The clinical research discussed in this textbook
reinforces the feasibility of selectively targeting genetic
alterations in cancer cell populations to kill cancer cells
while inflicting minimal toxicities. 22 The final chapter
discusses future directions for therapeutic development.

11. Gordon M. Cancer chemotherapy: Drug classification and
mechanism of action [cited 31 December 2010]. http://www.
pharmacology2000.com/Anticancer/classes1.htm .
12. Connors TA, Hare JR. Proceedings: Mechanism of action of
tumour inhibitory nitrosoureas. Br J Cancer 1975;31(2):264.
13. Kaina B, Christmann M, Naumann S, Roos WP. MGMT: key
node in the battle against genotoxicity, carcinogenicity and
apoptosis induced by alkylating agents. DNA Repair (Amst)
2007;6(8):1079 e 99.
14. Park WS, Ko EA, Jung ID, Son YK, Kim HK, Kim N, et al.
APE1/Ref-1 promotes the effect of angiotensin II on Ca2

þ

channel in human endothelial cells via suppres-
sion of NADPH oxidase. Arch Pharm Res 2008;31(10):1291 e 301.
15. Plummer R. Perspective on the Pipeline of Drugs Being
Developed with Modulation of DNA Damage as a Target. Clin
Cancer Res 2010;16(18):4527 e 31.
16. Rabik CA, Njoku MC, Dolan ME. Inactivation of O6-alkylgua-
nine DNA alkyltransferase as a means to enhance chemo-
therapy. Cancer Treat Rev 2006;32(4):261 e 76.
17. Bapat A, Fishel ML, Georgiadis M, Kelley MR. Going ape as an
approach to cancer therapeutics. Antioxid Redox Signal 2009;
11(3):651 e 68.
18. Drew Y, Plummer R. The emerging potential of poly(ADP-
ribose) polymerase inhibitors in the treatment of breast cancer.
Curr Opin Obstet Gynecol 2010;22(1):67 e 71.
19. Lichtenberg J, Jacox E, Welch JD, Kurz K, Liang X, Yang MQ,
et al. Word-based characterization of promoters involved
in human DNA repair pathways. BMC Genomics 2009;
10(Suppl. 1):S18.
20. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D,
Lopez E, et al. Specific killing of BRCA2-deficient tumours with
inhibitors of poly(ADP-ribose) polymerase. Nature 2005;
434(7035):913 e 7.
21. Cipak L, Jantova S. PARP-1 inhibitors: a novel genetically
specific agents for cancer therapy. Neoplasma 2010;57(5):401 e 5.
22. Wicha MS. Development of "synthetic lethal" strategies to target
BRCA1-deficient breast cancer. Breast Cancer Res 2009;11(5):108.
23. Lord CJ, McDonald S, Swift S, Turner NC, Ashworth A. A high-
throughput RNA interference screen for DNA repair determi-
nants of PARP inhibitor sensitivity. DNA Repair (Amst) 2008;
7(12):2010 e 9.
24. Tse AN, Carvajal R, Schwartz GK. Targeting checkpoint kinase
1 in cancer therapeutics. Clin Cancer Res 2007;13(7):1955 e 60.
25. Wesierska-Gadek J, Maurer M, Zulehner N, Komina O.
Whether to target single or multiple CDKs for therapy? That is
the question. J Cell Physiol 2011;226(2):341 e 9.
26. Luo M, He H, Kelley MR, Georgiadis M. Redox regulation
of DNA repair: Implications for human health and cancer
therapeutic development. Antioxid Redox Signal 2010;12(11):
1247 e 69.
27. Hanawalt PC. Subpathways of nucleotide excision repair and
their regulation. Oncogene 2002;21(58):8949 e 56.
28. Fleck O, Nielsen O. DNA repair. J Cell Sci 2004;117(Pt 4):515 e 7.
29. Essers J, van Steeg H, de Wit J, Swagemakers SM, Vermeij M,
Hoeijmakers JH, et al. Homologous and non-homologous
recombination differentially affect DNA damage repair in mice.
EMBO J 2000;19(7):1703 e 10.
30. Astsaturov I, Ratushny V, Sukhanova A, Einarson MB,
Bagnyukova T, Zhou Y, et al. Synthetic lethal screen of an
EGFR-centered network to improve targeted therapies. Sci
Signal 2010;3(140). ra67.
31. American Cancer Society I. Cancer Facts & Figures 2010 . Atlanta:
American Cancer Society, Inc.; 2010.
32. American Cancer Society I. Cancer Facts & Figures 2009 . Atlanta:
American Cancer Society, Inc.; 2009.

-activated K

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Acknowledgments
Financial support for this work was provided by the National Insti-
tutes of Health, National Cancer Institute CA121168, CA114571, and
CA121168S1 to MRK. Additional financial support was provided by
the Riley Children's Foundation and the Earl and Betty Herr Professor
in Pediatric Oncology Research to MRK. Also, thanks to Lana Christian
of CreateWrite, Inc., for her writing and editing assistance.

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