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Anti-Cancer
Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Anti-Cancer Agents')
ISSN: 1871-5206
Anti-Cancer Agents in Medicinal
Chemistry
Volume 8, Number 4, May 2008
Contents
DNA Repair as a Target for Anti-Cancer Therapy
Guest Editor: Robert M. Brosh Jr.
Editorial Pp. 350
Targeting Base Excision Repair for Chemosensitization
Pp. 351-357
S. Adhikari, S. Choudhury, P.S. Mitra, J.J. Dubash, S.P. Sajankila
and R. Roy
[Abstract]
Polynucleotide Kinase as a Potential Target for
Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase
I Inhibitors Pp. 358-367
N.K. Bernstein, F. Karimi-Busheri, A. Rasouli-Nia, R.
Mani, G. Dianov, J.N.M. Glover and M. Weinfeld
[Abstract]
Role of Mismatch Repair and MGMT in Response
to Anticancer Therapies, 2008, 8, 368-380
I. Casorelli, M.T. Russo and M. Bignami
[Abstract]
Tyrosyl-DNA Phosphodiesterase as a Target for
Anticancer Therapy Pp. 381-389
T.S. Dexheimer, S. Antony, C. Marchand and Y. Pommier
[Abstract]
Helicases as Prospective Targets for
Anti-Cancer Therapy Pp. 390-401
R. Gupta and R.M. Brosh, Jr
[Abstract]
Targeting Poly (ADP) Ribose Polymerase I (PARP-1)
and PARP-1 Interacting Proteins for Cancer Treatment
Pp. 402-416
E.T. Sakamoto Hojo and A.S. Balajee
[Abstract]
DNA Repair Proteins as Molecular Targets for
Cancer Therapeutics Pp. 417-425
M.R. Kelley and M.L. Fishel
[Abstract]
BRCA-FA Pathway as a Target for Anti-Tumor Drugs
Pp. 426-430
R. Litman, R. Gupta, R.M. Brosh Jr. and S.B. Cantor
[Abstract]
Repair and Translesion DNA Polymerases as Anticancer
Drug Targets Pp. 431-447
G. Maga and U. Hübscher
[Abstract]
Therapeutic Exploitation of Tumor Cell Defects in
Homologous Recombination Pp. 448-460
S.N. Powell and L.A. Kachnic
[Abstract]
Abstracts
[Back to top]
Editorial
A number of human proteins have been characterized which have
important roles in pathways responsible for sensing, responding,
and repairing DNA damage. Collectively, these proteins are
referred to as DNA repair or DNA damage response proteins,
but their functions are specific in terms of pathways that
can be potentially manipulated to modulate the biological
response to a given cytotoxic agent. Selective inactivation
of a DNA repair pathway may enhance existing or developing
anti-cancer therapies. The scope of this Hot Topics series
will be to discuss DNA repair proteins that can be targeted
to improve cancer therapeutic approaches. A collection of
review articles is presented that provides a unique prospective
of discussing emerging concepts and strategies to fight cancer
through DNA repair inhibition. Treatment with anti-cancer
drugs such as small molecule compounds that modulate the expression
or activity of a DNA repair protein in specific DNA damage
response pathways is proposed to represent a viable approach
to selectively kill cancer cells exposed to DNA damaging chemotherapy
or radiation.
DNA repair proteins that may be suitable targets for fighting
cancer are diverse and involve steps of pathways from a variety
of DNA repair processes. An overview of DNA repair proteins
as molecular targets for cancer therapeutics and discussion
of results from experimental studies providing proof-of-concept
is addressed by Drs. M. Kelley and M. Fishel. Dr. M. Bignami
and colleagues discuss the role of mismatch repair and O6
-methylguanine-DNA-methyltransferase in the response
to anti-cancer therapies. Inhibition of specific base excision
repair proteins to improve the efficacy of current cheomotherapy
strategies is presented in the review by Dr. R. Roy and co-workers.
Drs. G. Maga and U. Hübscher present translesion DNA
polymerases as a novel target for anti-cancer drugs. Rationale
for the development of Tyrosyl-DNA phophosphodiesterase 1
inhibitors is offered by Dr. Y. Pommier and colleagues. Cancer
therapy mediated by polynucleotide kinase inhibitors is discussed
by Drs. J.N.M. Glover, M. Weinfeld and colleagues. Drs. A.S.
Balajee and E.T. Sakamoto Hojo review the prospect of targeting
Poly(ADP) ribose polymerase and interacting proteins for cancer
treatment. Dr. S. Cantor and colleagues evaluate the evidence
that the BRCA-FA pathway is a promising target for anti-tumor
drugs. Drs. S. Powell and L. Kachnic elaborate on the therapeutic
exploitation of tumor cell defects in homologous recombination.
Drs. R. Gupta and R. Brosh propose that helicase-dependent
DNA repair pathways represent a viable approach to kill cancer
cells. Collectively, this Hot Topics review series provides
a timely discussion of how DNA repair proteins engaged in
distinct pathways of DNA maintenance represent viable candidates
for improving the efficacy of anti-cancer therapies.
Robert M. Brosh, Jr., Ph. D.
Laboratory of Molecular Gerontology
National Institute on Aging, NIH
5600 Nathan Shock Drive
Baltimore, MD 21224
USA
Tel: 410-558-8578
Fax: 410-558-8157
E-mail: broshr@grc.nia.nih.gov
[Back to top]
Targeting Base Excision Repair for Chemosensitization
S. Adhikari, S. Choudhury, P.S. Mitra, J.J. Dubash, S.P. Sajankila
and R. Roy
In both bacteria and eukaryotes the alkylated, oxidized,
and deaminated bases and depurinated lesions are primarily
repaired via an endogenous preventive pathway, i.e.
base excision repair (BER). Radiation therapy and chemotherapy
are two important modes of cancer treatment. Many of those
therapeutic agents used in the clinic have the ability to
induce the DNA damage; however, they may also be highly cytotoxic,
causing peripheral toxicity and secondary cancer as adverse
side effects. In addition, the damage produced by the therapeutic
agents can often be repaired by the BER proteins, which in
effect confers therapeutic resistance. Efficient inhibition
of a particular BER protein(s) may increase the efficacy of
current chemotherapeutic regimes, which minimizes resistance
and ultimately decreases the possibility of the aforementioned
negative side effects. Therefore, pharmacological inhibition
of DNA damage repair pathways may be explored as a useful
strategy to enhance chemosensitivity. Various agents have
shown excellent results in preclinical studies in combination
chemotherapy. Early phase clinical trials are now being carried
out using DNA repair inhibitors targeting enzymes such as
PARP, DNA-PK or MGMT. In the case of BER proteins, elimination
of N-Methylpurine DNA glycosylase (MPG) or inhibition
of AP-endonuclease (APE) increased sensitivity of cancer cells
to alkylating chemotherapeutics. MPG -
/ - embryonic stem cells and cells having MPG
knock-down by siRNA are hypersensitive to alkylating agents,
whereas inhibition of APE by small molecule inhibitors sensitized
cancer cells to alkylating chemotherapeutics. Thus, MPG and
other BER proteins could be potential targets for chemosensitization.
[Back to top]
Polynucleotide Kinase as a Potential Target for Enhancing
Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors
N.K. Bernstein, F. Karimi-Busheri, A. Rasouli-Nia, R.
Mani, G. Dianov, J.N.M. Glover and M. Weinfeld
The cytotoxicity of many antineoplastic agents is due
to their capacity to damage DNA and there is evidence indicating
that DNA repair contributes to the cellular resistance to
such agents. DNA strand breaks constitute a significant proportion
of the lesions generated by a broad range of genotoxic agents,
either directly, or during the course of DNA repair. Strand
breaks that are caused by many agents including ionizing radiation,
topoisomerase I inhibitors, and DNA repair glycosylases such
as NEIL1 and NEIL2, often contain 5’-hydroxyl and/or
3’-phosphate termini. These ends must be converted to
5’-phosphate and 3’-hydroxyl termini in order
to allow DNA polymerases and ligases to catalyze repair synthesis
and strand rejoining. A key enzyme involved in this end-processing
is polynucleotide kinase (PNK), which possesses two enzyme
activities, a DNA 5’-kinase activity and a 3’-phosphatase
activity. PNK participates in the single-strand break repair
pathway and the non-homologous end joining pathway for double-strand
break repair. RNAi-mediated down-regulation of PNK renders
cells more sensitive to ionizing radiation and camptothecin,
a topoisomerase I inhibitor. Structural analysis of PNK revealed
the protein is composed of three domains, the kinase domain
at the C-terminus, the phosphatase domain in the centre and
a forkhead associated (FHA) domain at the N-terminus. The
FHA domain plays a critical role in the binding of PNK to
other DNA repair proteins. Thus each PNK domain may be a suitable
target for small molecule inhibition to effectively reduce
resistance to ionizing radiation and topoisomerase I inhibitors.
[Back to top]
Role of Mismatch Repair and MGMT in Response to Anticancer
Therapies
I. Casorelli, M.T. Russo and M. Bignami
Tumor resistance to cytotoxic chemotherapy drugs and
their toxicity to normal cells are major clinical obstacles
to anticancer therapy effectiveness. Alterations in various
DNA repair pathways play a key role in the development of
both mechanisms of drug resistance and toxicity. Since deregulation
of the DNA damage response and alterations in DNA repair pathways
are relatively common in human cancer, the knowledge of these
alterations in cancer cells would be an important predictive
factor for the clinical response to chemotherapy and a useful
guide in designing an appropriate therapeutic strategy.
This review is focused on the mismatch repair (MMR) pathway
and the O6 -methylguanine-DNA-methyltransferase
(MGMT) repair protein. In particular, we examine how inactivation
of these DNA repair mechanisms might affect the response of
tumor cells to chemotherapy, with a special emphasis on agents
inducing methylation and oxidative DNA damage and interstrand
DNA cross-links (ICLs). In addition, we provide novel experimental
evidence indicating that MMR is required for efficient repair
of ICLs via stabilization of RAD51 containing repair
intermediates. Finally, we discuss possible emerging therapeutical
strategies for treating MMR-defective tumors.
[Back to top]
Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy
T.S. Dexheimer, S. Antony, C. Marchand and Y. Pommier
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently
discovered enzyme that catalyzes the hydrolysis of 3’-phosphotyrosyl
bonds. Such linkages form in vivo following the DNA
processing activity of topoisomerase I (Top1). For this reason,
Tdp1 has been implicated in the repair of irreversible Top1-DNA
covalent complexes, which can be generated by either exogenous
or endogenous factors. Tdp1 has been regarded as a potential
therapeutic co-target of Top1 in that it seemingly counteracts
the effects of Top1 inhibitors, such as camptothecin and its
clinically used derivatives. Thus, by reducing the repair
of Top1-DNA lesions, Tdp1 inhibitors have the potential to
augment the anticancer activity of Top1 inhibitors provided
there is a presence of genetic abnormalities related to DNA
checkpoint and repair pathways. Human Tdp1 can also hydrolyze
other 3’-end DNA alterations including 3’-phosphoglycolates
and 3’-abasic sites indicating it may function as a
general 3’-DNA phosphodiesterase and repair enzyme.
The importance of Tdp1 in humans is highlighted by the observation
that a recessive mutation in the human TDP1 gene
is responsible for the inherited disorder, spinocerebellar
ataxia with axonal neuropathy (SCAN1). This review provides
a summary of the biochemical and cellular processes performed
by Tdp1 as well as the rationale behind the development of
Tdp1 inhibitors for anticancer therapy.
[Back to top]
Helicases as Prospective Targets for Anti-Cancer Therapy
R. Gupta and R.M. Brosh, Jr
It has been proposed that selective inactivation of a
DNA repair pathway may enhance anti-cancer therapies that
eliminate cancerous cells through the cytotoxic effects of
DNA damaging agents or radiation. Given the unique and critically
important roles of DNA helicases in the DNA damage response,
DNA repair, and maintenance of genomic stability, a number
of strategies currently being explored or in use to combat
cancer may be either mediated or enhanced through the modulation
of helicase function. The focus of this review will be to
examine the roles of helicases in DNA repair that might be
suitably targeted by cancer therapeutic approaches. Treatment
of cancers with anti-cancer drugs such as small molecule compounds
that modulate helicase expression or function is a viable
approach to selectively kill cancer cells through the inactivation
of helicase-dependent DNA repair pathways, particularly those
associated with DNA recombination, replication restart, and
cell cycle checkpoint.
[Back to top]
Targeting Poly (ADP) Ribose Polymerase I (PARP-1) and PARP-1
Interacting Proteins for Cancer Treatment
E.T. Sakamoto Hojo and A.S. Balajee
Cancer is a disease of uncontrolled cellular proliferation.
Chemotherapy and radiation therapy are the two main modalities
for cancer treatment. However, some cancer types have been
found to be refractory to these treatments. Additionally,
certain chemicals that are used in clinical trials produce
high cytotoxicity as a secondary effect. Hence, current research
is focused on finding ways by which cancer cells can be specifically
sensitized to apoptotic death with minimal or no secondary
effects on normal healthy cells. Since the resistance of cancer
cells to DNA damaging agents stems from the modulation of
DNA repair pathways, pharmacological inhibition of these pathways
has been emerging as an effective tool for cancer treatment.
Inhibition of key proteins involved in the molecular cascade
of DNA damage detection and repair such as poly (ADP) ribose
polymerase I (PARP-1) and its interacting proteins [DNA dependent
protein kinase (DNA-PK) and Cockayne syndrome group B (CSB)]
has recently proven to be successful for the treatment of
various types of cancer cells and tumor xenografts in
vitro. This review summarizes some of the recent findings
and the potential application of DNA repair inhibitors in
cancer treatment.
[Back to top]
DNA Repair Proteins as Molecular Targets for Cancer Therapeutics
M.R. Kelley and M.L. Fishel
Cancer therapeutics include an ever-increasing array
of tools at the disposal of clinicians in their treatment
of this disease. However, cancer is a tough opponent in this
battle and current treatments which typically include radiotherapy,
chemotherapy and surgery are not often enough to rid the patient
of his or her cancer. Cancer cells can become resistant to
the treatments directed at them and overcoming this drug resistance
is an important research focus. Additionally, increasing discussion
and research is centering on targeted and individualized therapy.
While a number of approaches have undergone intensive and
close scrutiny as potential approaches to treat and kill cancer
(signaling pathways, multidrug resistance, cell cycle checkpoints,
anti-angiogenesis, etc.), much less work has focused on blocking
the ability of a cancer cell to recognize and repair the damaged
DNA which primarily results from the front line cancer treatments;
chemotherapy and radiation. More recent studies on a number
of DNA repair targets have produced proof-of-concept results
showing that selective targeting of these DNA repair enzymes
has the potential to enhance and augment the currently used
chemotherapeutic agents and radiation as well as overcoming
drug resistance. Some of the targets identified result in
the development of effective single-agent anti-tumor molecules.
While it is inherently convoluted to think that inhibiting
DNA repair processes would be a likely approach to kill cancer
cells, careful identification of specific DNA repair proteins
is increasingly appearing to be a viable approach in the cancer
therapeutic cache.
[Back to top]
BRCA-FA Pathway as a Target for Anti-Tumor Drugs
R. Litman, R. Gupta, R.M. Brosh Jr. and S.B. Cantor
Promising research on DNA repair signaling pathways predicts
a new age of anti-tumor drugs. This research was initiated
through the discovery and characterization of proteins that
functioned together in signaling pathways to sense, respond,
and repair DNA damage. It was realized that tumor cells often
lacked distinct DNA repair pathways, but simultaneously relied
heavily on compensating pathways. More recently, researchers
have begun to manipulate these compensating pathways to reign
in and kill tumor cells. In a striking example it was shown
that tumors derived from mutations in the DNA repair genes,
of BRCA-FA pathway, were selectively sensitive to inhibition
of the base excision repair pathway. These findings suggest
that tumors derived from defects in DNA repair genes will
be easier to treat clinically, providing a streamlined and
targeted therapy that spares healthy cells. In the future,
identifying patients with susceptible tumors and discovering
additional DNA repair targets amenable to anti-tumor drugs
will have a major impact on the course of cancer treatment.
[Back to top]
Repair and Translesion DNA Polymerases as Anticancer Drug
Targets
G. Maga and U. Hübscher
We have very recently highlighted possible connections
between DNA polymerases, the main enzymes in the DNA metabolism,
and human diseases (Ramadan, K., Maga, G. and Hübscher,
U.: DNA polymerases and diseases, In: Genome Integrity:
Facets and Perspectives ed. Lankenau, D.-H. Springer
Verlag, Heidelberg Germany, Vol 1, pp. 69-102, 2007). Beside
a role in DNA replication of the genome DNA polymerases have
fundamental functions in other aspect of DNA metabolism, such
as DNA repair, DNA recombination, translesion DNA synthesis
and cell cycle checkpoint. In the last decade many novel DNA
polymerases have been identified, but their exact cellular
functions still await clarification. We know that many DNA
polymerases have redundant functions. It is a fact that specific
inhibition of certain DNA polymerases is a promising approach
to develop anticancer drugs. In this review we will concentrate
on DNA repair proteins and translesion DNA polymerases as
possible targets for anti cancer drugs.
[Back to top]
Therapeutic Exploitation of Tumor Cell Defects in Homologous
Recombination
S.N. Powell and L.A. Kachnic
In the decade since the BRCA1 and BRCA2 genes were cloned,
much has been learned about the function of these two major
causes of familial breast cancer. BRCA2 has been shown to
play a direct role in the repair of DNA by homologous recombination,
by interacting with the Rad51 protein and facilitating the
formation of Rad51 aggregates at the site of DNA damage. It
likely plays a similar role when double strand breaks are
created in the course of normal DNA replication; the absence
of BRCA2 results in chromosomal instability, which is likely
secondary to the defect in DNA repair. In the absence of BRCA2,
the cell is more dependent on residual repair via
Rad52, which makes Rad52 a target for therapy in BRCA-deficient
tumors.
BRCA1 plays a role in sensing DNA damage and replication stress
and mediating the signaling responses. Therefore, in addition
to its role in mediating DNA repair by homologous recombination
via BRCA2, it can also signal cell cycle checkpoints
and mediate other transcriptional responses to DNA damage.
We have argued that the mechanism of cancer susceptibility
from BRCA1 or BRCA2 deficiency is mediated via the
defect in homologous recombination, since it is the main feature
they share in common. We and others have recently demonstrated
that the defect in homologous recombination changes the drug
sensitivity profile, rendering the BRCA-deficient breast cancers
sensitive to MitomycinC, cisplatin, etoposide and other drugs
that produce complex double-stranded lesions in DNA. Furthermore,
they show resistance to taxanes and navelbine. Fanconi anemia
defective cells also show sensitivity to the same class of
drugs, although their defect in homologous recombination in
response to strand breaks appears less marked than in BRCA-deficient
cells. However, Fanconi anemia cells also show chromosomal
fragility, and appear to have defects in maintenance of the
replication fork.
Therefore, knowledge of whether this specific DNA repair pathway
of homologous recombination is defective in breast cancer
cells would be valuable information in planning optimized
individual therapy. We have developed techniques to measure
the functional integrity of homologous recombination in human
breast cancers. Core biopsy samples are obtained and immediately
irradiated ex vivo, allowing 3-4 hours for the appearance
of Rad51, BRCA1 and FancD2 foci. Thin sections are obtained,
permeabilized and stained by immunofluorescent techniques.
We have identified tumors with defects in the ability to form
Rad51 and BRCA1 foci, where there is no known genetic predisposition,
implying that this BRCA-dependent repair pathway may be inactivated
in sporadic as well as familial breast cancers. Thus, functional
assays of homologous recombination could become a useful technique
to determine phenotype of human breast cancer, which in turn
will influence the choice of therapy.
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