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  • Review Article
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DNA and its associated processes as targets for cancer therapy

Nature Reviews Cancer volume 2, pages 188–200 (2002)Cite this article

Key Points

  • DNA is the molecular target for many anticancer drugs.

  • Alkylating agents generally interact non-specifically with DNA: the more effective ones tend to crosslink DNA.

  • Antitumour antibiotics tend to be more specific in their interactions with DNA and are most often associated with modest sequence selectivity and targeting protein–DNA complexes.

  • Code-reading molecules target either the major or minor groove of DNA and can read 1–2 turns of the helix. Polyamides target the minor groove, and triplex-forming molecules target the major groove.

  • The efficacy of the small molecules that react with DNA is more dependent on their effect on DNA structure than on their sequence selectivity.

  • Secondary DNA structures, such as G-quadruplex structures, represent a new class of molecular targets for DNA-interactive compounds that might be useful for targeting telomeres and transcriptional control.

  • There is good reason to expect DNA to be a clinically important target for many years to come. More selective and less toxic compounds are in preparation and strategies to use the newer agents that target molecular receptors, in combination with DNA-reactive drugs, will maintain interest in DNA as a molecular target.

Abstract

DNA is the molecular target for many of the drugs that are used in cancer therapeutics, and is viewed as a non-specific target of cytotoxic agents. Although this is true for traditional chemotherapeutics, other agents that were discovered more recently have shown enhanced efficacy. Furthermore, a new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective. How have these agents evolved, and what are their molecular targets?

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Figure 1: Classes of DNA-interactive agents and their molecular interactions with DNA.
Figure 2: Transcription can be targeted by DNA-interactive drugs.
Figure 3: Direct versus indirect readout for sequence-specific recognition of DNA.
Figure 4: Arg–Pro–Arg (RPR) polyamides target the minor groove.
Figure 5: Mechanisms of triplex-mediated interference with DNA information processing.
Figure 6: G-quadruplex structures.

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Acknowledgements

I thank D. M. Bishop for preparing, proofreading and editing the text and for helping to create the figures. L. H. H. is supported by grants from the National Cancer Institute, the National Foundation for Cancer Research and the Arizona Disease Control Research Commission.

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Authors and Affiliations

  1. College of Pharmacy, The University of Arizona, 1703 East Mabel, Tucson, 85721, Arizona, USA

    Laurence H. Hurley

  2. Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, 85724, Arizona, USA

    Laurence H. Hurley

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DATABASES

CancerNet:

chronic myelogenous leukaemia

non-Hodgkin's lymphoma

testicular cancer

 LocusLink:

ABL

BCL2

CNBP

c-FOS

hnRNP

HPRT

MDR1

c-MYB

c-MYC

NF-Y

RAF

RAP1

RAS

topoisomerase I

topoisomerase II

tubulin

 Medscape DrugInfo:

Bleomycin

chlorambucil

cisplatin

doxorubicin

etoposide

Gleevec

mitoxantrone

temozolomide

topotecan

 Saccharomyces Genome Database:

Sgs1

Glossary

ALKYLATION

The replacement of hydrogen on an atom by an alkyl group. The alkylation of nucleic acids involves a substitution reaction in which a nucleophilic atom (nu) of the nucleic acid displaces a leaving group from the alkylating agent: nu-H + alkyl-Y → alkyl-nu + H+ + Y−.

MYELOSUPPRESSION

A decrease in the ability of the bone-marrow cells to produce blood cells, including red blood cells, white blood cells and platelets.

INTERCALATION

Insertion of a flat aromatic molecule between adjacent base pairs of the double helix.

NUCLEOTIDE EXCISION REPAIR

(NER). A process carried out by mammalian cells that involves the recognition, removal and resynthesis of the restored DNA following DNA damage by bulky lesions.

TC-NER

Preferential removal of lesions from the DNA strands in genes that are actively transcribed by RNA polymerase II.

XPG

XPG encodes an endonuclease that is involved in nucleotide excision repair (NER) and transcription-coupled NER. It cuts the damaged DNA strand 3′ to sites of damage.

I-MOTIF

A tetrameric DNA structure with protonated cytosine–cytosine base pairs.

PHARMACODYNAMICS

The study of the biochemical and physiological effects of drugs and their mechanisms of action.

PHARMACOKINETICS

The study of the time course of a drug and its metabolites in the body after administration by any route.

MATRIX-ATTACHMENT REGION

AT-rich sequence of DNA that binds to a proteinaceous nuclear scaffold called the nuclear matrix.

AT-RICH SATELLITES

AT-rich satellite DNA is simple sequence DNA that is made up largely of AT base pairs in short repetitive sequences.

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Hurley, L. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2, 188–200 (2002). https://doi.org/10.1038/nrc749

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