• Carcinogenesis 2001 Nov;22(11):1893

 
Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes.

Frosina G.

DNA Repair Unit, Mutagenesis Laboratory, Istituto Nazionale Ricerca Cancro, Largo Rosanna Benzi no. 10, 16132 Genova, Italy. gfrosina@hp380.ist.unige.it

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DNA damage of endogenous origin may significantly contribute to human cancer.

A major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER).

BER is rather efficient in human cells but a certain amount of endogenous damage inevitably escapes mending and likely contributes to human carcinogenesis.

Apart from some glycosylases that are particularly sluggish (e.g. 8-oxoG DNA glycosylase), recent work suggests that the general rate-limiting steps of BER may be trimming of 2-deoxyribose 5-phosphate in case the process is started by a monofunctional glycosylase or trimming of a 3'-blocking fragment, in case BER is started by a bifunctional glycosylase or in the case of single-strand breaks produced by free radical attack. Overexpression of the 5'-deoxyribophosphodiesterase (dRPase) domain of DNA polymerase beta, on the one hand, and of yeast APN1 protein, containing an efficient 3' repair activity, on the other, may lead to improved BER in mammals.

The recently characterized S3 protein of Drosophila, containing both dRPase and 3'-trimming activities, could also be considered for overexpression studies. The possible protecting role of enhanced BER could be investigated in cultured rodent embryonic fibroblasts undergoing spontaneous transformation, a most interesting system that merits rediscovery.

Publication Types:

• Review

• Review, Tutorial

PMID: 11532852 [PubMed - indexed for MEDLINE]

Burcham PC.

Department of Clinical and Experimental Pharmacology, The University of Adelaide, Adelaide, SA 5005, Australia. pburcham@medicine.adelaide.edu.au

Recent improvements in the ability to detect chemically modified bases in DNA have revealed that not only does the genetic material incur damage by foreign chemicals, but that it also sustains injury by reactive products of normal physiological processes. This review summarises current understanding of the DNA-damaging potential of various substances of endogenous origin, including oxidants, lipid peroxidation products, alkylating agents, estrogens, chlorinating agents, reactive nitrogen species, and certain intermediates of various metabolic pathways. The strengths and weaknesses of the existing database for DNA damage by each class of substance are discussed, as are future strategies for resolving the difficult question of whether endogenous chemicals are significant contributors to spontaneous mutagenesis and cancer development in vivo. Copyright 1999 Elsevier Science B.V.

Publication Types:

• Review

• Review, Academic

PMID: 10415429 [PubMed - indexed for MEDLINE]

The role of free radicals in disease.

Florence TM.

Centre for Environmental and Health Science Pty Ltd, Sydney, NSW.

Evidence is accumulating that most of the degenerative diseases that afflict humanity have their origin in deleterious free radical reactions.

These diseases include atherosclerosis, cancer, inflammatory joint disease, asthma, diabetes, senile dementia and degenerative eye disease.

The process of biological ageing might also have a free radical basis.

Most free radical damage to cells involves oxygen free radicals or, more generally, activated oxygen species (AOS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals. The AOS can damage genetic material, cause lipid peroxidation in cell membranes, and inactivate membrane-bound enzymes.

Humans are well endowed with antioxidant defences against AOS; these antioxidants, or free radical scavengers, include ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), beta-carotene, coenzyme Q10, enzymes such as catalase and superoxide dismutase, and trace elements including selenium and zinc.

The eye is an organ with intense AOS activity, and it requires high levels of antioxidants to protect its unsaturated fatty acids.

The human species is not genetically adapted to survive past middle age, and it appears that antioxidant supplementation of our diet is needed to ensure a more healthy elderly population.

Publication Types:

• Review

• Review, Tutorial

PMID: 7619452 [PubMed - indexed for MEDLINE]

Free radicals and antioxidants in food and in vivo: what they do and how they work.

Halliwell B, Murcia MA, Chirico S, Aruoma OI.

Pharmacology Group, University of London Kings College, UK.

A wide variety of oxygen free radicals and other reactive oxygen species can be formed in the human body and in food systems.

Transition metal ions accelerate free-radical damage.

Antioxidant defenses, both enzymic and nonenzymic, protect the body against oxidative damage, but they are not 100% efficient, and so free-radical damage must be constantly repaired.

Nonenzymatic antioxidants are frequently added to foods to prevent lipid peroxidation. Several lipid antioxidants can exert prooxidant effects toward other molecules under certain circumstances, and so antioxidants for food and therapeutic use must be characterized carefully.

Methods of measuring oxidative damage and trapping free radicals in vivo are briefly discussed. Such methods are essential in checking proposals that increased intake of food-derived antioxidants (such as antioxidant vitamins) would be beneficial to humans.

Publication Types:

• Review

• Review, Tutorial

PMID: 7748482 [PubMed - indexed for MEDLINE]

Intracellular antioxidants: from chemical to biochemical mechanisms.

Chaudiere J, Ferrari-Iliou R.

UFR de Biologie, Universite Paris 7, France.

Intracellular antioxidants include low molecular weight scavengers of oxidizing species, and enzymes which degrade superoxide and hydroperoxides.

Such antioxidants systems prevent the uncontrolled formation of free radicals and activated oxygen species, or inhibit their reactions with biological structures. Hydrophilic scavengers are found in cytosolic, mitochondrial and nuclear compartments.

Ascorbate and glutathione scavenge oxidizing free radicals in water by means of one-electron or hydrogen atom transfer.

Similarly, ergothioneine scavenges hydroxyl radicals at very high rates, but it acts more specifically as a chemical scavenger of hypervalent ferryl complexes, halogenated oxidants and peroxynitrite-derived nitrating species, and as a physical quencher of singlet oxygen. Hydrophobic scavengers are found in cell membranes where they inhibit or interrupt chain reactions of lipid peroxidation.

In animal cells, they include alpha-tocopherol (vitamin E) which is a primary scavenger of lipid peroxyl radicals, and carotenoids which are secondary scavengers of free radicals as well as physical quenchers of singlet oxygen.

The main antioxidant enzymes include dismutases such as superoxide dismutases (SOD) and catalases, which do not consume cofactors, and peroxidases such as selenium-dependent glutathione peroxidases (GPx) in animals or ascorbate peroxidases (APx) in plants. The reducing coenzymes of peroxidases, and as a rule all reducing components of the antioxidant network, are regenerated at the expense of NAD(P)H produced in specific metabolic pathways. Synergistic and co-operative interactions of antioxidants rely on the sequential degradation of peroxides and free radicals as well as on mutual protections of enzymes.

This antioxidant network can induce metabolic deviations and plays an important role in the regulation of protein expression and/or activity at the transcriptional or post-translational levels. Its biological significance is discussed in terms of environmental adaptations and functional regulations of aerobic cells.

Publication Types:

• Review

• Review, Tutorial

PMID: 10541450 [PubMed - indexed for MEDLINE]

The role of iron in cancer.

Weinberg ED.

Department of Biology, Indiana University, Bloomington 47405, USA.

Numerous laboratory and clinical investigations over the past few decades have observed that one of the dangers of iron is its ability to favour neoplastic cell growth.

The metal is carcinogenic due to its catalytic effect on the formation of hydroxyl radicals, suppression of the activity of host defence cells and promotion of cancer cell multiplication.

In both animals and humans, primary neoplasms develop at body sites of excessive iron deposits. The invaded host attempts to withhold iron from the cancer cells via sequestration of the metal in newly formed ferritin. The host also endeavours to withdraw the metal from cancer cells via macrophage synthesis of nitric oxide. Quantitative evaluation of body iron and of iron-withholding proteins has prognostic value in cancer patients.

Procedures associated with lowering host iron intake and inducing host cell iron efflux can assist in prevention and management of neoplastic diseases.

Pharmaceutical methods for depriving neoplastic cells of iron are being developed in experimental and clinical protocols.

Publication Types:

• Review

• Review, Tutorial

PMID: 8664805 [PubMed - indexed for MEDLINE]