Induction, repair and biological relevance of radiation-induced DNA lesions in eukaryotic cells

Frankenberg-Schwager, M.

doi:10.1007/bf01210408

Cited by 202 publications

(73 citation statements)

References 130 publications

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“…Thus, our data support our previously reported notion that that transgenerational instability is not attributable to specific subset of DNA lesions, such as double-strand DNA breaks, but rather is triggered by generalized DNA damage in male germ cells (10). Indeed, irradiation results in a wide spectrum of DNA lesions, ranging from base damage to double-strand DNA breaks (19), whereas exposure to ethylnitrosourea mainly causes alkylation of DNA (20). This also holds true for exposure to the anticancer drugs analyzed in the present study.…”

Section: Discussionsupporting

confidence: 80%

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Glen

Dubrova

2012

Proc. Natl. Acad. Sci. U.S.A.

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The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy.epigenetic | genetic risk

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Section: Discussionsupporting

confidence: 80%

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Glen

Dubrova

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Radiation-induced cell kill is related to DNA double-strand breaks (Frankenberg-Schwager, 1990). Several ways of interaction between both treatments may occur on the DNA level.…”

Section: Discussionmentioning

confidence: 99%

Carboplatin- and cisplatin-induced potentiation of moderate-dose radiation cytotoxicity in human lung cancer cell lines

Groen¹,

Sleijfer²,

Meijer³

et al. 1995

Br J Cancer

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Summary The interaction between moderate-dose radiation and cisplatin or carboplatin was studied in a cisplatin-sensitive (GLC4) and -resistant (GLC4-CDDP) human small-cell lung cancer cell line. Cellular toxicity was analysed under oxic conditions with the microculture tetrazolium assay. For the platinum and radiation toxicity with the clinically relevant dose ranges applied, this assay was used to obtain information on cell survival after the treatments. Apart from effects on cell survival effects on DNA were also investigated. Configurational DNA changes could be induced by platinum drugs and thereby these drugs might change the frequency of DNA double-strand breaks (dsbs). DNA fragmentation assayed with the clamped homogeneous electric field (CHEF) technique was used as a measure for dsbs in DNA. The radiosensitising effect of the platinum drugs was expressed as enhancement ratio (ER) calculated directly from survival levels of the initial slope of the curve. The highest ER for cisplatin in GLC4 was 1.39 and in GLC4-CDDP 1.38. These were all at 75% cell survival. Carboplatin showed increased enhancement with prolonged incubation up to 1.21 in GLC4 and was equally effective as cisplatin in GLC4-CDDP. According to isobologram analysis, prolonged incubation with both platinum drugs showed at least additivity with radiation for both cell lines at clinically achievable doses. GLC4-CDDP showed cross-resistance to radiation. The radiosensitising capacity of both lung cancer cell lines was not dependent on their platinum sensitivity.

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“…To test this, here we have analysed the effects of paternal exposure to the alkylating agent ethylnitrosourea (ENU) on the manifestation of genomic instability in the offspring of treated male mice. In contrast to irradiation which produces a wide spectrum of DNA lesions [Frankenberg-Schwager, 1990], exposure to ENU mainly causes alkylation of DNA at the Nand O-positions, resulting predominantly in base substitution mutations [Shibuya and Morimoto, 1993]. ENU can also induce DNA lesions attributable to either fragile alkali-labile sites [Friedberg et al, 2006] or the conversion of alkylation-induced DNA damage into double-strand breaks during DNA replication [Galli and Schiestl, 1999].…”

Section: Introductionmentioning

confidence: 99%

Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

Dubrova

Hickenbotham

Glen

et al. 2008

Environ and Mol Mutagen

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Recent data show that the effects of ionising radiation are not restricted to the directly exposed parental germ cells, but can also manifest in their non-exposed offspring, resulting in elevated mutation rates and cancer predisposition. The mechanisms underlying these transgenerational changes remain poorly understood. One of the most important steps in elucidating these mechanisms is to investigate the initial cellular events that trigger genomic instability. Here we have analysed the effects of paternal treatment by ethylnitrosourea, an alkylating agent which is known to form specific types of DNA adducts, on the transgenerational effects in the first-generation (F 1 ) offspring of exposed CBA/Ca and BALB/c male mice. Mutation rates at two expanded simple tandem repeat loci were significantly elevated in the F 1 germline of both strains. Pre-and post-meiotic exposures resulted in similar increases in mutation rate in the F 1 germline. Within each strain mutation rates were equally elevated in the germline of male and female F 1 offspring of the directly exposed males. The results of our study suggest that transgenerational instability is not attributed to a specific sub-set of DNA lesions, such as double strand breaks, and is most probably triggered by a stress-like response to a generalised DNA damage.2

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Induction, repair and biological relevance of radiation-induced DNA lesions in eukaryotic cells

Cited by 202 publications

References 130 publications

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Carboplatin- and cisplatin-induced potentiation of moderate-dose radiation cytotoxicity in human lung cancer cell lines

Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

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