Recombinant human interferon beta ser protects against zidovudine-induced genetic damage in AIDS patients

Shafik, Hasnaa M.; Nokta, Mostafa; Pollard, Richard B.

doi:10.1016/0166-3542(91)90026-n

Cited by 24 publications

(15 citation statements)

References 18 publications

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“…Mitochondrial damage has been reported in humans [Lewis et al, 2001;. Also reported were significantly increased frequencies of chromosomal aberrations (>8%) in lymphocytes of AIDS patients receiving AZT therapy compared with AIDS patients not receiving AZT [Shafik et al, 1991].…”

Section: Introductionmentioning

confidence: 93%

Genetic alterations in K‐ras and p53 cancer genes in lung neoplasms from Swiss (CD‐1) male mice exposed transplacentally to AZT

Hong

Dunnick

Herbert

et al. 2007

Environ and Mol Mutagen

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A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg of 3'-azido-3'-deoxythymidine (AZT)/kg bw/day, through a 18 to 19-day gestation [National Toxicology Program, NIH Pub. No. 04-4458, 2004]. The incidences of alveolar/bronchiolar adenomas and carcinomas, in the 200 and 300 mg/kg male treatment groups, were significantly greater than that of the controls. In the present study, we evaluated the benign and malignant lung neoplasms from this bioassay for point mutations, in the K-ras and p53 cancer genes that are often mutated in human lung tumors. K-ras and p53 mutations were detected by cycle sequencing of polymerase chain reaction-amplified DNA, isolated from formalin-fixed, paraffin-embedded neoplasms. K-ras mutations were detected in 25 of 38 (66%) of the AZT-induced lung tumors, and the predominant mutations were codon 12 G-->T transversions. p53 mutations were detected in 32 of 38 (84%) of the AZT-induced lung tumors, with the predominant mutations being exon 8, codon 285 A-->T transversions, and exon 6, codon 198 T-->A transversions. No K-ras or p53 mutations were detected in five tumors, examined from control mice. The patterns of mutations identified in the lung tumors suggest that incorporation of AZT or its metabolites into DNA, oxidative stress, and genomic instability may be the contributing factors to the mutation profile and development of lung cancer in these mice.

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Section: Introductionmentioning

confidence: 93%

Genetic alterations in K‐ras and p53 cancer genes in lung neoplasms from Swiss (CD‐1) male mice exposed transplacentally to AZT

Hong

Dunnick

Herbert

et al. 2007

Environ and Mol Mutagen

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“…Published studies of the genotoxic effects of AZT support the concept that the predicted strand termination that occurs when AZT is incorporated into DNA produces both largescale DNA damage (chromosomal aberrations, sister chromatid exchanges, and large deletions) and point mutations. For example, the frequency of chromosomal aberrations in the lymphocytes of seven AIDS patients receiving AZT therapy was 8 ± 2%, compared with 0.5 ± 0.3% in four patients not receiving AZT, a value similar to that seen in healthy controls [34]. In addition, dose-related increases in chromosomal aberrations were seen in the bone marrow of mice given AZT in drinking water for 28 d [6].…”

Section: Discussionmentioning

confidence: 99%

Skin tumorigenesis and Ki-ras and Ha-ras mutations in tumors from adult mice exposed in utero to 3′-azido-2′,3′-dideoxythymidine

et al. 1998

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This study was designed to evaluate the potential initiating effects of transplacental 3'-azido-2',3'-dideoxythymine (AZT) and the role of ras mutational activation in skin tumors induced in a two-stage mouse skin model. In addition, mouse liver and lung tumors from a transplacental AZT tumorigenicity study reported elsewhere (Olivero et al., J Natl Cancer Inst 89:1602-1608, 1997) were examined for evidence of ras activation. For both tumor studies, pregnant CD-1 mice were given either vehicle or 25 mg of AZT daily on days 12-18 of gestation. In the 1997 study, the offspring were given no further exposure and were killed at 1 yr of age. For the skin tumor study, all mice received twice-weekly topical 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment from weeks 5-35; half of the mice had been exposed to AZT in utero. At weeks 16-18, 30, 31, and 34-41, the skin tumor incidences in mice given AZT and TPA were significantly higher than in mice given TPA alone (P < or = 0.05). At week 41, the average numbers of tumors per mouse were 1.44+/-0.36 (mean +/- standard error of the mean) and 0.57+/-0.13 for mice given AZT plus TPA and TPA alone, respectively (P = 0.006). Mutagenesis in ras exons I and II was determined by polymerase chain reaction (PCR) and dye-terminator cycling sequencing of PCR products. Ha-ras exon I codons 12 and 13 were mutated in 11 of 19 tumors (58%) from mice given AZT and TPA and in one of 15 tumors (7%) from mice given TPA alone (P= 0.004). The only mutation in Ha-ras codon 12 (four in four tumors examined) was a G-->A transition in the second base, and the major mutation in codon 13 (six in seven tumors examined) was a G-->T transversion in the second base. In skin tumors, AZT exposure did not increase the number of Ha-ras codon 61 mutations, and no Ki-ras mutations were observed. Analysis of ras mutations in liver and lung tumors from mice exposed to AZT in utero (Olivero et al., J Natl Cancer Inst 89:16021608, 1997) with no TPA promotion showed no significant AZT-related increases.

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“…Les INTI peuvent être incorporés dans l'ADN [92][93][94][95][96][97]. Ainsi a été rapportée chez l'humain une incorporation d'AZT dans l'ADN des lymphocytes du sang du cordon chez le nouveau-né ainsi que chez des adultes traités par l'AZT [93,94].…”

Section: Effets Des Inti Sur L'adn Génomiqueunclassified

“…Par ailleurs, chez le singe, une incorporation de l'AZT au sein de l'ADN du testicule foetal a été rapportée lorsque la mère est exposée à cette substance [97]. Des effets génotoxiques secondaires à l'incorporation ont été décrits in vitro ou in vivo chez l'animal comme l'induction de micro-noyaux, des échanges chromatiniens et des aberrations chromosomiques [92,98,99].…”

Section: Effets Des Inti Sur L'adn Génomiqueunclassified

“…Chez l'homme traité par l'AZT (< 12 mois), une étude a montré une augmentation des aberrations chromosomiques lymphocytaires chez sept patients comparés à quatre patients non traités [92]. Bien que des concentrations efficaces de certains INTI dans le plasma séminal parfois supérieures à celle du plasma sanguin aient été rapportées [100], une seule étude sur le génome du spermatozoïde de patients sous thé-rapie INTI incluant au moins un analogue nucléosidique a été publiée [101].…”

Section: Effets Des Inti Sur L'adn Génomiqueunclassified

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Impact des inhibiteurs nucléosidiques de la transcriptase inverse sur l’ADN mitochondrial et génomique des spermatozoïdes lors de l’Assistance Médicale à la Procréation

Sergerie

Martinet

Kiffer

et al. 2004

Gynécologie Obstétrique & Fertilité

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Recombinant human interferon beta ser protects against zidovudine-induced genetic damage in AIDS patients

Cited by 24 publications

References 18 publications

Genetic alterations in K‐ras and p53 cancer genes in lung neoplasms from Swiss (CD‐1) male mice exposed transplacentally to AZT

Genetic alterations in K‐ras and p53 cancer genes in lung neoplasms from Swiss (CD‐1) male mice exposed transplacentally to AZT

Skin tumorigenesis and Ki-ras and Ha-ras mutations in tumors from adult mice exposed in utero to 3′-azido-2′,3′-dideoxythymidine

Impact des inhibiteurs nucléosidiques de la transcriptase inverse sur l’ADN mitochondrial et génomique des spermatozoïdes lors de l’Assistance Médicale à la Procréation

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