Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells

Arnaudeau, Catherine; Miranda, Erika Tenorio; Jenssen, Dag; Helleday, Thomas

doi:10.1016/s0921-8777(00)00052-5

Cited by 51 publications

(35 citation statements)

References 33 publications

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“…Chemical compounds, such as cisplatin and cytosine arabinoside, previously described as recombinogenic in mammalian cells, were also classified as recombinogenic in the A. nidulans diploid strain (Beaula Helen and Subramanyan, 1991;Arnaudeau et al, 2000;Miyamoto et al, 2007). Since mitotic HR may trigger neoplasms, this study highlights the need for further investigation of the genotoxic potential of IMD in mammalian cells, especially due to the long elimination time of IMD from milk and animal tissues, which may pose a food risk to humans.…”

Section: Discussionmentioning

confidence: 72%

“…According to Knudson's hypothesis (1993), the heterozygous state of a mutationbearing cell ("first hit") could be lost when it is exposed to cancer-promoting events ("second hit"). Chemical compounds may act as tumor promoter agents in heterozygous cells of a defective tumor suppression gene through the induction of somatic HR, a process involved in the repair of naturally occurring DNA injuries arising during the S phase of the cell cycle (Knudson, 1993;Arnaudeau et al, 2000;Helleday, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Since the information on genotoxic effects of IMD is scarce and since the carcinogenic potential of a chemical compound may be assessed through its effect on homologous recombination as well (Arnaudeau et al, 2000;Miyamoto et al, 2007;de Castro-Prado et al, 2009;Franco et al, 2010), this study aimed to investigate whether IMD is recombinogenic in Aspergillus nidulans diploid cells and capable of inducing the homozygosity of genes previously present in the heterozygous condition.…”

Section: Introductionmentioning

confidence: 99%

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Induced mitotic homologous recombination by the babesicide imidocarb dipropionate in Aspergillus nidulans diploid cells

Santos

Sant’Anna²,

Franco³

et al. 2012

Genet. Mol. Res.

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ABSTRACT. Imidocarb dipropionate (IMD) is a chemotherapeutic agent prescribed for the treatment and control of babesiosis; it is known to be a nucleic acid synthesis inhibitor. Although it is an effective babesicide, there are reports of persistent IMD residues retained at high levels in edible tissues of cattle, swine and sheep, raising concerns about potential effects on humans. Since the carcinogenic potential of a chemical compound can be assessed through its effect on the homologous recombination, we investigated whether IMD is recombinogenic in Aspergillus nidulans diploid cells and whether it is capable of inducing homozygosis in genes that were previously heterozygous. This analysis was done with a homozygotization assay applied to a heterozygous diploid strain of A. nidulans. IMD used at non-toxic concentrations (2.5 to 10.0 μM) was recombinogenic, demonstrated by homozygotization indices higher than 2.0 for diploid markers. A diploid homozygous for genetic markers from chromosomes I and II was also produced. Since DNA replication blockers that induce DNA strand breaks have been classified as potent inducers of homologous recombination, Genotoxicity of imidocarb in Aspergillus nidulansthe recombinogenic potential of IMD may be due to induction of recombinational repair.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Induced mitotic homologous recombination by the babesicide imidocarb dipropionate in Aspergillus nidulans diploid cells

Santos

Sant’Anna²,

Franco³

et al. 2012

Genet. Mol. Res.

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“…Further, the excessive recombination might contribute to the loss of heterozygosity that leads to the cocarcinogenic property of vanillin. 30 Apoptosis gene NFjB was not affected by vanillin introduction (Fig. 2), whereas p21, cyclin B, and p53 were affected by vanillin administration.…”

Section: Figmentioning

confidence: 91%

Vanillin Differentially Affects Azoxymethane-Injected Rat Colon Carcinogenesis and Gene Expression

Chong

Yazan

et al. 2012

Journal of Medicinal Food

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Vanillin is the substance responsible for the flavor and smell of vanilla, a widely used flavoring agent. Previous studies reported that vanillin is a good antimutagen and anticarcinogen. However, there are also some contradicting findings showing that vanillin was a comutagen and cocarcinogen. This study investigated whether vanillin is an anticarcinogen or a cocarcinogen in rats induced with azoxymethane (AOM). Rats induced with AOM will develop aberrant crypt foci (ACF). AOM-challenged rats were treated with vanillin orally and intraperitoneally at low and high concentrations and ACF density, multiplicity, and distribution were observed. The gene expression of 14 colorectal cancer-related genes was also studied. Results showed that vanillin consumed orally had no effect on ACF. However, high concentrations (300 mg/kg body weight) of vanillin administered through intraperitoneal injection could increase ACF density and ACF multiplicity. ACF were mainly found in the distal colon rather than in the mid-section and proximal colon. The expression of colorectal cancer biomarkers, protooncogenes, recombinational repair, mismatch repair, and cell cycle arrest, and tumor suppressor gene expression were also affected by vanillin. Vanillin was not cocarcinogenic when consumed orally. However, it was cocarcinogenic when being administered intraperitoneally at high concentration. Hence, the use of vanillin in food should be safe but might have cocarcinogenic potential when it is used in high concentration for therapeutic purposes.

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“…Because inhibitors of DNA synthesis and inducers of DNA strand breaks have been described as the most potent inducers of homologous recombination in mammalian cells (Arnaudeau et al 2000) and taking into account the DNA fragmentation caused by the Topo I inhibitors in human cells (Pommier 2006), this present study investigates the recombinogenic potential of CPT and CPT-11 for their ability to induce gene homozygosis and mitotic recombination in heterozygous diploid cells. In order to achieve our goal, a diploid strain of A. nidulans, which is heterozygous for several nutritional markers, as well as the homozygotization assay (Pires and Zucchi 1994), previously used to characterize the recombinogenic potential of several anticancer agents, such as cisplatin and cytosine arabinoside (Miyamoto et al 2007), were employed.…”

Section: Introductionmentioning

confidence: 99%

Gene homozygosis and mitotic recombination induced by camptothecin and irinotecan in Aspergillus nidulans diploid cells

Esquissato

Sant’Anna

Franco

et al. 2014

An. Acad. Bras. Ciênc.

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Mitotic recombination is a process involved in carcinogenesis which can lead to genetic loss through the loss of heterozygosity. The recombinogenic potentials of two anticancer drugs topoisomerase I inhibitors, camptothecin (CPT) and irinotecan (CPT-11), were evaluated in the present study. The homozygotization assay, which assess the induction of mitotic recombination and gene homozygosis, as well as the heterozygous A757//UT448 diploid strain of Aspergillus nidulans were employed. The three non-cytotoxic concentrations of CPT (3.5 ng mL -1 , 10.5 ng mL -1 and 17.4 ng mL -1 ) were found to induce both mitotic recombination and gene homozygosis. CPT treatment produced three diploids homozygous, for nutritional and conidia color genes, and Homozygotization Indices (HI) significantly different from negative control. On the other hand, only the highest CPT-11 concentration tested (18 µg mL -1 ), corresponding to the maximal single chemotherapeutic dose, produced HI values higher than 2.0 and significantly different from negative control HI values. The recombinogenic effects of both topoisomerase I blockers were associated with the recombinational repair of DNA strand breaks induced by CPT and CPT-11. The anticancer drugs CPT and CPT-11 may be characterized as secondary malignancies promoters in cancer patients after chemotherapy treatment.

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Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells

Cited by 51 publications

References 33 publications

Induced mitotic homologous recombination by the babesicide imidocarb dipropionate in Aspergillus nidulans diploid cells

Induced mitotic homologous recombination by the babesicide imidocarb dipropionate in Aspergillus nidulans diploid cells

Vanillin Differentially Affects Azoxymethane-Injected Rat Colon Carcinogenesis and Gene Expression

Gene homozygosis and mitotic recombination induced by camptothecin and irinotecan in Aspergillus nidulans diploid cells

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