Relationships between functionality and genetic toxicology of selected DNA-damaging agents

Brendel, Martin; Ruhland, A.

doi:10.1016/0165-1110(84)90003-4

Cited by 122 publications

(52 citation statements)

References 158 publications

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“…Moreover, snm1 cells are capable of repairing an ICL on a plasmid, suggesting that the activity of Snm1 may be related to the modulation of chromosomal structure (39). The sensitivity of snm1 mutants to all ICL agents tested suggests that Snm1 is involved in an ICL agent-independent step and therefore probably after the formation of ICLs (6,25,49). This notion is consistent with the fact that snm1 mutants are capable of creating DSBs after treatment with 8-methoxypsoralen plus UVA light, in contrast to NER mutants, which are not able to incise the DNA near the ICL (40,42).…”

Section: Discussionmentioning

confidence: 99%

“…The formation and repair of ICLs in cells are complex processes, with major differences between ICL agents. The sensitivity of a cell to a certain ICL agent is dependent on all steps in the processing of ICLs, ranging from uptake and metabolization to damage recognition and repair (6). A number of major DNA damage repair pathways are involved in the repair of ICLs.…”

Section: Discussionmentioning

confidence: 99%

“…Most of these agents cause a number of different lesions in DNA, including monoadducts, DNAprotein cross-links, and DNA intrastrand cross-links and ICLs. The latter are the main cause of cell death, although they constitute only a small percentage of the total number of adducts (6,36). Resistance of tumors to cross-linking agents can be caused by a variety of mechanisms, including increased repair of ICLs (1,5,31).…”

mentioning

confidence: 99%

“…The gene mutated in one of these strains is SNM1, which is allelic with PSO2 and encodes a nuclear 76-kDa protein (9,23,47). snm1 mutants are sensitive to a number of agents that cause ICLs, but they are only mildly sensitive to monofunctional alkylating agents and 254-nm UV light (UV 254 nm ) and are not hypersensitive to gamma rays (6,25,49). In exponentially growing cells, the expression of SNM1 can be induced by ICL agents or UV 254 nm (61).…”

mentioning

confidence: 99%

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Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Dronkert

Wit

Boeve

et al. 2000

Molecular and Cellular Biology

117

110

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DNA interstrand cross-links (ICLs) represent lethal DNA damage, because they block transcription, replication, and segregation of DNA. Because of their genotoxicity, agents inducing ICLs are often used in antitumor therapy. The repair of ICLs is complex and involves proteins belonging to nucleotide excision, recombination, and translesion DNA repair pathways in Escherichia coli, Saccharomyces cerevisiae, and mammals. We cloned and analyzed mammalian homologs of the S. cerevisiae gene SNM1 (PSO2), which is specifically involved in ICL repair. Human Snm1, a nuclear protein, was ubiquitously expressed at a very low level. We generated mouse SNM1 ؊/؊ embryonic stem cells and showed that these cells were sensitive to mitomycin C. In contrast to S. cerevisiae snm1 mutants, they were not significantly sensitive to other ICL agents, probably due to redundancy in mammalian ICL repair and the existence of other SNM1 homologs. The sensitivity to mitomycin C was complemented by transfection of the human SNM1 cDNA and by targeting of a genomic cDNA-murine SNM1 fusion construct to the disrupted locus. We also generated mice deficient for murine SNM1. They were viable and fertile and showed no major abnormalities. However, they were sensitive to mitomycin C. The ICL sensitivity of the mammalian SNM1 mutant suggests that SNM1 function and, by implication, ICL repair are at least partially conserved between S. cerevisiae and mammals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Dronkert

Wit

Boeve

et al. 2000

Molecular and Cellular Biology

117

110

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“…DNA is a target molecule for underlying molecular mechanisms of MMC toxicity in antitumor therapy (24,25). Accordingly, the accumulation of intracellular ROS generating oxidative damage to cellular components, particularly DNA, was observed in the Trr1 shRNA knockdown cells (Fig.…”

Section: Elevated γ-H2ax Foci As a Biomarker Of Dna Damage Inmentioning

confidence: 95%

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Koedrith

Seo

2011

Experimental and Therapeutic Medicine

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Abstract. Thioredoxin reductase 1 (Trr1) is an antioxidant and redox regulator that functions in governing the cellular redox state and survival against oxidative insults in mammals. However, this selenoprotein is also overexpressed in various forms of malignant cancers, leading to the hypothesis that Trr1 may be a potential target for cancer therapy. A quinone anticancer drug, mitomycin C (MMC), has been clinically used in the treatment of several types of tumors, including those of the colon. MMC exerts its activity via ROS induction and further results in DNA cross-linkage. To evaluate the significant role of Trr1 in MMC resistance in human colon cancer (RKO) cells, specific reduction in the expression of Trr1 was achieved using short-hairpin RNA (shRNA)-based interference. Our results showed that stable Trr1 shRNA knockdown manifested higher cellular susceptibility to MMC in comparison to that in wild-type cells. In addition, increased intracellular ROS accumulation appeared in the Trr1 shRNA knockdown cells compared to the RKO wild-type cells, in proportion to a relatively higher fraction of the DNA damage reporter protein phosphorylated histone 'γ-H2AX'. Notably, a neutral comet assay demonstrated that DNA double-strand breaks were highly induced in the Trr1-deficient cancer cells in the presence of MMC, presumably stimulating cancer cell death. Our results also revealed that MMC-induced apoptosis was associated with enhancement of oxidative damage to DNA. These results suggest that the specific knockdown of Trr1 expression via shRNA vector interference technology may be a potent molecular strategy by which to enhance the effectiveness of MMC-mediated killing in human colon cancer cells, through acceleration of double-strand DNA damage-oxidative stress as a trigger for apoptosis. This implies that Trr1 may be a prime target for enhancing the effectiveness of MMC chemotherapy in combination with specific RNA interference.

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Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

Denny¹

2003

Burger's Medicinal Chemistry and Drug Discovery

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Synthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents remain important DNA alkylators. Methotrexate, and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. Cytosine arabinoside and more recent compounds like gemcitabine, fludarabine, cladribine, and pentostatin inhibit DNA polymerase action during DNA synthsis. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs targeted at DNA. The increasing power of organic chemistry increasingly allows the synthesis of close analogs of cytotoxic, but complex, natural products as potential drugs; recent examples are synthetic analogs of the duocarmycins and the epothilones. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy, or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive non‐tumor cell populations.

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Relationships between functionality and genetic toxicology of selected DNA-damaging agents

Cited by 122 publications

References 158 publications

Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Disruption of Mouse SNM1 Causes Increased Sensitivity to the DNA Interstrand Cross-Linking Agent Mitomycin C

Enhancement of the efficacy of mitomycin C-mediated apoptosis in human colon cancer cells with RNAi-based thioredoxin reductase 1 deficiency

Synthetic DNA‐Targeted Chemotherapeutic Agents and Related Tumor‐Activated Prodrugs

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