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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Mitomycin-C (Mitomycin-C KyowaTM), now produced mainly by Kyowa Kirin Ltd, is a member of a group of naturally occurring antitumor antibiotics produced by Streptomyces caespitosus (griseovinaceseus) (Figure 5.38). First isolated in 1958, it is unusually rich in chemical functional groups for such a small molecule. The components of the molecule essential for its mode of action are the quinone, aziridine, and carbamate moieties, and its mechanism of action includes a bioreductive step. Therefore, mitomycin is regarded as a “bioreductive agent” (see Chapter 10), although it is described here due to its DNA cross-linking properties. Mechanistic pathway showing the bioreduction of mitomycin-C (Mitomycin-C KyowaTM) followed by DNA cross-linking.
Fanconi Anemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Fanconi anemia a rare genetic disorder that typically manifests as congenital anomalies, progressive BMF (from thrombocytopenia or leukopenia to pancytopenia), and increased susceptibility to leukemia and solid tumors. The molecular mechanisms of FA lie in mutations in the 22 genes encoding components of the FA pathway, leading to nonfunctional FA proteins that increase sensitivity to crosslinking agents, hamper interstrand crosslink repair, and contribute to genomic instability. While observation of characteristic clinical features aids in FA diagnosis, examination of chromatid breaks induced by DNA crosslinking agents is invaluable for confirming its identity. Furthermore, use of molecular techniques allows identification of specific gene mutations, yielding genetic insights that can be exploited for improved treatment and prevention of this fatal syndrome.
Mutagenic Consequences Of Chemical Reaction with DNA
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
One possibility is that the lesion requiring this type of repair consists of a strand break opposite a damaged base. In this case, repair might occur by the same mechanism as Cole116 has suggested for DNA cross-linking agents. However, Bridges62,130 used special growth conditions to produce cells containing less than two complete genomes and found that repair and mutation were essentially normal. This would preclude recombination of the type envisaged by Cole, and suggest that such lesions, like released cross-links, were likely to undergo error-prone repair with a high probability.
Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in the Chinese population
Published in Annals of Medicine, 2021
Liye Wang, Qinglian Zhai, Qianyi Lu, Kaping Lee, Qiufan Zheng, Ruoxi Hong, Shusen Wang
Some studies identified a subgroup of TNBC with a deficiency of DNA repair, mainly due to mutations or methylation of BRCA1/2, and other genes involved in DNA damage repair pathway [13,44]. A clinical trial (NCT00494234) for a poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, olaparib, in patients with BRCA1 or BRCA2 mutations and advanced breast cancer, provided an impressive ORR of 44% [45]. A randomized, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)-negative metastasis breast cancer, detected a longer progression-free survival (PFS) of 7.0 months in the olaparib group than the 4.2 months (HR = 0.58, 95%CI: 0.43–0.80, p<.001), but no statistically significant improvement in OS [46,47]. Given that most BRCA1/2 carriers are attributed to TNBC [48], olaparib could provide a significant benefit among TNBC patients deficient in DNA damage repair. Except for BRCA1/2, many mutations associated with TNBC are mainly distributed in DNA damage repair pathway, including the above-mentioned PALB2, RAD21 and MSH2, along with some other genes that were not detected in our study. Therapies designed for these mutated genes are scarce. It is still unclear whether these mutated genes can be treatment targets or not, but the utility of DNA cross-linking agents in combination with targeted agents has been reported to improve the curative effect for patients with DNA damage repair [31].
Incidence of Fanconi anaemia in phenotypically normal aplastic anaemia patients in West Bengal
Published in Hematology, 2018
Atreyee Dutta, Rajib De, Tuphan Kanti Dolai, Pritha Pal, Shanoli Ghosh, Pradip Kumar Mitra, Ajanta Halder
Many international researches have been made on the FA patients using DNA cross-linking agents. A study showed that FA patients have high susceptibility to DNA cross-linking agents [13]. Another study was conducted in Southern Brazil on 17 patients has found seven confirmed FA cases [4]. A research was made on FA patients with atypical phenotypes which is very much frequent in FA. They used DEB test for the detection of the disease [17]. Again a large cohort study applied flow-based MMC sensitivity test to evaluate FA phenotype in fibroblasts [20]. A study in Serbia was performed on FA-affected children and found the percentage of DNA cross-linker-induced aberrant cells was increased more than 26 times in FA patients compared to non-FA patients [22]. This study also supports this observation of DNA cross-linker-induced chromosomal breakage is very high in FA patients. A case report published from Bangladesh showed genetic study should be done if possible in all the cases of suspected FA, siblings, parents and close blood relatives. Also said that the screening of the FANCA gene for mutations supports the clinical diagnosis of FA [23]. Our study also justifies the fact of the high percentage of consanguinity is found among FA patients.
BRCA mutations in pancreatic cancer and progress in their targeting
Published in Expert Opinion on Therapeutic Targets, 2021
Samer Alkassis, Omid Yazdanpanah, Philip Agop Philip
The presence of DNA cross-linking activates ATR, which induces phosphorylation of Fanconi anemia (FA) core complex and helps to excise the DNA defect [21]. While the DNA crosslink repair process which involves nucleotide excision repair is in process, DSBs are produced in the proximity of the incised oligonucleotide. Subsequently, this accumulation of DSBs needs repair by HR. Therefore, mutations in HR genes (such as BRCA1, BRCA2, XRCC2, and XRCC3) can result in hypersensitivity to crosslinking agents such as mitomycin C or cisplatin [20,22].