DNA Damage and Repair in Human Cancer: Molecular Mechanisms and Contribution to Therapy-Related Leukemias

Abstract

Most antitumour therapies damage tumour cell DNA either directly or indirectly. Without repair, damage can result in genetic instability and eventually cancer. The strong association between the lack of DNA damage repair, mutations and cancer is dramatically demonstrated by a number of cancer-prone human syndromes, such as xeroderma pigmentosum, ataxia-telangiectasia and Fanconi anemia. Notably, DNA damage responses, and particularly DNA repair, influence the outcome of therapy. Because DNA repair normally excises lethal DNA lesions, it is intuitive that efficient repair will contribute to intrinsic drug resistance. Unexpectedly, a paradoxical relationship between DNA mismatch repair and drug sensitivity has been revealed by model studies in cell lines. This suggests that connections between DNA repair mechanism efficiency and tumour therapy might be more complex. Here, we review the evidence for the contribution of carcinogenic properties of several drugs as well as of alterations in specific mechanisms involved in drug-induced DNA damage response and repair in the pathogenesis of therapy-related cancers.

Caspase-9 is required for normal hematopoietic development and protection from alkylator-induced DNA damage in mice

“…13,14 Hypermethylation of the BRCA1 promoter is also more common in tAML than in de novo AML. 15 There is also evidence of increased DNA damage in tAML cells, including microsatellite instability, a sign of DNA damage that is rare in de novo AML. 15 tAML is also associated with accelerated telomere shortening, which is linked to genomic instability.…”

“…15 There is also evidence of increased DNA damage in tAML cells, including microsatellite instability, a sign of DNA damage that is rare in de novo AML. 15 tAML is also associated with accelerated telomere shortening, which is linked to genomic instability. 16,17 In addition, peripheral blood CD34 1 cells from patients before the development of tAML have elevated production of mitochondrial reactive oxygen species (ROS), sustained ROS elevation, The online version of this article contains a data supplement.…”

Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy

“…Of the potential mechanisms of MDR cancer cells, the most predominantly reported ones include the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family [76], apoptosis induction [77], autophagy induction [78], cancer stem cell regulation [79], miRNA regulation [80], hypoxia induction [81], DNA damage and repair [82], and epigenetic regulation [83]. Currently, looking for novel compounds with anti-MDR activity is a promising approach to solving this cancer drug resistance problem; in combination with anticancer drugs, these compounds may increase the anticancer effect, which has led to increased intracellular drug retention and the recovery of cell sensitivity to chemotherapeutic drugs in combined treatment.…”

The Potential of Targeting DNA Repair Deficiency in Acute Myeloid Leukemia

“…The occurrence of AML can be de novo; however, a number of AML cases are therapy-related [7]. As the overall-survival rate of many cancers is increasing, so too is the number of living people who have received cytotoxic treatments.…”

“…These people are at risk of developing secondary neoplasms, particularly haematological neoplasms. As a result of this, a rise in the frequency of patients presenting with therapy-related AML (t-AML) can be seen [7]. T-AML is categorised as any AML occurring in patients which have previously received cytotoxic drug treatments or radiotherapy which targeted active bone marrow sites [8].…”