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 共查询到8条相似文献,搜索用时 4 毫秒
1.
Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.  相似文献   

2.
Earlier theoretical investigations of the mechanism of radiation damage to DNA/RNA nucleobases have claimed OH radical addition as the dominating pathway based solely on energetics. In this study we supplement calculations of energies with the kinetics of all possible reactions with the OH radical through hydrogen abstraction and OH radical addition onto carbon sites, using DFT at the ωB97X‐D/6‐311++G(2df,2pd) level with the Eckart tunneling correction. The overall rate constants for the reaction with adenine, guanine, thymine, and uracil are found to be 2.17×10?12, 5.64×10?11, 2.01×10?11, and 5.03×10?12 cm3 molecules?1 s?1, respectively, which agree exceptionally well with experimental values. We conclude that abstraction of the amine group hydrogen atoms competes with addition onto C8 as the most important reaction pathway for the purine nucleobases, while for the pyrimidine nucleobases addition onto C5 and C6 competes with the abstraction of H1. Thymine shows favourability against abstraction of methyl hydrogens as the dominating pathway based on rate constants. These mechanistic conclusions are partly explained by an analysis of the electrostatic potential together with HOMO and LUMO orbitals of the nucleobases.  相似文献   

3.
The effectiveness of hydroxycinnamic acids (HCAs), that is, caffeic acid (CaA), chlorogenic acid (ChA), sinapic acid (SA), ferulic acid (FA), 3‐hydroxycinnamic acid (3‐HCA), and 4‐hydroxycinnamic acid (4‐HCA), as pBR322 plasmid DNA‐cleaving agents in the presence of CuII ions was investigated. Compounds bearing o‐hydroxy or 3,5‐dimethoxy groups on phenolic rings (CaA, SA, and ChA) were remarkably more effective at causing DNA damage than the compounds bearing no such groups; furthermore, CaA was the most active among the HCAs examined. The involvement of reactive oxygen species (ROS) and CuI ions in the DNA damage was affirmed by the inhibition of the DNA breakage by using specific scavengers of ROS and a CuI chelator. The interaction between CaA and CuII ions and the influence of ethylenediaminetetraacetic acid (EDTA), the solvent, and pH value on the interaction were also studied to help elucidate the detailed prooxidant mechanism by using UV/Vis spectroscopic analysis. On the basis of these observations, it is proposed that it is the CaA phenolate anion, instead of the parent molecule, that chelates with the CuII ion as a bidentate ligand, hence facilitating the intramolecular electron transfer to form the corresponding CaA semiquinone radical intermediate. The latter undergoes a second electron transfer with oxygen to form the corresponding o‐quinone and a superoxide, which play a pivotal role in the DNA damage. The intermediacy of the semiquinone radical was supported by isolation of its dimer from the CuII‐mediated oxidation products. Intriguingly, CaA was also the most cytotoxic compound among the HCAs toward human promyelocytic leukemia (HL‐60) cell proliferation. Addition of exogenous CuII ions resulted in an effect dichotomy on cell viability depending on the concentration of CaA; that is, low concentrations of CaA enhanced the cell viability and, conversely, high concentrations of CaA almost completely inhibited the cell proliferation. On the other hand, when superoxide dismutase was added before, the two stimulation effects of exogenous CuII ions were significantly ameliorated, thus clearly indicating that the oxidative‐stress level regulates cell proliferation and death. These findings provide direct evidence for the antioxidant/prooxidant mechanism of cancer chemoprevention.  相似文献   

4.
The 5′,8-cyclo-2′-deoxypurines (cdPus) affect the DNA structure. When these bulky structures are a part of clustered DNA lesions (CDL), they affect the repair of the other lesions within the cluster. Mitochondria are crucial for cell survival and have their own genome, hence, are highly interesting in the context of CDL repair. However, no studies are exploring this topic. Here, the initial stages of mitochondrial base excision repair (mtBER) were considered—the strand incision and elongation. The repair of a single lesion (apurinic site (AP site)) accompanying the cdPu within the double-stranded CDL has been investigated for the first time. The type of cdPu, its diastereomeric form, and the interlesion distance were taken into consideration. For these studies, the established experimental model of short oligonucleotides (containing AP sites located ≤7 base pairs to the cdPu in both directions) and mitochondrial extracts of the xrs5 cells were used. The obtained results have shown that the presence of cdPus influenced the processing of an AP site within the CDL. Levels of strand incision and elongation were higher for oligos containing RcdA and ScdG than for those with ScdA and RcdG. Investigated stages of mtBER were more efficient for DNA containing AP sites located on 5′-end side of cdPu than on its 3′-end side. In conclusion, the presence of cdPus in mtDNA structure may affect mtBER (processing the second mutagenic lesion within the CDL). As impaired repair processes may lead to serious biological consequences, further studies concerning the mitochondrial repair of CDL are highly demanded.  相似文献   

5.
Development of potential cancer treatment strategies by using an exogenous reactive oxygen species (ROS)‐generating agent (prooxidant) or redox intervention, has attracted much interest. One effective ROS generation method is to construct a prooxidant system by polyphenolic compounds and CuII ions. This work demonstrates that CuII and the stilbene–chroman hybrid with a catechol moiety could synergistically induce pBR322 plasmid DNA damage, as well as cell cycle arrest and apoptosis of HepG2 cells. Additionally, an interesting acid/base‐promoted prooxidant reaction was found. The detailed chemical mechanisms for the reaction of the hybrid with CuII in acid, neutral and base solutions are proposed based on UV/Vis spectral changes and identification of the related oxidative intermediates and products.  相似文献   

6.
UV‐light irradiation induces the formation of highly mutagenic lesions in DNA, such as cis‐syn cyclobutane pyrimidine dimers (CPD photoproducts), pyrimidine(6‐4)pyrimidone photoproducts ((6‐4) photoproducts) and their Dewar valence isomers ((Dew) photoproducts). Here we describe the synthesis of defined DNA strands containing these lesions by direct irradiation. We show that all lesions are efficiently repaired except for the T(Dew)T lesion, which cannot be cleaved by the repair enzyme under our conditions. A crystal structure of a T(6‐4)C lesion containing DNA duplex in complex with the (6‐4) photolyase from Drosophila melanogaster provides insight into the molecular recognition event of a cytosine derived photolesion for the first time. In light of the previously postulated repair mechanism, which involves rearrangement of the (6‐4) lesions into strained four‐membered ring repair intermediates, it is surprising that the not rearranged T(6‐4)C lesion is observed in the active site. The structure, therefore, provides additional support for the newly postulated repair mechanism that avoids this rearrangement step and argues for a direct electron injection into the lesion as the first step of the repair reaction performed by (6‐4) DNA photolyases.  相似文献   

7.
8.
Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, α-aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, DMBA, DMBA & α-aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. New α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with α-aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.  相似文献   

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