Hypoxia--a hallmark of solid tumors--makes hypoxic cells radioresistant. On the other hand, DNA, the main target of anticancer therapy, is not sensitive to the near UV photons and hydrated electrons, one of the major products of water radiolysis under hypoxic conditions. A possible way to overcome these obstacles to the efficient radio- and photodynamic therapy of cancer is to sensitize the cellular DNA to electrons and/or ultraviolet radiation. While incorporated into genomic DNA, modified nucleosides, 5-bromo-2'-deoxyuridine in particular, sensitize cells to both near-ultraviolet photons and γ rays. It is believed that, in both sensitization modes, the reactive nucleobase radical is formed as a primary product which swiftly stabilizes, leading to serious DNA damage, like strand breaks or cross-links. However, despite the apparent similarity, such radio- and photosensitization of DNA seems to be ruled by fundamentally different mechanisms. In this review, we demonstrate that the most important factors deciding on radiodamage to the labeled DNA are (i) the electron affinity (EA) of modified nucleoside (mNZ), (ii) the local surroundings of the label that significantly influences the EA of mNZ, and (iii) the strength of the chemical bond holding together the substituent and a nucleobase. On the other hand, we show that the UV damage to sensitized DNA is governed by long-range photoinduced electron transfer, the efficiency of which is controlled by local DNA sequences. A critical review of the literature mechanisms concerning both types of damage to the labeled biopolymer is presented. Ultimately, the perspectives of studies on DNA sensitization in the context of cancer therapy are discussed.
Incorporated into genomic DNA, 5-substituted uracils could be employed in human cancer radiotherapy if they could be sensitized to dissociate upon reaction with hydrated electrons. Using the B3LYP/6-31++G(d,p) method, we calculate electron affinities and energy profiles related to the dissociation of the respective anions for a series of uracil derivatives. We demonstrate that for a uracil analogue to be an efficient electron acceptor the uracil substituent has to possess significant electron-withdrawing power. On the other hand, in order to ensure effective dissociation of the anion, the chemical bond holding together the substituent and uracil residue should be relatively weak. Our theoretical predictions are in excellent agreement with the results of our negative ion photoelectron spectroscopy experiments. We propose two new potential sensitizers that seem to possess the required properties, although they have never been tested in radiobiological experiments.
The enhancement of radiodamage to DNA labeled with halonucleobases is attributed to the reactive radical produced from a halonucleobase by the attachment of an electron. We examined at the B3LYP/6-31++G** level electron capture by four brominated nucleobases (BrNBs): 8-bromo-9-methyladenine, 8-bromo-9-methylguanine, 5-bromo-1-methylcytosine, and 5-bromo-1-methyluracil followed by the release of the bromide anion and a nucleobase radical. We demonstrate that neutral BrNBs in both gas and aqueous phases are better electron acceptors than unsubstituted NBs and that resulting anion radicals, BrNBs(•-), can easily transform into the product complex of the bromide anion and the nucleobase radical ([Br(-)···NB(•)]). The overall thermodynamic stimulus for the process starting with the neutral BrNB and ending with the isolated bromide anion and the NB(•) radical is similar in the case of all four BrNBs studied, which suggests their comparable radiosensitizing capabilities.
BackgroundAlveolar echinococcosis (AE) caused by Echinococcus multilocularis infections is a dangerous old disease in the Northern Hemisphere. The aim of the paper was to collect and analyze data on human AE in Poland in the last two decades.Methodology/Principal FindingsThe sources of data were both the cases officially registered and detected by an active field and laboratory surveillance. The cases were verified by clinical, epidemiological, and laboratory criteria. Altogether 121 human cases of AE were detected. Among these 83 (68,6%) cases were classified as confirmed, 16 as probable and 22 as possible. During the two decades a continuous increase in detection rate was noticed. The cases were 6–82 years old at the time of diagnosis (mean - 47.7 years). Sex ratio M/F was 0.86/1.0. The AE was fatal in 23 (19%) patients (mean age at death - 54.1 years). Family agglomeration of AE was found in 4 foci, involving 9 patients. Seventy six of the cases were diagnosed in an advanced stage of disease. In all cases the liver was the primary location of AE. In 30 (24.8%) patients a spread to other organs was observed. Ninety four of the patients were treated with albendazole. In 73 (60%) patients a surgical operation was performed, including 15 liver transplantations.Conclusions/SignificanceThe studies confirmed that AE is an emerging disease in Poland, which is the fourth country in Europe with over 120 cases detected. The results also indicate the need of a wider national programme for implementation of screening in the highest AE risk areas (north-eastern Poland) with an effort to increase the public awareness of the possibility of contracting E. multilocularis, and above all, training of the primary care physicians in the recognition of the risk of AE to allow for an early detection of this dangerous disease.
Some Acanthamoeba species are distributed in natural and man-made environments, in a wide range of soil and aquatic habitats, also in clinical settings. The amphizoic organisms can exist as facultative parasites -causative agents of serious human disease, Acanthamoeba keratitis. The vision-threatening eye disease occurring particularly in contact lens wearers is reported with increasing prevalence in different regions of the world. The amoebic keratitis is difficult to diagnose as clinical symptoms are similar to those observed in other eye diseases. Moreover, bacterial, viral, fungal, and amoebic co-infections frequently occur also amoebae act as carriers for ~ species pathogenic for humans, e.g. from Pseudomonas, Legionella, Mycobacterium and Escherichia genera thus the corneal disease is frequently misdiagnosed. Complex etiology, late proper recognition of amoebic infections, and the exceptional resistance of Acanthamoeba cysts to chemicals are important factors influencing diagnostic and therapeutic difficulties. Surgical interventions are needed as an alternative treatment in refractory Acanthamoeba keratitis. It should be taken into consideration that the knowledge and awareness of increasing threat generated by the amphizoic amoebae are still insufficient. This compilation presents selected aspects of eye disease that is becoming the increasingly significant for human health worldwide.
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