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1
Content available remote Sensitivity of Vi phages III to γ-radiation in the presence of cisplatin
100%
EN
In this study we determined Vi bacteriophage III sensitivity to native cisplatin, γ radiation (60Co) or to irradiated cisplatin, and checked the possibility of enhanced Vi bacteriophage III inactivation under combined exposure to cisplatin and γ radiation. We used highly purified phage suspensions in 0.9% NaCl solution or phosphate-buffered saline. Phage suspensions were titrated using a double agar layer method. Our study implies that survival of Vi bacteriophage III shows an exponential inverse correlation with cisplatin concentration in the incubation medium and the time of phage incubation in the presence of cisplatin. The use of irradiated cisplatin reduces phage survival in comparison with suspensions containing non-irradiated cisplatin. Irradiation of phage suspension with cisplatin causes a significant increase of phage inactivation in comparison with either treatment alone. Our results suggest that presence of cisplatin in irradiated medium enhances the radiobiological effect on Vi bacteriophages III.
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100%
EN
Cisplatin has been used for over 40 years in various cancer chemotherapies. Toxicity induced by cisplatin-based therapeutic regimens include gastrointestinal toxicity, myelotoxicity, neurotoxicity, ototoxicity and nephrotoxicity. Cisplatin-based regimens have been associated with a wide range of cardiovascular complications. In this paper, we report 2 cases of cisplatin induced cardiotoxicity. We present cases of 2 young patients who developed acute myocardial infarction during combination chemotherapy with bleomycin, etoposide and cisplatin. The first patient had acute anterior wall ST elevation myocardial infarction and the second one had acute myocardial infarction with peripheral arterial thromboembolism. Cisplatin use can result in cardiovascular events. Clinicians should be very cautious while managing patients on cisplatin-based chemotherapy. Early recognition of cardiotoxicity will allow for timely prevention of permanent cardiac damage.
EN
Extracts from rodent liver cells contain an abundant protein that recognizes DNA adducts induced by the chemical carcinogen N-acetoxy-acetylaminofluorene (AAAF). This protein also has a strong affinity for DNA damaged by cisplatin (DDP), but not by benzo(a)pyrene diolepoxide or UV-radiation, and has been termed AAAF/DDP-DDB. Here we purified this protein from rat tissue and analyzed it by mass spectrometry and identified it as mitochondrial transcription factor A (TFAM). Experiments with bacterially expressed recombinant TFAM confirmed its high affinity for DNA damaged by AAAF. Assuming its abundance and specificity for AAAF induced lesions, TFAM may significantly impede recognition and repair of DNA adducts induced by AAAF and other derivatives of 2-aminofluorene.
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tom 17
37-41
EN
Lung cancer is one of the most lethal types of cancer due to a lack of proper treatment. The rare presence of molecular therapy targets forces the use of platinum-based drugs. Cisplatin, approved by the USA as an anticancer therapy in the 1970s, is still one of the most prominent therapies against lung cancer. Unfortunately, the biggest limitation of cisplatin-based therapy is the development of cisplatin resistance. Cancer cells overcome the vast DNA damage caused by the drug in a variety of ways such as detoxication and extracellular transport of the drug, enhanced repair mechanisms, omitting apoptosis and epigenetic alterations. Chemotherapy resistance is an issue that so far cannot be dealt with. Nevertheless, better understanding of the molecular pathways behind cisplatin resistance brings hope for better therapy outcomes in lung cancer patients.
EN
Proteins recognizing DNA damaged by the chemical carcinogen N-acetoxy-acetylaminofluorene (AAAF) were analyzed in nuclear extracts from rat tissues, using a 36 bp oligonucleotide as a substrate and electrophoretic mobility shift and Southwestern blot assays. One major damage-recognizing protein was detected, whose amount was estimated as at least 105 copies per cell. Levels of this protein were similar in extracts from brain, kidney and liver, but much lower in extracts from testis. The affinity of the detected protein for DNA damaged by AAAF was about 70-fold higher than for undamaged DNA. DNA damaged by cis-diamminedichloroplatinum (cis-DDP), benzo(a)pyrene diolepoxide (BPDE) or UV-radiation also bound this protein with an increased affinity, the former more strongly and the latter two more weakly as compared to AAAF-damaged DNA. The detected AAAF/DDP-damaged-DNA-binding (AAAF/DDP-DDB) protein had a molecular mass of about 25 kDa and was distinct from histone H1 or HMGB proteins, which are known to have a high affinity for cis-DDP-damaged DNA. The level of this damage-recognizing protein was not affected in rats treated with the carcinogen 2-acetylaminofluorene. The activity of an AAAF/DDP-DDB protein could also be detected in extracts from mouse liver cells but not from the Hep2G human hepatocellular carcinoma.
EN
The motivation to this work results from the recognition of cis-dia mminedi - chloroplatinum(II) (cisplatin) hydration processes as essential for the fate of this drug in host organism. Applying quantum chemical calculations, there were evaluated the first stages of water molecule impact on platinum complexes: cisplatin and its trans isomer. Non-empirical quantum chemical calculations have been performed for reactions of cisand trans-diamminedichloroplatinum(II) (transplatin) with the water molecule, as sum - ing the associative mode of reactions running with the addition of a fifth ligand to a square planar d8 complex and formation of a trigonal-bipyramidal structure of the transition state. For the obtained structures of reactants, transition states, and products, the ther mo - dynamic characteristics (energies and Gibbs free energies) were estimated. Energetics for the ligand exchange reactions were estimated both in gas phase and water solution by using the PCM model. The hydration reactions under consideration are principally endothermic except of the solvated transplatin. Basing on our ab in itio ZORA calculations, the possible role of relativistic effects in the reaction mechanism is pointed out as well. Ob - tained results may throw some light on processes which determine the inter change of pro-drug (cisplatin) into activated drug (aqua-form) and implicate their significance in de signing of anticancer, Pt-containing chemotherapeutics.
EN
Ototoxicity of cisplatin is one of the major dose limiting side effects. Cisplatin-dependent ototoxicity is known to be associated with reactive oxygen species. Protective effect of taxifolin, being a flavanone found in onions, milk thistle, French maritime, and Douglas fir bark, against cisplatin-associated ototoxicity will be examined in this study. There are no studies in the literature examining the protective effect of taxifolin against cisplatin-induced ototoxicity. 50 mg/kg taxifolin was orally administered to TXC group rats (n-6), and distilled water was orally administered as solvent to CG (n-6) and HG (n-6) groups. One hour later, 5 mg/kg cisplatin was administered intraperitoneally (i.p) to TXC and CG groups. This procedure was repeated once a day for 7 days. At the end of this period, all animals were sacrificed by high-dose anesthesia (50 mg/kg thiopental sodium) and biochemical and histopathological examinations were performed on the dissected cochlea tissue. Our biochemical test results showed that oxidant parameters were significantly increased whereas antioxidant parameters were significantly decreased in the cisplatin group (CG) compared to taxifolin (TXC) and healthy (HG) groups (P <0.0001 for both parameters). Histopathological results showed that severe cochlear vestibular membrane degeneration, dilated conjunctival blood vessels, edema and destruction developed in the cisplatin group. However, no pathological findings were found in the taxifolin-treated group except for mild degeneration and edema. This information suggests that taxifolin may be useful in the treatment of cisplatin-associated oxidative cochlear damage.
EN
Introduction: Proton beam radiotherapy is an advanced cancer treatment technique, which would reduce the effects of radiation on the surrounding healthy cells. The usage of radiosensitizers in this technique might further elevate the radiation dose towards the cancer cells. Material and methods: The present study investigated the production of intracellular reactive oxygen species (ROS) due to the presence of individual radiosensitizers, such as bismuth oxide nanoparticles (BiONPs), cisplatin (Cis) or baicalein-rich fraction (BRF) from Oroxylum indicum plant, as well as their combinations, such as BiONPs-Cis (BC), BiONPs-BRF (BB), or BiONPs-Cis-BRF (BCB), on HCT-116 colon cancer cells under proton beam radiotherapy. Results: It was found that the ROS in the presence of Cis at 3 Gy of radiation dose was the highest, followed by BC, BiONPs, BB, BRF, and BCB treatments. The properties of bismuth as a radical scavenger, as well as the BRF as a natural compound, might contribute to the lower intracellular ROS induction. The ROS in the presence of Cis and BC combination were also time-dependent and radiation dose-dependent. Conclusions: As the prospective alternatives to the Cis, the BC combination and individual BiONPs showed the capacities to be developed as radiosensitizers for proton beam therapy.
EN
Introduction. Cancer is a leading cause of mortality. Hepatocellular cancer is one of the malignancies associated with poor outcome and resistance to pharmacotherapy. Cancer stem cells (CSCs) contribute to resistance to therapy and hence lead to the treatment failure of tumors. Aim. This study aims to explore the expression of CSCs in response to cisplatin treatment in HepG2 hepatocellular cancer cell line. Material and methods. Cell proliferation test, CCK-8, was used to evaluate the cell proliferation following cisplatin treatment for 72 hours. The expressions of CSC markers CD44, CD90, and CD133 were assessed by flow cytometric analysis. Results. The results showed a dose-dependent decrease in cell proliferation and increased expression of CSC markers CD44 and CD90 in response to cisplatin. Conclusion. Understanding the roles of CSC markers may point to new targets and therapeutic strategies to predict and overcome cisplatin resistance.
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tom 77
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nr 1
183-193
EN
Cisplatin is an antineoplastic drug, used for the treatment of ovarian cancer. SMEDDS has many advantages such as enhanced bioavailability, lymphatic targeting and ease of manufacture. The main objective of this study was to prepare and characterize Cisplatin loaded SMEDDS formulation and to evaluate antitumoral activity with cell viability studies. Cisplatin SMEDDS formulation was prepared and characterized physicochemically. In vitro release studies and cell viability studies were performed and evaluated. The mean droplet size of Cisplatin SMEDDS was measured as 25,4±1,9 nm and PDI was 0,241±0,018. Refractive index of the formulation was measured as 1,471±0,001. pH values of Cisplatin SMEDDS (dilution ratio 1:10 w) were measured as 5,84±0,09 and (dilution ratio 1:10 pH 6,8 PBS) 6,51±0,14. Viscosity of formulation was measured as 284 mPa. According to in vitro release studies, %78,17 of Cisplatin were released from Cisplatin SMEDDS. The formulation performed cytotoxic effect to A2780 cells; vitality was found 20,26% at 0,02 µg/mL. It was concluded that, Cisplatin SMEDDS could be beneficial for the treatment of ovarian cancer and it could be promising alternative due to its enhanced bioavailability.
12
Content available remote Recognition and repair of DNA-cisplatin adducts.
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EN
Anticancer activity of cisplatin (cis-diamminedichloroplatinum) is believed to result from its interaction with DNA. The drug reacts with nucleophilic sites in DNA forming monoadducts as well as intra- and interstrand crosslinks. DNA-cisplatin adducts are specifically recognized by several proteins. They can be divided into two classes. One constitutes proteins which recognize DNA damage as an initial step of the nucleotide excision and mismatch repair pathways. The other class contains proteins stabilizing cellular DNA-protein and protein-protein complexes, including non-histone proteins from the HMG (high-mobility-group) family. They specifically recognize 1,2-interstrand d(GpG) and d(ApG) crosslinks of DNA-cisplatin adducts and inhibit their repair. Many HMG-domain proteins can function as transcription factors, e.g. UBF, an RNA polymerase I transcription factor, the mammalian testis-determining factor SRY and the human mitochondrial transcription factor mtTFA. Moreover, it seems that some proteins, which probably recognize DNA-cisplatin adducts non-specifically, e.g. actin and other nuclear matrix proteins, can disturb the structural and functional organization of the nucleus and whole cell. The formation of complexes between DNA and proteins in the presence of cisplatin and the changes in the cell architecture may account for the drug cytotoxicity.
EN
The DFF40/CAD endonuclease is primarily responsible for internucleosomal DNA cleavage during the terminal stages of apoptosis. It has been previously demonstrated that the major HMG-box-containing chromatin proteins HMGB1 and HMGB2 stimulate naked DNA cleavage by DFF40/CAD. Here we investigate the mechanism of this stimulation and show that HMGB1 neither binds to DFF40/CAD nor enhances its ability for stable binding to DNA. Comparison of the stimulatory activities of different truncated forms of HMGB1 protein indicates that a structural array of two HMG-boxes is required for such stimulation. HMG-boxes are known to confer specific local distortions of DNA structure upon binding. Interestingly, the presence of DNA strand cross-links formed by cisplatin or transplatin, which may somehow mimic distortions induced by HMG-boxes, also affects DNA cleavage by the nuclease. The data presented suggest that changes induced in DNA conformation upon HMG-box binding makes the substrate more accessible to cleavage by DFF40/CAD nuclease and thus may contribute to preferential linker DNA cleavage during apoptosis.
14
Content available remote Poszukiwanie nowych leków na bazie cisplatyny
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tom [Z] 52, 7-8
531-544
EN
Cancer therapy is one most the challenging tasks for medicine at the end of this century. The subject of discussion in this paper is cisplatin which about thirty years ago has awaked a hope for an effective treatment of cancer. The following problems have been reviewed : the effect of various substituents on the biological activity of the compounds : cis-PtAm2X2 (where Am is ammine or amine and X is an anionic group), the mechanism of action of cisplatin and the structures of its coordination compounds with DNA. The side effects of cisplatin therapy, in particular its nefrotoxicity and the attempts to establish the structure-activity relationship have been discussed. The second and third generation of platinum-based drugs are presented, including the cisplatin drugs which are joint with some biologically active compounds. They act as the vectors delivering the drug directly to the cancerous cells, hereby decreasing toxicity of these drugs.
EN
Acquired drug resistance of tumor cells is frequently observed in cancer patients un­dergoing chemotherapy. We studied murine leukemia L1210 cells sensitive and resis­tant to the cytotoxic action of cisplatin and showed that cisplatin-resistant leukemia cells were also refractory to TGF /β1-dependent growth inhibition and apoptosis. Ad­dressing the question about the mechanisms responsible for the cross-resistance to cisplatin and TGF /β1, we found that cisplatin- and TGF /β1-resistant L1210 cells pos­sessed a decreased expression of type I TGF /β1 receptor, while the expression of type II TGFβ1 receptor was not affected. Western blot analysis of Smad proteins 2, 3, 4, 6, and 7, which participate in signal transduction pathway down-stream of the TGF /β1 receptors, revealed an increased expression of Smad 6, inhibiting TGF β1 action, only in cisplatin- and TGFβ1-resistant L1210 cells. TGFβ1 and especially the cytotoxic mis­tletoe agglutinin increased Smad 6 expression in TGF β1-sensitive but not in TGF /β1-resistant L1210 cells. TGF /β1-resistant L1210 cells also differed from TGF /β1-sensitive cells by the lack of expression of the pro-apoptotic p53 protein and higher level of expression of the anti-apoptotic Bcl-2 protein. Thus, the described co-expression of tumor cell refractoriness to an anti-cancer drug and to the inhibitory cytokine TGF β1 is accompanied by multiple changes in the TGF β1 signal transduction pathway and in other regulatory systems of the target cells. Besides, we found that various anti-tumor drugs and cytotoxic plant lectins increased the level of TGF β1 expression in both TGF β1-sensitive and -resistant L1210 cells. A hypothesis is proposed that TGF β1 can at least partly mediate the effect of cell-stressing agents and, thus, the development of TGF β1 resistance may be responsible for the appearance of tumor cell refractoriness to the action of some anti-cancer drugs.
EN
In this study we determined Vi bacteriophage III sensitivity to native cisplatin, γ radiation (60Co) or to irradiated cisplatin, and checked the possibility of enhanced Vi bacteriophage III inactivation under combined exposure to cisplatin and γ radiation. We used highly purified phage suspensions in 0.9% NaCl solution or phosphate-buffered saline. Phage suspensions were titrated using a double agar layer method. Our study implies that survival of Vi bacteriophage III shows an exponential inverse correlation with cisplatin concentration in the incubation medium and the time of phage incubation in the presence of cisplatin. The use of irradiated cisplatin reduces phage survival in comparison with suspensions containing non-irradiated cisplatin. Irradiation of phage suspension with cisplatin causes a significant increase of phage inactivation in comparison with either treatment alone. Our results suggest that presence of cisplatin in irradiated medium enhances the radiobiological effect on Vi bacteriophages III.
18
Content available Rak szyjki macicy – czy zawsze chirurgia?
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EN
Worldwide, cervical cancer is the second most common genital malignancy in the females. Estimated number of women affected therewith reaches 1.4 million. In Poland, cervical cancer is the fourth most common cancer, preceded by breast cancer, lung cancer and endometrial cancer, and the fifth most common cause of cancer-related mortality. Cervical cancer usually affects women aged 45-59. Current standards of treatment of cervical cancer include surgery (still the basic modality at stages 0, IA, IB and IIA), radiotherapy, chemotherapy and radiochemotherapy, which are implemented at stages IB-IVB. Surgical treatment of cervical cancer patients is classified as follows: primary treatment, treatment of coexisting genital conditions prior to planned radiochemotherapy, treatment of recurrent cervical cancer and palliative treatment. Low efficacy of radiotherapy and chemotherapy as the sole treatment modalities in cervical cancer resulted in increased interest in radiochemotherapy, i.e. a technique combining radiation with cytotoxic drugs. Randomized trials revealed an improvement of 3-years’ survival by 10-18% and the drug used most often was cisplatin administered alone or combined with a 96-hours’ infusion of fluorouracil. Cervical cancer is currently considered one of the tumors, where multimodal treatment is a therapeutic standard.
PL
W skali świata rak szyjki macicy jest drugim co do częstości występowania nowotworem narządów płciowych u kobiet. Szacuje się, że liczba kobiet chorych na raka szyjki macicy na świecie sięga 1,4 miliona. W Polsce rak szyjki macicy zajmuje czwarte miejsce – po raku sutka, płuc i endometrium – oraz piąte miejsce jako przyczyna zgonów wśród kobiet z powodu nowotworów złośliwych. Rak szyjki macicy najczęściej rozwija się u kobiet pomiędzy 45. a 59. rokiem życia. Współczesne standardy leczenia raka szyjki macicy obejmują: leczenie chirurgiczne, które wciąż jest podstawą w stopniu 0, IA, IB, IIA, radioterapię, chemioterapię oraz radiochemioterapię, które stosuje się w stopniach od IB do IVB. Leczenie chirurgiczne u chorych z rakiem szyjki macicy dzieli się na następujące typy: leczenie pierwotne, leczenie współistniejących patologii narządów płciowych przed planowaną radiochemioterapią, leczenie nawrotów raka szyjki macicy i leczenie paliatywne. Niska skuteczność radioterapii i chemioterapii stosowanych samodzielnie w raku szyjki macicy spowodowała wzrost zainteresowania radiochemioterapią, czyli metodą łączącą leczenie promieniami i lekami cytotoksycznymi. W badaniach randomizowanych stwierdzono poprawę 3-letniego przeżycia o 10-18%, a lekiem najczęściej stosowanym jest cisplatyna podawana oddzielnie lub w skojarzeniu z 96-godzinnym wlewem fluorouracylu. Rak szyjki macicy należy obecnie do nowotworów, w których leczenie skojarzone stanowi standard terapeutyczny.
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