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Protein kinase inhibitors, widely exploited for elucidation of the biological functions of kinases, have more recently come under active consideration as potential chemo­therapeutic agents for tumour and other diseases. A brief overview is presented of diverse approaches to the design and development of selective protein kinase inhi­bitors, and related problems such as donor and acceptor specificities, stereochemical aspects, emerging relationships between protein, sugar and nucleoside kinases. In particular, and contrary to popular belief that ATP-competitive inhibifcrs cannot be selective because of the close homology of the ATP catalytic sites, numerous examples are presented of such inhibitors which are both potent and selective for a given kinase or class of kinases. Some of these are undergoing preclinical trials. Attention is also directed to the role of cellular and viral protein kinases in the ljfe cycle of viruses, and the potential of these enzymes, especially those encoded by, and essential for repli­cation of, a given virus as targets for antiviral chemotherapy.
Out of 481 selected patients treated under basic and specialist health care a group of 53 patients taking antibiotics and chemotherapeutic iroslawagents because of infections of respiratory and digestive systems has been separated. Research on these patients included an assessment of their diet, a sociological survey questionnaire and a questionnaire concerning the way in which the drugs are taken. In the case of 19 people surveyed (35.8%) an incorrect way of taking drugs in relation to meals has been stated, which created a risk of decrease in or lack of the drugs activity. In the light of the above observations, it seems important to educate patients and physicians and draw their attention to the possibility of pharmacotherapy complications connected with the interactions between antibiotics and chemotherapeutic agents and food.
Spośród 481 losowo wybranych pacjentów leczonych w podstawowej i specjalistycznej opiece zdrowotnej wyodrębniono grupę 53 pacjentów zażywających antybiotyki i chemioterapeutyki z powodu zakażeń układu oddechowego i pokarmowego. Badania u tych pacjentów objęły ocenę sposobu żywienia, kwestionariusz badań socjologicznych i kwestionariusz dotyczący sposobu zażywania leków. U 19 badanych (35,8%) stwierdzono nieprawidłowy względem posiłków sposób zażywania leków, co stwarzało ryzyko zmniejszenia lub braku ich działania. W świetle powyższych obserwacji ważna jest edukacja pacjentów i lekarzy w celu zwrócenia uwagi na możliwości powikłań farmakoterapii związanych z interakcjami pomiędzy antybiotykami i chemioterapeutykami a żywnością.
This brief overview describes some of the properties of various cellular phospho­transferase systems, with particular emphasis on nucleoside 5'-triphosphate (NTP)- dependent protein kinases and nucleoside kinases, for which it is widely and impli­citly assumed that ATP is the intracellular phosphate donor. Numerous examples are presented, based on the in vitro properties of these enzymes, to show that ATP is not the only, or frequently not even the major, phosphate donor, and that this is probably reflected in vivo. It is pointed out that in vitro studies of donor and acceptor speci­ficities of kinases must take account of the intracellular concentrations of nucleoside 5-triphosphates, a problem also relevant to the design of nucleoside analogues as chemotherapeutic agents. Attention is also drawn to NTP analogues as substrates/ inhibitors of protein kinases, and to several examples of low-molecular mass non- peptide substrates of these enzymes.
In this study, we investigated apoptosis induced in human trisomic and diabetic fibroblasts by daunorubicin (DNR) and its derivative, idarubicin (IDA). The cells were incubated with DNR or IDA for 2 h and then cultured in a drug-free medium for a further 2–48 h. The apoptosis in the cultured cell lines was assessed by biochemical analysis. We found that both drugs induced a timedependent loss of mitochondrial membrane potential, and a significant increase in intracellular calcium and caspase-3 activity. Mitochondrial polarization and changes in the level of intracellular calcium were observed during the first 2–6 h after drug treatment. Caspase-3 activation occurred in the late stages of the apoptotic pathway. Our findings also demonstrated that idarubicin was more cytotoxic and more effective than daunorubicin in inducing apoptosis in trisomic and diabetic fibroblasts.
A capillary electrophoresis (CE) method for the simultaneous determination of residues of six quinolones (enrofloxacin, ciprofloxacin, ofloxacin, lomefloxacin, norfloxacin, cinoxacin) in chicken, hen, and swine tissue samples were developed and validated. The sample preparation consisted of a solid phase extraction on C-18 cartridges prior to the analysis by CE with UV detection. The method was validated in terms of selectivity, linearity, precision, accuracy, recovery, and stability. The calibration curves were linear to at least 10-1 000 ng/g for all quinolones with r² > 0.999. The values of decision limits (CCα) and detection capabilities (CCβ) for the analysed substances were between 3.2-16.9 and 3.5-20.3 ng/g, respectively. The CE method was robust and specific, allowing reliable quantification of quinolone residues in animal tissues and should also be useful for clinical and biomedical investigations.
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-inter- strand 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.
Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2 and ribonucleotide reductase (RNR). FANCD2 plays an important role in the resistance of cells to DNA damage agents and the activation of DNA damage checkpoints, while RNR is critical for the completion of DNA replication and repair in response to DNA damage and replication stress. Regulation of FANCD2 and RNR suggests that cancer cells depend on PI3K-Akt-mTOR signaling for survival in response to DNA damage, indicating that the PI3K-AktmTOR pathway promotes resistance to chemotherapy and radiotherapy by enhancing DNA damage repair.
Content available remote Drug-mediated ototoxicity and tinnitus: alleviation with melatonin
This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin’s low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.
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