Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Chinese hamster cell mutant (V-C8) isolated previously, which is approximately 100 fold more sensitive to mitomycin C (MMC) than its parental wild-type V79 cells (judged by D10 values), was further characterized. V-C8 cells exhibit an increased sensitivity towards other cross-linking agents, such as cis-DDP (approximately 40-fold), DEB (approximately 30-fold), and also to adriamycin (approximately 5-fold), and the monofunctional alkylating agents: MMS (approximately 5-fold) and EMS (approximately 6-fold). V-C8 cells show a higher level induction of chromosomal aberrations by cross-linking agents (MMC, cis-DDP, and DEB) and an increased level of spontaneous chromosomal aberrations in comparison to the wild-type V79 cells. To determine whether the V-C8 mutant represents a new complementation group among Chinese hamster cell mutants that also display the extreme sensitivity to MMC, V-C8 cells were fused with irs1, irs1SF, UV20, UV41, and V-H4 cells. In all cases, the derived hybrids regained the MMC sensitivity similar to wild-type cells, indicating that the V-C8 mutant belongs to a new sixth complementation group.
Somat Cell Mol Genet 1993 Sep
PMID:Genetic diversity of mitomycin C-hypersensitive Chinese hamster cell mutants: a new complementation group with chromosomal instability. 829 Oct 21

We previously reported that mRNA loses the ability to direct in vitro peptide synthesis after incubation with cisplatin. The present study was designed to determine the step in translation that is affected. The rates of translation reactions inhibited by cisplatin were biphasic, having an initial rate comparable to that of the uninhibited reaction before decreasing. Analysis of cisplatin-inhibited reactions in sucrose density gradients showed a decrease in polyribosome formation. These results are consistent with an inhibition of the initiation step of protein synthesis. Individual steps in initiation were tested by analyzing the formation of ribosomal subunits in sucrose gradients that resolve the incomplete complexes. Cisplatin caused an accumulation of 48 S particles accompanied by a decreased amount of completed 80 S initiation complexes. Similar results were obtained in experiments utilizing radiolabeled methionine or mRNA. We conclude that cisplatin blocks the initiation of translation by preventing the joining of the 60 S ribosomal subunit to the 48 S preinitiation subunit.
Mol Pharmacol 1993 Mar
PMID:Cisplatin inhibits in vitro translation by preventing the formation of complete initiation complex. 845 Aug 39

Cisplatin is a prominent member of the effective broad spectrum antitumor drugs. The clinical usage of cisplatin is, however, restricted due to some adverse side effects including renal toxicity. The present study demonstrates the protective effect of a Zinc-chelate of histidine, [Zn-Hist], against cisplatin induced nephrotoxicity and gastrointestinal toxicity as shown by decreases in BUN, creatinine and lower incidence of diarrhoea. The observed inhibition in cisplatin induced renal and hepatic lipid peroxidation by [Zn-Hist] pretreatment, suggests an importance for Zn in stabilisation of membrane integrity probably through the displacement of the redox-active metals that may be responsible for inducing peroxidative damage at target sites. The findings also suggest that cisplatin may play biochemical role in arginine-metabolism including nitric oxide (NO) production.
Biochem Mol Biol Int 1995 Jul
PMID:Reduction of cis-platinum induced nephrotoxicity by zinc histidine complex : the possible implication of nitric oxide. 852 48

The interaction of DNA molecule with some coordination compounds of the divalent platinum: cis-DDP, trans-DDP, [(NH3)4Pt]Cl2 and K2PtCl4 was studied. It was shown that the transition of the cis-DDP, trans-DDP, and [PtCl4]2- to aquo-complexes is necessary for their binding with DNA in solution. It was shown that the labile chloride groups are responsible for the formation of the energetically strong binding. The distance between chloride groups in cis-DDP is optimal for incorporation of two groups of DNA bases into the first coordination sphere of platinum. The complexes are also stabilized with phosphate in the external coordination sphere of platinum. The sterical non-conformity between the DNA structure and positions of chloride groups and the orientation of the amino groups in trans-DDP are the main obstructions for the formation of bidentate DNA-trans-DDP complexes. The existence of more than two vacant positions for binding with DNA in [PtCl4]2- does not stabilise the complex. The compound [(NH3)4Pt]Cl2 cannot produce coordination bonds with DNA, because its first coordination sphere is completed with amino groups; it interacts with DNA, forming principally different complexes.
Mol Biol (Mosk)
PMID:[Interaction of DNA molecules with divalent platinum coordination complexes. II. Effect of the nature and location of ligands in the first platinum coordination sphere]. 855 62

The alteration of Ca(2+)-binding protein regucalcin mRNA expression in the kidney cortex of rats administered cisplatin and cephaloridine, which can induce kidney damage, was investigated. Cisplatin (0.25, 0.5 and 1.0 mg/100 g body weight) or cephaloridine (25, 50 and 100 mg/100 g) was intraperitoneally administered in rats, and 1, 2 and 3 days later they were sacrificed. The alteration in serum findings after the administration of cisplatin (1.0 mg/100 g) or cephaloridine (50 and 100 mg/100 g) demonstrated chemically induced kidney damage; blood urea nitrogen (BUN) concentration increased markedly and serum inorganic phosphorus or calcium concentration decreased significantly. Moreover, the administration of cisplatin (1.0 mg/100 g) or cephaloridine (100 mg/100 g) caused a remarkable increase of calcium content in the kidney cortex of rats, indicating kidney damage. The expression of regucalcin mRNA in the kidney cortex was markedly reduced by the administration of cisplatin or cephaloridine in rats, when the mRNA levels were analyzed by Northern blotting using rat liver regucalcin cDNA (0.9 kb). The mRNA decreases were seen with the used lowest dose of cisplatin or cephaloridine. The present study clearly demonstrates that the mRNA expression of Ca(2+)-binding protein regucalcin in the kidney cortex of rats is decreased by chemically induced kidney damage.
Mol Cell Biochem 1995 Oct 04
PMID:Suppressed expression of calcium-binding protein regucalcin mRNA in the renal cortex of rats with chemically induced kidney damage. 858 14

Exposure of HeLa cells to Cisplatin resulted in cell death characteristic of a suicide process known as apoptosis, as stated by morphologic features, extensive and specific DNA fragmentation and in situ end labeling of DNA breaks. The apoptotic cell death was induced timely in a dose-dependent manner, without any primary necrosis at the concentrations used. In contrast to other reports, the death in this cell line was accompanied by low-molecular weight DNA fragmentation. These results and their relevance to the apoptotic process are discussed.
Biochem Mol Biol Int 1995 Nov
PMID:Internucleosomal DNA cleavage in HeLa cells exposed to cisplatin. 858 42

The distribution of cisplatin in freeze-dried cryosections of rabbit bone marrow cells was measured with an imaging system. Cisplatin contains a single atom of platinum per molecule which allowed the concentration of the drug to be measured throughout the cryosections. This technique was chosen because it does not require the separation of cells into homogeneous subpopulations. X-ray imaging measured not only the distribution of the element labeling the drug, but also other elements which were used to follow the effect of the drug on membrane ion transport. In samples incubated for 10 hr in cisplatin a high selectivity in the uptake of this drug was observed. Only a few of the large early cells were found to accumulate this drug, while in the smaller more mature cells platinum could not be detected. Most of the platinum accumulated in the cytoplasm and was not evenly distributed. Cells containing high levels of platinum lost their cytoplasmic potassium and gained extracellular sodium and chloride. In some cases cells that contain lower concentrations of platinum with normal levels of potassium were found, indicating that the alteration of the membrane permeability or the inhibition of the K/Na pump did not occur during the initial accumulation of the drug. This membrane permeability or pump change requires the accumulation of high concentrations of the drug, resulting in the loss of potassium and the gain of sodium.
Exp Mol Pathol 1995 Aug
PMID:Distribution of cisplatin in bone marrow cells: quantitative X-ray imaging. 875 52

Platinum and trace metal distributions of a human ovarian adenocarcinoma cell line, IGROV1, and a subline resistant to the antitumor agent cisplatin were compared using nuclear microprobe analysis. The cisplatin-resistant cell line IGROV1-DDP exhibited a cytologically heterogeneous cell population. Two subpopulations were distinguished, small mononuclear cells, morphologically similar to the parental cells IGROV1, and enlarged polynuclear cells. Quantitative mapping of platinum and essential trace metal such as manganese, iron, copper and zinc was performed at the cellular level. Elemental maps were obtained with 2 mu m spatial resolution. Platinum appeared uniformly distributed within the cells, in all cell types. The same was true for copper and zinc. In some cases, iron maps showed preferential localization in the perinuclear region, especially in IGROV1-DDP polynuclear cells. Cisplatin resistance was associated with decreased platinum and iron concentrations and increased levels of copper and zinc. Decreased drug accumulation was encountered in both subpopulations of the resistant cell line. In contrast, high inter-individual variation of copper content was noticed in this cell line suggesting that in vitro cisplatin selection of human ovarian adenocarcinoma resistant cells can bring about the emergence of distinct cellular phenotypes.
Cell Mol Biol (Noisy-le-grand) 1996 Feb
PMID:Quantitative mapping of platinum and essential trace metal in cisplatin resistant and sensitive human ovarian adenocarcinoma cells. 883 69

A cis-diamminedichloroplatinum [DDP (cisplatin)]-resistant population of Schizosaccharomyces pombe was developed through chronic exposure of the 972 h- strain to increasing concentrations of the drug. The resulting cells, designated wtr2, were 5.25-fold resistant to DDP, are resistance was retained by clone isolated from this population in the absence of drug for > or = 5 months. After backcrossing and isolation of a single clone, random spore analysis gave a segregation ratio close to 1:1 for DDP resistance and sensitivity. Tetrad analysis confirmed a mendelian 2:2 segregation, suggesting that a single nuclear gene was responsible for the DDP-resistant phenotype. Stable diploids obtained from the mating of a resistant spore carrying the ade6-216 marker with the mei2-102-ade6-210 meiosis-deficient mutant remained resistant, indicating that the resistant phenotype was expressed dominantly. There was no difference between the accumulation of the DDP analog [3H]dichloro(ethylenediamine)-platinum(II) into whole cells derived from the sensitive and the resistant spores obtained from the last backcross. The resistant clones from a single tetrad did not have an increased level of glutathione and were collaterally sensitive to cadmium and arsenite. We conclude that in S. pombe, a stable and dominant DDP-resistant phenotype can be mediated by a single allele, that the phenotype is not accompanied by cross-resistance to cadmium or arsenite, and that the mechanism is not associated with a significant alteration in glutathione level or DDP uptake.
Mol Pharmacol 1996 Nov
PMID:Isolation and characterization of a cisplatin-resistant strain of Schizosaccharomyces pombe. 891 38

The genetic mechanisms underlying cisplatin (DDP) resistance in yeast were investigated by examining the cytotoxicity of DDP to Schizosaccharomyces pombe mutants that were either hypersensitive or resistant to Cd. Despite reports that have linked glutathione (GSH) to DDP resistance in human cancer cells, we found that a mutant of S. pombe that was hypersensitive to Cd by virtue of a 15-fold reduction in GSH level and lack of phytochelatin production was as tolerant as the wild-type strain to DDP. A mutant that harbored a mutation in hmt1, the gene encoding an ATP-binding cassette-type transporter for vacuolar sequestration of a phytochelatin/Cd complex, exhibited only mild hypersensitivity to DDP even though it was 100-fold more sensitive to Cd. Overexpression of hmt1 in wild-type or mutant cells conferred tolerance to Cd but failed to do the same for DDP. However, a strain that produced 6-fold more sulfide than wild-type cells was found to be 6-fold more resistant to DDP and twice as resistant to Cd; an association between DDP resistance and sulfide production was observed in three other strains that were examined, and overproduction of sulfide was accompanied by reduced platination of DNA. These results indicate that GSH and the GSH-derived phytochelatin peptides do not play critical roles in determining sensitivity to DDP in S. pombe but rather identify increased production of sulfide as a possible new mechanism of DDP resistance that may also be relevant to human cells.
Mol Pharmacol 1997 Jan
PMID:Role of determinants of cadmium sensitivity in the tolerance of Schizosaccharomyces pombe to cisplatin. 901 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>