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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rat-liver cells (Ac2F cells) were transfected with cisplatin-damaged eucaryotic expression vectors carrying luciferase cDNA (cis-DDP-pVJ3luc) and incubated. The lysate of the incubated cells was subjected to a luciferase activity assay. Graded decrease in the activity was observed with increasing levels of platination of the plasmid DNA. In another experiment, Ac2F cells were pre-incubated in the presence of cisplatin ranging in concentration from 0.5 to 3 mu M. The viable cells were transfected with cis-DDP-pVJ3luc and incubated in the absence of this drug. The lysate of the incubated cells was subjected to the same assay. The level of the luciferase activity was raised with increasing cisplatin concentration. These results suggest that the repair activity for cis-DDP-pVJ3luc DNA is enhanced in Ac2F cells exposed to cisplatin.
Biochem Mol Biol Int 1996 Apr
PMID:Enhancement of DNA repair activity in rat-liver cells exposed to cisplatin. 913 66

DNA-protein crosslinking by cis-dichlorodiammineplatinum (II) (cis-DDP) was applied to study chromatin structure in situ. Histone H1 (H5) is crosslinked to DNA in significant amounts whereas core histones remain practically unattached. "Protein image hybridization" experiments show that the 5'-region of the D metanogaster hsp 70 gene is free of histone H1 in both control nuclei and nuclei isolated from heat-shocked embryos.
Biochem Mol Biol Int 1996 Apr
PMID:Mapping protein-DNA interactions with CIS-DDP: chromatin structure of promoter region of D. Melanogaster hsp 70 gene. 913 69

An affinity gel matrix containing an enzyme (DD-peptidase) with specific beta-lactam binding properties was characterized with respect to its binding and reactivity behavior with penicillin. The data show that immobilization of DDP by reaction with the enzymes susceptible amino groups resulted in changes in catalytic activity on a tripeptide substrate, penicillin binding efficiency and pH stability of drug binding. Properties unaffected by immobilization were the drug-enzyme complex stability, binding reaction mechanism, drug selectivity and method of complex desorption. The affinity of DDP for penicillin-G was investigated by surface plasmon resonance. These characteristics were compared with those of the soluble enzyme. Conditions for elution of the bound drug were determined and a method for immobilizing Streptomyces DDP by which its binding site structure is sustained was also evaluated.
J Mol Recognit
PMID:Effect of immobilization on the penicillin binding and reactivity properties of DD-peptidase from Streptomyces R61. 917 61

Effects of cis-diamminedichloroplatinum (cisplatin) on rat kidney were investigated. Clinical parameters in rat urine and blood were studied. Blood urea nitrogen (BUN) and creatinine in blood and K+ in urine increased, but Na+ in urine decreased. Contents of total P450 and metabolic activities towards lauric acid and arachidonic acid in rat renal microsomes were not changed by cisplatin treatment. The levels of P450 isozymes (CYP4A1, 4A2, 4A8 and 2C23) were determined in rat renal microsomes by immunoblotting. The levels of CYP4A2 and 4A8 which are lauric acid omega-hydroxylases were not changed, but the levels of CYP2C23 and 4A1 were increased significantly by cisplatin treatment. Effects of clofibrate, a typical inducer for CYP4A1, on rat kidney were compared with those of cisplatin. Clofibrate induced palmitoyl CoA oxidase (a marker enzyme of peroxysome), CYP4A1, and CYP4A2 and reduced triglyceride level in plasma. Cisplatin had similar effects to clofibrate and induced peroxysomes as well as CYP4A1, although the effects were at a lesser extent than those of clofibrate. The induction levels of CYP4A1 correlated with increased levels of BUN. The present findings suggest that induction of P450 by cisplatin may take part in the renal injury or nephrotoxicity of cisplatin.
Res Commun Mol Pathol Pharmacol 1998 Jan
PMID:cis-Diamminedichloroplatinum induces peroxisomes as well as CYP4A1 in rat kidney. 952 52

This study was designed to investigate the cisplatin-induced alteration in renal antioxidant system and the nephroprotection with ebselen. Male Wistar rats were injected with (1) vehicle control; (2) cisplatin; (3) ebselen; and (4) cisplatin plus ebselen. Rats were sacrificed three days post-treatment and plasma as well as kidney were isolated and analyzed. Plasma creatinine increased 598% following cisplatin administration alone which decreased by 158% with ebselen pretreatment. Cisplatin-treated rats showed a depletion of renal glutathione (GSH) levels (52% of control), while cisplatin plus ebselen injected rats had GSH values close to the controls. Antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities decreased 38, 75 and 62% of control, respectively, and malondialdehyde (MDA) levels increased 174% of control following cisplatin administration, which were restored to control levels after ebselen treatment. The renal platinum level did not significantly change with ebselen pretreatment. This study suggests that the protection offered by ebselen against cisplatin-induced nephrotoxicity is partly related to the sparing of antioxidant system.
Mol Cell Biochem 1998 Jan
PMID:Protection by ebselen against cisplatin-induced nephrotoxicity: antioxidant system. 954 91

The A1 adenosine receptor (A1AR) contributes to the cytoprotective action of adenosine under conditions known to generate reactive oxygen species (ROS). Pharmacological manipulation of A1AR expression has been shown to modulate this cytoprotective role. In this study, we provide evidence that ROS generated could increase the expression of the A1AR and thereby offset the detrimental effects of ROS. Incubation of DDT1MF-2 smooth muscle cells with ROS-generating chemotherapeutic agents, such as cisplatin (2.5 microM) or H2O2 (10 microM), elicited an increase in A1AR expression within 24 hr. The induction by H2O2 was reduced by the ROS scavenger catalase but not superoxide dismutase. Inhibition of nuclear factor kappa B (NF kappa B) by pyrrolidine dithiocarbamate (200 microM), dexamethasone (100 nM), or genistein (1 microM) abrogated the cisplatin-mediated increase in A1AR. Cisplatin promoted rapid translocation of NF kappa B (but not AP-1) to the nucleus, as detected by electrophoretic mobility shift assays and by Western blotting. A putative NF kappa B sequence in the A1AR promoter effectively competed with labeled kappa B probe for binding in nuclear preparations derived from DDT1MF-2 cells. Transient transfection of DDT1MF-2 cells with the A1AR promoter coupled to firefly luciferase reporter gene led to cisplatin-inducible and pyrrolidine dithiocarbamate-sensitive luciferase activity, suggesting the presence of functional NF kappa B binding site(s) in the A1AR promoter sequence. Treatment of cells with (R)-phenylisopropyladenosine (1 microM), an agonist of the A1AR, reduced cisplatin-mediated lipid peroxidation, which was reversed after blockade of the A1AR. These data suggest that ROS can increase the expression of the A1AR by activating NF kappa B regulatory site(s) on this gene and thereby enhance the cytoprotective role of adenosine.
Mol Pharmacol 1998 Apr
PMID:Oxidative stress increases A1 adenosine receptor expression by activating nuclear factor kappa B. 954 56

We investigated the roles of p53 and Bcl-2 homologues in the induction of apoptosis by cisplatin and paclitaxel in wild-type p53-expressing human ovarian carcinoma cells and cisplatin-resistant derivatives that have lost p53 function. Cisplatin induced apoptosis in parental A2780 but not in cisplatin-resistant A2780/cp70 cells, whereas paclitaxel induced apoptosis in both cell lines. Immunoprecipitation of p53 using antibodies specific for p53 conformation (pAb 1620 and pAb 240) showed that there were no relative changes in p53 conformation before and after cisplatin treatment in either cell line. A2780/cp70 cells have lost p53 function, yet they have wild-type p53 gene sequence. However, A2780/cp70 cells constitutively express more p53 in a form detected by pAb 240, an antibody that also detects mutant conformations of p53 that are transcriptionally inactive. There were no changes in levels of Bcl-2, Bcl-XL, or 24-kDa Bax over 72 hr after exposure to cisplatin or paclitaxel, but each agent led to up-regulation of Bak and 21-kDa Bax in A2780 cells. Paclitaxel, but not cisplatin, increased Bak and 21-kDa Bax levels in A2780/cp70 cells. These data suggest that apoptosis in A2780 and A2780/cp70 is associated with an increased level of Bak and 21 kDa Bax after drug-induced damage and that functional p53 may be required for this effect after cisplatin but not after paclitaxel.
Mol Pharmacol 1998 May
PMID:Cisplatin- and paclitaxel-induced apoptosis of ovarian carcinoma cells and the relationship between bax and bak up-regulation and the functional status of p53. 958 7

Cisplatin (cis-diamminedichloroplatinum II), a potent antitumor compound, stimulates immune responses by activating monocytes/macrophages and other cells of the immune system. However, the mechanism by which cisplatin activates these cells is poorly characterised. Our earlier findings indicate that cisplatin treatment stimulates rapid tyrosine phosphorylation in a number of cellular proteins in murine macrophages. This initial tyrosine phosphorylation is an important regulatory mechanism and is followed by activation of several other proteins. In the present study, we report the involvement of other key molecules and the role of tyrosine phosphorylation in their activation in the signaling cascade of cisplatin. We observed the involvement of Ras (a low molecular weight GTP-binding protein) and ERK-1 (a MAP kinase) in this signaling cascade. Cisplatin treatment results in an increase in the expression of both Ras and ERK-1 in a dose-dependent manner, which was dependent upon tyrosine phosphorylation. Genistein a PTK inhibitor inhibited the cisplatin induced expression of Ras and ERK-1. These findings indicate that Ras and ERK-1 are important signaling molecules involved in the tumoricidal activation of macrophages with cisplatin and is dependent on initial tyrosine phosphorylation.
Biochem Mol Biol Int 1998 Jul
PMID:Involvement of Ras and MAP kinase (ERK-1) in cisplatin-induced activation of murine bone marrow-derived macrophages. 967 53

We investigated the influence of granisetron, a 5-HT3 receptor antagonist, on the increase in 5-hydroxytryptamine (5-HT) release induced by cisplatin from the isolated ileum of the ferret, a species known to vomit in response to cisplatin. 2-Methyl-5-HT, a selective 5-HT3 receptor agonist, increased the release of 5-HT from the ferret ileum in a concentration-dependent manner within the range of 10(-7) to 10(-6)M. The 5-HT release induced by 2-methyl-5-HT was significantly inhibited by a concomitant perfusion with granisetron (10(-6)M). Cisplatin also increased the 5-HT release from the ferret ileum within the range of 10(-8) to 10(-6)M, in a concentration-dependent manner. Granisetron (10(-6)M) also significantly inhibited the cisplatin-induced 5-HT release. Since the cisplatin-induced 5-HT release was significantly inhibited by tetrodotoxin, the possible involvement of an interneuron pathway in the cisplatin-induced 5-HT release mechanism was suggested in the ileal tissue. It is likely that granisetron inhibited the cisplatin-induced 5-HT release from the gut EC cells by producing blockade of an EC cell 5-HT3 receptor.
Res Commun Mol Pathol Pharmacol 1998 Jun
PMID:Granisetron, a 5-HT3 receptor antagonist, inhibited cisplatin-induced 5-hydroxytryptamine release in the isolated ileum of ferrets. 973 4

Oxaliplatin is a clinical anticancer drug with a pharmacological profile distinct from that of cisplatin. Our studies compared site- and region-specificity of lesions induced by oxaliplatin and cisplatin in naked and intracellular DNA, respectively. Oxaliplatin adducts in naked Simian virus 40 (SV40 DNA) were mapped by repetitive primer extension. The sites of oxaliplatin adducts were nearly identical to the sites of cisplatin adducts and were focused in G clusters and GNG motifs probably reflecting intrastrand cross-links. Although alkaline agarose electrophoresis of specific SV40 fragments showed that oxaliplatin formed interstrand cross-links, the levels of this lesion type were low. Drug-induced lesions in discrete loci of cellular DNA were assessed by the polymerase chain reaction stop assay in human tumor A2780 cells. Oxaliplatin at 200 microM induced approximately 1300, approximately 1500, approximately 800, and approximately 300 lesions/10(6) bp in the human beta-globin, c-myc, and HPRT genes and in mitochondrial DNA, respectively. Cisplatin formed two to six times more lesions in the same regions. For both drugs, lesion frequencies seem to parallel the density of drug-binding motifs in the nuclear regions, whereas mitochondrial DNA was disproportionately less affected. Despite less potent induction of DNA lesions, oxaliplatin was more cytotoxic than cisplatin against A2780 cells. Because our findings clearly demonstrate that oxaliplatin forms covalent adducts with a similar sequence- and region-specificity to that of cisplatin, other properties of oxaliplatin adducts, factors other than DNA binding, or both determine the unique features of the mechanism of action of oxaliplatin.
Mol Pharmacol 1998 Nov
PMID:Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. 980 12


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