Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary resistance to vincristine (VCR) has been selected in rhabdomyosarcoma xenograft HxRh12 by sequential administration of VCR at 1.5 and subsequently 3 mg/kg/passage. The resistant tumor (HxRh12/VCR-3) was approximately 4-fold resistant to VCR and resistance was stable in the absence of selecting pressure (greater than 2 yr). HxRh12/VCR-3 was 2- to 3-fold cross-resistant to L-phenylalanine mustard (L-PAM) but only slightly cross-resistant to ifosfamide. To determine whether selection for primary resistance to L-PAM conferred cross-resistance to VCR we selected an L-PAM-resistant subline of rhabdomyosarcoma xenograft HxRh28 (HxRh28/L-PAM-13). This tumor was 2- to 3-fold resistant to L-PAM and 3-(p-fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)-aminophenyl]-L- alanyl-L-methionine ethoxyhydrochloride, cross-resistant to cyclophosphamide and ifosfamide, and completely resistant to VCR under in vivo conditions. Pharmacokinetic studies in HxRh12/VCR-3 showed decreased retention of [G-3H]VCR but not alteration in metabolism. Expression of mdr1, a gene that encodes P-glycoprotein, associated with the multiple drug resistance phenotype, was examined. Expression of mdr1 was detected in both HxRh12 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM. Data suggest that mechanisms other than those associated with "classical" multiple drug resistance confer resistance in these tumors. In clinical evaluation against childhood rhabdomyosarcoma, L-PAM has demonstrated only slight activity in patients relapsing on conventional therapy (including VCR) but demonstrated marked activity in patients with advanced previously untreated disease. It appears likely, therefore, that cross-resistance between VCR and L-PAM as demonstrated in this model may have clinical significance.
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PMID:Reciprocal cross-resistance in human rhabdomyosarcomas selected in vivo for primary resistance to vincristine and L-phenylalanine mustard. 289 Apr 32

HL60 cells resistant to Adriamycin contain a 32P-labeled, Mr 150,000 surface membrane protein (p150) which is not detected in cells sensitive to drug. The levels of phosphorylation of this protein increase with increasing levels of resistance. Analysis of plasma membranes prepared from cells labeled with [14C]glucosamine shows, however, that both sensitive cells and those exhibiting an 80-fold increase in drug resistance contain essentially identical levels of a highly glycosylated Mr 150,000 protein. Identical results are obtained when cells are labeled with [14C]galactose or [14C]mannose. Limited proteolytic digestion of [14C]glucosamine-labeled p150 from sensitive and resistant cells shows that the glycopeptides formed are identical. Additional studies involving binding of proteins to insolubilized lectin indicate that 32P-labeled p150 is glycosylated. Polyacrylamide gel electrophoresis of p150 followed by silver staining shows no difference in the levels of this protein in sensitive and 80-fold drug-resistant cells. Further studies show that two-dimensional tryptic peptide maps of 125I-labeled p150 of sensitive and resistant cells are essentially the same. It has also been found that treatment of cells with 12-O-tetradecanoylphorbol-13-acetate followed by [14C]glucosamine labeling results in a selective decrease in the glycosylation of p150 of sensitive and resistant cells. TPA has an identical effect on the phosphorylation of p150 in cells resistant to drug. HL60 cells have also been examined for the presence of the Mr 170,000 to 180,000 P-glycoprotein. Using immunoblot analysis with a monoclonal antibody directed against the P-glycoprotein we did not detect the presence of this protein in membranes of drug-sensitive or -resistant HL60 cells. The results of this study suggest that Adriamycin resistance in HL60 cells may be related to a modified form of a protein contained in cells sensitive to drug. Proteins active in drug resistance in this system may be distinct from those described for other cell lines.
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PMID:Adriamycin resistance in HL60 cells and accompanying modification of a surface membrane protein contained in drug-sensitive cells. 362 Nov 92

This study has investigated domperidone (DOM) and quinidine (QD) interaction in the Wistar rat experimental model of repeated administration. We used nonconventional administration model consistent with occasional administration method. Difference in administration was related to sequence of domperidone alone or with quinidine dosage. Expected domperidone-quinidine interactions could have its origin both in the ability of quinidine to inhibit P-glycoprotein (P-gp) activity as well as cytochrome P450-mediated metabolism of both compounds. There also were examined kinetics of acetaminophen (PAM) administered (30 mg/kg) with domperidone as an indicator of gastric emptying, showing domperidone prokinetic activity, as well as quinidine anticholinergic activity. Domperidone (30 mg/kg) with PAM and with/without quinidine (25 mg/kg) was administered orally according to the disposition regiment different for six examined rat groups. DOM and PAM concentrations in plasma were assayed by HPLC method. Following changes were observed: domperidone did not modify the duration of the uptake phase of acetaminophen; quinidine prolongs gastric emptying time (as a result of anticholinergic action); quinidine given as the fourth or fifth dose with domperidone promotes growth of its concentration in plasma; analysis of changes in the value of AUC(0-2) at the initial three weeks of experiment suggests intensity of domperidone absorption processes, the following week increase in the value AUC(4-6) suggests inhibition of domperidone hepatic biotransformation and the mechanism of induction of absorption during domperidone administration is different from the absorption - inducing effects of quinidine. Both effects are superimposed and produce large, 2, 3-fold change in domperidone's AUC(0-6).
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PMID:QUINIDINE AND DOMPERIDONE INTERACTIONS IN THE RAT EXPERIMENTAL MODEL OF REPEATED ADMINISTRATION. 2964 32