Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with refractory metastatic renal cell carcinoma (RCC) were enrolled in a phase II study with teniposide (VM26) and cyclosporin A (CSA) to investigate (1) the effect of CSA on the response rate to VM26; and (2) the effect of CSA on the pharmacokinetics and pharmacodynamics of VM26. Sixteen patients initially received VM26 alone (200 mg m(-2) day(-1) i.v.). No objective responses were observed and all patients crossed over to receive at least an additional two courses (range 2-5) of VM26 plus CSA (5 mg kg(-1) 2h(-1) followed by 30 mg kg(-1) 48h(-1) i.v.). At the end of the 2-h loading dose of CSA, whole-blood CSA levels ranged from 2250 to 3830 ng ml(-1), whereas at the end of the 48-h CSA infusion, CSA ranged from 1830 to 4501 ng ml(-1). CSA significantly (P<0.01) increased the area under the curve (AUC) of VM26. The variation in the paired AUC of VM26 was 50%. Terminal half-life of VM26 was significantly (P<0.01) increased (1.72-fold) after CSA administration, whereas the systemic clearance of VM26 was decreased by 1.4-fold (P<0.01). The nadir neutrophil count after VM26 plus CSA (median 700 microl(-1), range <100 to 2860 microl(-1)) was lower than after VM26 alone (median 1900 microl(-1), range 200 to 6000 microl(-1)). Increased haematological toxicity after CSA could be explained by the increase in the VM26 AUC and by inhibition of P-glycoprotein (P-gp) activity in haematopoietic precursor cells. Bilirubin concentrations in the serum were increased after VM26 plus CSA compared with VM26 alone (P<0.01). Among the 15 patients evaluable for response, one had a minor response, eight had stable disease, and six had progressive disease. In conclusion, the dose of CSA we used achieved plasma concentrations within the effective range for P-gp inhibition. CSA affected both the pharmacokinetics and pharmacodynamics of VM26 in the patients, principally by increasing the plasma concentrations of the antineoplastic drug and VM26 haemopoietic toxicity.
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PMID:Cyclosporin A as a multidrug-resistant modulator in patients with renal cell carcinoma treated with teniposide. 904 30

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.
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PMID:Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer. 937 86

Renal cell carcinoma (RCC) displays strong resistance against many chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part of this resistance. The involvement of another resistance mechanism, involving the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By culturing the human RCC lines RC2 and RC21 in the presence of increasing concentrations of etoposide, we derived the variant sublines RC2E, RC21A and RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross-resistance (approximately 200- and 3500-fold respectively) to vinblastine. Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E) and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western blotting and the reverse transcriptase/polymerase chain reaction. Decreased amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or differences in methylation status of the promoter gene of RC21E, were not found. These cell lines represent a model of a solid tumor in which overexpression of Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of topoII alpha are represented.
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PMID:Decreased levels of topoisomerase II alpha in human renal cell carcinoma lines resistant to etoposide. 939 88

The purpose of this study was to investigate how the vinca alkaloid vinblastine influences DNA parameters and the mechanisms of multidrug resistance in renal cell carcinoma. After exposing cell cultures of human renal carcinoma to progressively increasing concentrations of vinblastine the cell lines were examined by flow cytometric DNA analysis to assess the S-phase and G2/M-phase fraction and by a modified MTT assay. It was shown that the exposed cells became P-glycoprotein-positive by staining the cells with a monoclonal antibody (JSB-1). The flow cytometric analysis revealed, with prolonged vinblastine exposure, correlated increases in the S-phase and G2/M-phase fractions (P = 0.0001). When vinblastine-free medium was used for culturing, the changed DNA characteristics returned to their original values. Comparing the DNA parameters with the IC50 (concentration when cell growth is inhibited by 50%) we found a strong correlation between these parameters (P = 0.0001). In conclusion, DNA analysis of long-term vinblastine exposure may provide insight into events leading to multidrug resistance. Furthermore, analysis of the DNA profile might also be an important investigation before planning therapy with vinblastine for renal cell carcinoma.
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PMID:Influence of vinblastine on DNA parameters and multidrug resistance in renal cell carcinoma in vitro. 963 45

Three newly synthesized imidazothiazole derivatives (N276-12, N276-14, N276-17) were examined regarding their ability and mechanism as a chemosensitizing agent against multidrug resistance 1 (MDR1)-mediated and multidrug resistance-associated protein (MRP)-mediated MDR. All three N276 compounds almost completely reversed the acquired resistance to vincristine (VCR), vinblastine (VBL), and doxorubicin (DXR) in MDR1-overexpressing human cancer cell lines (KB/VJ300 and T24/VCR). Their reversal effect against acquired resistance to VCR, DXR, and etoposide (VP16) was partial but clearly observed in the cell line expressing MRP (KB/VP4). All three N276 compounds enhanced the intracellular accumulation of [3H]VCR in MDR1-overexpressing KB/VJ300 cells through the inhibition of the increased efflux of the drug. They (100 microM) almost completely inhibited the photoaffinity labeling of P-glycoprotein encoded by the MDR1 gene. All the N276 compounds also remarkably enhanced the sensitivity to VBL and DXR in both MDR1- and MRP-overexpressing renal cell carcinoma (RCC) cell line (NKK1), whereas they showed no potentiation of these anticancer agents in an RCC cell line (KPK1) expressing neither MDR1 nor MRP. The combination chemotherapy of VCR or VP16 with N276-12 significantly increased the life span of mice inoculated i.p. or i.v. with drug-resistant P388/VCR cells without any significant side effects, whereas chemotherapy with the anticancer agent alone did not increase the life span at all. These results suggest that these newly synthesized imidazothiazole derivatives can be a useful chemosensitizing agent against not only MDR1- but also MRP-mediated MDR.
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PMID:Development of novel reversal agents, imidazothiazole derivatives, targeting MDR1- and MRP-mediated multidrug resistance. 970 Jul 23

Therapy of advanced renal cell carcinoma remains difficult. New therapeutic schemes besides cytokine treatment should be evaluated. The following study analyzes the in vitro toxicity of treosulfan on spheroids of 8 primary cultures of renal cell carcinoma cells. these data were compared to the toxicity of vinblastine. All investigations were performed in regard to the P-glycoprotein (Pgp) expression of the cells, which is one of the main causes of multidrug resistance. Four Pgp positive and four Pgp negative spheroids were incubated with the drugs in increasing doses. Toxicity was measured using the MTT toxicity assay as well as trypan blue exclusion. Significantly higher toxicity of treosulfan compared to vinblastine could be demonstrated. In addition, the effects of treosulfan were not related to Pgp expression. These results are encouraging and a phase II study analyzing the efficacy of treosulfan in patients with advanced renal cell carcinoma has been initiated in our institution.
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PMID:[Treosulfan displays cytotoxic effect on spheroids of primary cell cultures of renal cell carcinoma independent of p-glycoprotein expression]. 973 87

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.
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PMID:Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study. 981 87

Tc-99m sestamibi is a substrate of P-glycoprotein (Pgp) that has been proposed for use as a functional imaging agent for the multidrug resistance-1 phenotype. In vitro, retention of sestamibi by cells that overexpress Pgp can be modified by the presence of Pgp antagonists. In a Phase I trial of the Pgp reversal agent PSC 833, we show that the effects of this reversal agent can also be demonstrated in patients. Nine patients with metastatic renal carcinoma were studied three times: at baseline, approximately 1 day after vinblastine infusion, and while on PSC 833. One patient with metastatic adrenocortical cancer was also studied. Time activity curves and areas under the curve (AUCs) were obtained for tumor, liver, lung, and myocardium, and organ:heart AUC ratios were generated. With PSC 833, tumor visualization was enhanced, and statistically significant increases were found in AUC ratios for tumor and liver compared to baseline. For the liver, significant differences were also found between the vinblastine versus PSC 833 scans but not between the baseline versus vinblastine scans. This study demonstrates that sestamibi retention by tumor and liver is altered in the presence of the reversal agent PSC 833, presumably reflecting inhibition of Pgp. Thus, sestamibi may be useful in vivo as a means of monitoring the effects of this and other reversal agents on various tumors and normal tissues that express Pgp.
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PMID:Detection of in vivo P-glycoprotein inhibition by PSC 833 using Tc-99m sestamibi. 981 18

Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.
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PMID:Intrinsic drug resistance in primary and metastatic renal cell carcinoma. 1037 90

The multidrug resistant (MDR) phenotype is a well-studied subject that has been recognized as a determinant underlying specific types of drug resistance in human cancer. Although it is clear that the P-glycoprotein plays a major role in MDR, it is not clear whether post-translational modifications such as phosphorylation have any major impact on its modulation. The laboratory of Dr. Bruce Chabner was one of the first to describe increased expression and activity of protein kinase C (PKC) associated with the MDR phenotype. Since that time, a similar correlation has been observed in many other MDR cell lines. Most of these studies have been performed with doxorubicin-selected cells that have acquired MDR and have shown increased PKC activity, mainly for PKC-a isoenzyme. Intrinsic MDR in human renal cell carcinoma lines has been shown to correlate directly with PKC activity, but further studies with intrinsic MDR cell lines are needed before any conclusions can be drawn. More recent evidence suggests that there is a complex biochemical process by which PKC isoenzymes differentially phosphorylate specific serine residues in the linker region of P-glycoprotein which may lead to alterations in P-glycoprotein ATPase and drug-binding functions. To further complicate matters, PKC plays an important role in anti-apoptotic pathways, which can confound the dissection and elucidation of drug-resistance mechanisms. However, these areas are still under active investigation and not fully answered. Further studies are needed to specifically answer the question of whether PKC directly modulates basal and/or drug-stimulated P-glycoprotein function. This manuscript reviews the majority of the literature on PKC and MDR, as well as offers caveats for interpretation of these studies to answer the above questions.
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PMID:P-Glycoprotein, Multidrug Resistance and Protein Kinase C. 1038


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