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)

One potential explanation for why renal cell carcinoma is usually poorly responsive to chemotherapy is intrinsic multidrug resistance. Dipyridamole (DP) is one of several agents known to bind to P-glycoprotein and potentially reverse multidrug resistance in vitro, and dosages needed to obtain appropriate levels in vivo appear to be well tolerated. The current study was undertaken to evaluate the combination of vinblastine (VLB) and DP in patients with advanced renal cell carcinoma and no prior chemotherapy. From August 1989 through December 1989, 15 patients with inoperable recurrent or metastatic renal cell carcinoma were treated with VLB 0.2 mg/kg (i.v. slow push) and concurrently received DP75 mg p.o. q.i.d. starting 48 hours before and continuing 48 hours after VLB administration. Courses were repeated every 3 weeks for a maximum of 8 weeks, or until disease progression or undue toxicities ensued. The predominant toxicities seen were mild neurotoxicity and leukopenia. Only 1 patient had grade IV leukopenia, and no lethal toxicities occurred. No objective responses were seen; 2 patients had stable disease for 29 and 30+ months. The median survival was 9 months (range: 2.5-30+). We conclude that at the dose and schedule used in this study, the combination of VLB and DP may be administered with acceptable toxicities, but is ineffective in the treatment of advanced renal cell carcinoma.
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PMID:A phase II trial of vinblastine plus dipyridamole in advanced renal cell carcinoma. A Hoosier Oncology Group Study. 831 Oct

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

Signal transducer and activator of transcription (STAT) 3 is a key factor in homeostasis of the oral mucosa by regulating the production of inflammatory cytokines. Sunitinib is a substrate of P-glycoprotein (multidrug resistance (MDR)-1/ABCB1) and breast-cancer resistance protein (BCRP/ABCG2). In this retrospective study, we evaluated the association between sunitinib-induced stomatitis and STAT3, ABCB1, and ABCG2 polymorphisms in patients with metastatic renal cell carcinoma (mRCC). Fifty-two Japanese patients with RCC treated with sunitinib were retrospectively genotyped to elucidate a potential association between STAT3, ABCB1, and ABCG2 polymorphisms and stomatitis development. Stomatitis occurred in 22 out of 52 patients. The TT+TC genotypes at STAT3 rs744166 had an odds ratio of 5.00 against CC genotype for the stomatitis development (95% confident interval, 0.97-25.8). In the Kaplan-Meier method for the cumulative incidence of stomatitis, a statistically significant difference was observed between the TT+TC and CC genotypes in STAT3 rs744166 (p=0.037). Both multiple logistic regression analysis and Cox proportional-hazards regression analysis show STAT3 rs744166 TT+TC genotypes and serum creatinine in each patient were significant independent factors for stomatitis development. In conclusion, STAT3 polymorphism may be a novel risk factor for sunitinib-induced stomatitis in patients with mRCC.
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PMID:Association of Single Nucleotide Polymorphisms in STAT3, ABCB1, and ABCG2 with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patients. 2838 1

Recombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of autoimmune diseases and acute coronary syndrome because of its ability to expand and activate T regulatory (Treg) cells. However, several medical conditions potentially benefiting from rIL-2 administrations are characterized by an intrinsic prothrombotic risk, thus requiring concurrent anticoagulation. In our systematic review of the literature, we investigated the potential for drug interactions between oral anticoagulants and rIL-2 by assessing the influence of rIL-2 administration on transporters and cytochromes determining the pharmacokinetics of (direct) oral anticoagulants. We extracted data from 12 studies, consisting of 11 animal studies and one study in humans. Eight studies investigated the pharmacokinetics of P-glycoprotein (P-gp) substrates and reported that the intraperitoneal rIL-2 administration may inhibit intestinal P-gp. Four studies on hepatic cytochrome P450 yielded conflicting results. The only human study included in this systematic review concluded that rIL-2 suppresses the hepatic cytochrome P450, but only if given at higher doses. Based on the results from animal studies, the co-administration of rIL-2 and dabigatran etexilate, a substrate of intestinal P-gp, may lead to higher dabigatran plasma concentrations and bioavailability. Human studies should confirm whether this potential interaction is clinically relevant.
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PMID:Potential Drug Interactions between Recombinant Interleukin-2 and Direct Oral Anticoagulants: Indirect Evidence from In Vivo Animal Studies. 3232 20