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)

The feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubicin without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment.
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PMID:The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat. 791 32

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T1/2 = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vdss 376 L/m2.
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PMID:A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors. 938 46

To assess the therapeutic efficacy in the combination of mitomycin C (MMC), 5'-deoxy-5-fluorouridine (5'-DFUR), etoposide (VP-16) and medroxyprogesterone acetate (MPA) (McVD-MPA) to anthracycline-resistant tumor as a salvage chemotherapy, a phase II trial was conducted in patients with relapsed breast cancer. Fifty-five patients were enrolled in this trial and 54 were assessable, who had all previously been treated with an anthracycline regimen. The treatment schedule was designed with the intravenous administration of MMC (6 mg/m2) on day 1 followed by peroral administration of VP-16 (75 mg/m2) on day 2, 4, 6 and the peroral administration of 5'-DFUR (600 mg/m2) and MPA (400 mg/m2) on day 1 through 21 in one cycle. The overall tumor response rate was 40.7% (22/54) including 16.6% (9 cases) in complete response and 24.0% (13 cases) in partial response, and the long no change (NC) was observed in 18.5% (10/54) out of 44.4% (24/54) in NC. Of the patients with primary resistance to anthracycline 30.0% responded to McVD-MPA therapy. Bone and liver metastases responded in 50.0% and 50.0%, whereas soft tissue and lung metastases responded in 36.8% and 35.2%, respectively. The mean time to response and response duration were 2.7 and 15.6 months, respectively. The overall survival of the patient treated with the McVD-MPA was superior to the non-treatment of second line therapy, and the median survival between McVD-MPA and non-treatment was 86 days and 50 days, respectively. The major adverse effect was observed in hematological toxicity (31.7%) such as leukopenia and thrombocytopenia and non-hematological toxicity of gastrointestinal events (31.7%), the toxicity was less than grade 2, and was tolerable during the treatment. In the experiment of MDA-MB-231 breast cancer cell line that was overexpressed with P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP), the mechanism(s) by which McVD-MPA induces the antitumor effect to anthracycline-resistant tumor may be explained at least in part as follows: i) The treatment of MMC suppressed the expression of P-gp and MRP in a dose-and time-dependent manner, connecting the increase of the intracellular concentration of VP-16; ii) The treatment of MMC enhanced the expression of thymidine phosphorylase to increase the production of 5-FU from 5'-DFUR in the antiangiogenic effect of MPA. These results indicate that the combination chemotherapy of the McVD-MPA may be an effective regimen to anthracycline-resistant tumor as a salvage chemotherapy to prolong the survival in the patient with relapsed breast cancer.
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PMID:A phase II trial of mitomycin C, 5'-deoxy-5-fluorouridine, etoposide and medroxyprogesterone acetate (McVD-MPA) as a salvage chemotherapy to anthracycline-resistant tumor in relapsed breast cancer and its mechanism(s) of antitumor action. 1129 87

Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
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PMID:Pharmacogenetics of irinotecan. 1276 80

Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
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PMID:Clinical pharmacokinetics of everolimus. 1474 18

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.
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PMID:High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. 1705 Dec 46

To elucidate the impact of genetic variations in breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (MDR1/ABCB1) on the pharmacokinetics of sunitinib, we carried out a pharmacogenetic study in a clinical setting and pharmacokinetic analysis using Abcg2(-/-), Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice. Nineteen renal cell carcinoma patients were enrolled in this study. The plasma concentrations of sunitinib and its active metabolite were determined and the area under the concentration-time curve (AUC) was calculated. Genetic polymorphisms in ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A and 3435C>T) were examined. The dose-adjusted AUC(0-24) of sunitinib was significantly higher in patients with a heterozygous variant for ABCG2 421C>A than in wild-type patients (p = 0.02), and one homozygous patient showed the highest dose-adjusted AUC(0-24). The ABCB1 polymorphisms were not associated with the dose-adjusted AUC(0-24). The maximum concentration and AUC(0-4) of sunitinib were significantly higher in Abcg2(-/-), Abcb1a/1b(-/-) and Abcb1a/1b;Abcg2(-/-) mice than wild-type mice when sunitinib was given orally but not intraperitoneally. Incidence of thrombocytopenia and hypertension and poor compliance were associated with the systemic exposure to sunitinib and its active metabolite. These results suggest that the loss of protein expression of ABCG2 by genetic polymorphism is associated with an increase in the systemic exposure to sunitinib and sunitinib-induced toxicity.
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PMID:Impact of genetic variation in breast cancer resistance protein (BCRP/ABCG2) on sunitinib pharmacokinetics. 2267 43

The multi-drug resistance protein -1 or P-glycoprotein-1 ( P-gp1) functions as Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Increased P-gp1 expression in lymphocytes of patients with systemic lupus erythematosus (SLE) may influence steroid requirements for disease control. This study evaluates P-gp1 functional activity in CD5+, CD7+ and CD20+ lymphocytes in SLE children and its impact on clinical outcome. 44 SLE children and 50 healthy controls were studied. Estimation of P-gp1 function was based on the efflux of Rhodamine-123 using flow cytometry. Results were expressed as percentage of lymphocytes with high P-gp1 activity. The P-gp1 function in CD5+, CD7+ and CD20+ lymphocytes was significantly higher in patients compared to controls (with P value < 0.05 for each lymphocyte population). The expression of active P-gp1 in CD5+ and CD7+ lymphocytes correlated positively with disease activity as estimated by SLEDAI and ESR. P-gp1 expression in SLE lymphocytes was also found to correlate significantly with some disease manifestations specially lupus nephritis, thrombocytopenia and ANA positivity. Steroids low responders whose SLEDAI were > or = 11 while receiving 1 mg/Kg/day of prednisolone demonstrated higher P-gp1 functions in CD 5+ and CD 7+ lymphocytes compared to high responders whose SLEDAI were < 11 while receiving < 1 mg/Kg/day of prednisolone. CD5+ lymphocyte's P-gp1 function was found to be lower in the patients receiving cyclophosphamide in addition to steroids compared to those on steroids only. It is concluded that measuring P-gp1 function in CD5+ and CD7+ lymphocytes could be one of the prognostic and therapeutic indices in SLE.
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PMID:P-glycoprotein-1 functional activity in CD5+CD7+ and CD20+ lymphocytes in systemic lupus erythematosus children: relation to disease activity, complications and steroid response. 2461 50

There is no consensus on second-line treatment for women with metastatic or locally advanced breast cancer over-expressing HER-2 protein in whom treatment with a taxane + trastuzumab has failed. Capecitabine is one option. Adding lapatinib does not prolong survival. Trastuzumab emtansine (Kadcyla, Roche) has received EU marketing authorisation for use in this setting. It consists of two covalently bound drugs: trastuzumab, a monoclonal antibody that binds to HER-2 receptors, and DM1, a cytotoxic microtubule inhibitor. DM1 is derived from maytansine, a cytotoxic drug abandoned in the 1980s because it proved to be too toxic after systemic administration. Clinical evaluation of trastuzumab emtansine is based on an unblinded trial versus capecitabine + lapatinib in 991 patients. The use of lapatinib in all patients in the control group is questionable. An interim analysis suggested that overall survival was about 6 months longer with trastuzumab emtansine (30.9 versus 25.1 months). In addition to the adverse effects of trastuzumab (thrombocytopenia, heart failure, etc.), trastuzumab emtansine causes frequent and potentially life-threatening hepatic toxicity, peripheral neuropathy, and urinary tract infections. Trastuzumab emtansine appears to be less toxic to the skin and mucous membranes than the capecitabine + lapatinib combination. DM1 is metabolised by cytochrome P450 isoenzymes CYP3A4 and CYP3A5 and is also a P-glycoprotein substrate, creating a potential risk of multiple pharmacokinetic interactions. Trastuzumab emtansine appears to be teratogenic and embryotoxic. The international nonproprietary name of this drug is easily confused with trastuzumab. In practice, it is best to at least wait for the full results of the only available comparative trial of trastuzumab emtansine before drawing conclusions about its harm-benefit balance and its possible use if it represents a real therapeutic advance.
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PMID:Trastuzumab emtansine. An inadequately assessed combination of two cytotoxic drugs. 2562 44

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown their efficacy in kidney transplantation, but their wider introduction has been limited by relative high discontinuation rates. Their main advantage compared with calcineurin inhibitors (CNIs) is their relative lack of nephrotoxicity. They differ mainly in pharmacokinetic characteristics and have variable inter- and intra-individual pharmacokinetics. They are metabolized by cytochrome (CYP)-3A4/5 and CYP2C8 enzymes and are substrates for P-glycoprotein (P-gp). Their most important adverse effects are thrombocytopenia, leukopenia, hypercholesterolemia, stomatitis, diarrhea, and, although rare, interstitial pneumonitis. The narrow therapeutic window makes therapeutic drug monitoring (TDM) essential to prevent toxicity or rejection. As we discuss here, the main future challenge is to further optimize mTOR inhibitor (mTORi)-based immunosuppressive therapy.
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PMID:Sirolimus and everolimus in kidney transplantation. 2605 May 78


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