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 camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5-2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily x5 schedule has been developed further with dose escalation using granulocyte-colony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.
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PMID:Camptothecin analogues: studies from the Johns Hopkins Oncology Center. 752 Aug 44

Increasing evidence suggests that P-glycoprotein (Pgp) expression can mediate drug resistance in refractory breast cancer. We studied 33 patients with refractory breast cancer enrolled in a pilot study of oral amiodarone as a Pgp antagonist given in combination with infusional doxorubicin or vinblastine. Whenever possible, tumors were biopsied and Pgp expression was assayed. Patients received either 60 mg/m2 doxorubicin over 96 h or 8.5 mg/m2 vinblastine over 120 h by continuous intravenous infusion. Beginning with the second cycle of chemotherapy, 600-800 mg amiodarone was given orally each day. Patients who experienced toxicity due to amiodarone but were responding to chemotherapy were placed on quinidine. Partial responses were observed in 9 of 33 patients on study and were sometimes observed after the first cycle of chemotherapy, before amiodarone was given, suggesting that some patients may have responded to treatment because of the infusional schedule. Toxicities were primarily the known side effects of the antineoplastic agents and of amiodarone. The major amiodarone toxicity was gastrointestinal, with nausea, vomiting, anorexia, or diarrhea being noted in 21 patients. Biopsy samples were obtained from 29 patients and in 21 cases, viable tumor tissue was present and the results were interpretable. Of the 21 samples, 9 had Pgp expression as determined by immunohistochemical staining; 12 were considered negative. The presence of Pgp expression was associated with an acceleration of the time to treatment failure. Whereas normal-tissue toxicities related to the combination of a Pgp antagonist with chemotherapy were not observed, amiodarone was associated with too many untoward effects to be utilized as a drug resistance-reversing agent.
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PMID:A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer. 788 54

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor-risk ALs.
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PMID:Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. 869 37

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.
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PMID:Phase I and pharmacokinetic study of the P-glycoprotein modulator dexniguldipine-HCL. 908 15

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

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations < or = 1000 ng / ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg / kg for both LD and CD with 30 mg / m(2) doxorubicin; these dosages were increased to 2 and 10 mg / kg and 50 mg / m(2), respectively. Thirty-one patients were treated. Nausea / vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng / ml were achieved at a 2 mg / kg LD and a 10 mg / kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC(50) of P-glycoprotein expressing 8226 / Dox(6) in patients' serum was decreased from 5.9 to 1.3 microg / ml (P < 0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 +/- 13.7 (mean +/- SD) liter / h/m(2), which was lower than the 49.0 +/- 16.9 liter / h/m(2) without PSC-833 (P < 0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg / kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg / m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.
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PMID:Phase I study of intravenous PSC-833 and doxorubicin: reversal of multidrug resistance. 1122 52

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.
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PMID:Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study. 1156 81

Patient-controlled analgesia (PCA) has become standard procedure in the clinical treatment of pain. Its widespread use in patients with all kinds of diseases opens a variety of possible interactions between analgesics used for PCA and other drugs that might be administered concomitantly to the patient. Many of these drug interactions are of little clinical importance. However, some drug interactions have been reported to result in serious clinical problems. Drug interactions can either predominantly affect the pharmacokinetics or pharmacodynamics of the drug. Most important pharmacokinetic drug interactions occur at the level of drug metabolism or protein binding. Acceleration of methadone metabolism caused by cytochrome P450 (CYP) 3A4 induction by antiretroviral drugs or rifampicin (rifampin) has caused methadone withdrawal symptoms. Lack of morphine formation from codeine as a result of CYP2D6 inhibition by quinidine results in an almost complete loss of the analgesic effects of codeine. Alterations of methadone protein binding caused by an inhibition of alpha1-acid glycoprotein synthesis by alkylating substances are another possibility for predominantly pharmacokinetically based drug interactions during PCA. Furthermore, inhibition of P-glycoprotein by anticancer drugs could result in altered transmembrane transport of morphine, methadone or fentanyl, although this has not been shown to be of clinical relevance. Synergistic effects of systemically administered opioids with spinally or topically delivered opioids or anaesthetics have been reported frequently. The same is true for the opioid-sparing effects of coadministered non-opioid analgesics. Antidepressants, anticonvulsants or alpha2-adrenoreceptor agonists have also been shown to exert additive analgesic effects when administered together with an opioid. Inconsistent findings, however, are reported regarding the treatment of patients with opioid-induced nausea and sedation, since coadministration of antiemetics either increased or decreased the respective adverse effects or revealed additional unwanted drug effects.
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PMID:Drug interactions with patient-controlled analgesia. 1182 96

Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2-3 were observed more often with VAD + cyclosporin A than with VAD only: nausea (30% versus 8%, P = 0.015), mucositis (18% versus 5%, P = 0.13), infection (45% versus 35%, P = 0.50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (-18.5%, 26.9%)]. The median progression-free survival (PFS) was 8.6 months (VAD + cyclosporin A) versus 5.8 months (VAD): [log rank P = 0.16, hazard ratio = 0.71, 95% CI (0.44, 1.15)], and median overall survival was 13 months versus 14.6 months [log rank P = 0.89, hazard ratio = 0.96, 95% CI (0.62, 1.72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp-positive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.
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PMID:Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). 1184 23

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


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