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

---

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.
...
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.
...
PMID:A pilot study of amiodarone with infusional doxorubicin or vinblastine in refractory breast cancer. 788 54

A frequent dose-limiting effect of irinotecan (CPT-11) is its gastrointestinal toxicity (diarrhea), which is thought to be related to biliary excretion of CPT-11 and its metabolites. Accordingly, we have investigated the mechanism of biliary excretion of these compounds. In vivo pharmacokinetic studies revealed that the biliary excretion of the four anionic forms of CPT-11 and its metabolites was reduced in Eisai hyperbilirubinemic rats, which carry a mutation of the hepatic canalicular multispecific organic anion transporter (cMOAT) gene. The protein encoded by this gene is expressed on the bile canalicular membrane and is responsible for the transport of organic anions into bile. Detailed analysis using isolated liver bile canalicular membrane vesicles to identify transport systems showed that cMOAT is responsible for biliary excretion of the low-affinity component of the carboxylate form of CPT-11 and the high-affinity component of both the lactone and carboxylate forms of SN-38 glucuronide. The carboxylate form of SN-38 is transported by cMOAT alone. Transport of the high-affinity component of CPT-11 was inhibited by verapamil and PSC-833, but their effect on the transport of its low-affinity component was minimal. In addition, ATP dependence in the uptake of CPT-11 by membrane vesicles obtained from a P-glycoprotein (P-gp)-overexpressing cell line was observed. Thus P-gp may be responsible for transport of the high-affinity component of the carboxylate form of CPT-11.
...
PMID:Multiplicity of biliary excretion mechanisms for the camptothecin derivative irinotecan (CPT-11), its metabolite SN-38, and its glucuronide: role of canalicular multispecific organic anion transporter and P-glycoprotein. 975 28

Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P-glycoprotein (P-gp) drug efflux pump. As CYP3A4 enzymes and P-gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea.
...
PMID:Increased tacrolimus levels in a pediatric renal transplant patient attributed to chronic diarrhea. 1073 Oct 62

20 (S) Camptothecin was discovered in the early 60's as a result of the intensive screening of natural products by the NCI. Camptothecin lactone was poorly water soluble and was administered as the sodium salt in phase I trials. Despite some encouraging responses in early studies, continued evaluation of this compound revealed severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhoea. The reversible opening of the lactone ring of a camptothecin is pH-dependent and yields a ring-opened carboxylate form which has greatly reduced activity in vivo and in vitro. Under physiological conditions, the carboxylate form predominates, but the exact position of this equilibrium in vivo also depends on other factors such as protein-binding and differential metabolism and elimination. The site of action of camptothecin is a complex formed by the nuclear enzyme topoisomerase I and DNA, which represents a novel target for cancer chemotherapy. The principal role of topoisomerase I is the relaxation of DNA required for transcription and replication. The transient covalent complexes formed by the linking of the enzyme and the 3' extremity of a nicked DNA strand are stabilised in the presence of camptothecin and involved in collisions with replication forks. The ensuing arrest of the fork is accompanied by the generation of permanent double-strand breaks which are thought to be responsible for the antiproliferative properties of camptothecin. The acquisition of resistance to camptothecin in cell culture appears, in general, to be due to a reduction in content and activity of topo-isomerase I. Single-point mutations of the gene of the enzyme have been detected in a number of these resistant variants. Camptothecin appears to be a poor substrate of P-glycoprotein and its intracellular accumulation is not appreciably reduced in cells expressing the multidrug-resistant phenotype. Several water soluble and active derivatives of camptothecin have been synthetized of which CPT-11 and topotecan are the most advanced in clinical trials. These compounds represent two different approaches to the problem of the poor water solubility of camptothecin lactone. CPT-11 is a soluble prodrug which is converted in vivo to the highly active SN-38, whereas topotecan itself is water-soluble due to the presence of a tertiary amine substitution which is charged at physiological pH. These two compounds present different pharmacological properties in the clinical setting.
...
PMID:[Pharmacology of camptothecin and its derivatives]. 1084 37

mdr1a-deficient mice lack P-glycoprotein and spontaneously develop colitis with age. Helicobacter spp. are gram-negative organisms that have been associated with colitis in certain mouse strains, but Helicobacter spp. have been excluded as contributing to the spontaneous colitis that develops in mdr1a-/- mice. We wished to determine whether infection with either H. bilis or H. hepaticus would accelerate the development of inflammatory bowel disease (IBD) in mdr1a-/- mice. We found that H. bilis infection induced diarrhea, weight loss, and IBD in mdr1a-/- mice within 6 to 17 weeks post-inoculation and before the expected onset of spontaneous IBD. Histopathology of H. bilis-induced IBD included crypt hyperplasia, inflammatory cell infiltrates, crypt abscesses, and obliteration of normal gut architecture. Reverse transcription-polymerase chain reaction and Taqman analysis from colonic tissue showed increased transcripts for interferon-gamma and interleukin-10 from H. bilis-infected colitic mdr1a-/- mice. Additionally, mesenteric lymph nodes had increased cellularity with expansion of CD4+ and CD8+ T cells and B cells and increased proliferation to soluble H. bilis antigens with elaboration of interferon-gamma, tumor necrosis factor-alpha and interleukin-10. In contrast, H. hepaticus infection of mdr1a-/- mice did not accelerate disease but rather delayed the onset of spontaneous colitis which was milder in severity. mdr1a-/- mice infected with Helicobacter spp. may provide a useful tool to explore the pathogenesis of microbial-induced IBD in a model with a presumed epithelial cell "barrier" defect.
...
PMID:Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance-deficient (mdr1a-/-) mice. 1183 95

1. The diverse physiological actions of somatostatin are mediated by a family of G-protein coupled receptors (SSTRs). Several peptide analogues of somatostatin such as octreotide have been developed for therapeutic use, including treatment of gastrointestinal disorders such as secretory diarrhoea. However, their development as anti-diarrhoeal agents has been limited by poor oral bioavailability, necessitating parenteral administration. This in vitro study investigated the anti-secretory potential of a group of novel, non-peptide, somatostatin-receptor agonists that selectively activate specific SSTR subtypes to assess their potential for oral administration. 2. The ability of the agonists to inhibit forskolin-stimulated chloride secretion was measured using a sensitive bioassay system in isolated rat colonic mucosa. 3. The SSTR-2 selective agonist, L-779,976 was 10-times more potent than octreotide as an inhibitor of secretion when added to the basolateral surface of rat colon. Non-peptide agonists selective for SSTR1 (L-797,591), SSTR3 (L-796,778), SSTR4 (L-803,087) or SSTR5 (L-817,818) showed little or no anti-secretory activity in this preparation. 4. L-779,976 was able to inhibit secretion when applied to the luminal surface at sub-micromolar concentrations suggesting that it can cross the colonic epithelium. The anti-secretory potency of luminal L-779,976 was increased 3 fold in the presence of GF120918, a known inhibitor of P-glycoprotein. 5. Non-peptide somatostatin receptor agonists may provide a basis for the development of new, orally available anti-diarrhoeal therapies.
...
PMID:Anti-secretory properties of non-peptide somatostatin receptor agonists in isolated rat colon: luminal activity and possible interaction with P-glycoprotein. 1190 57

Described is a case of a boy with congenital acute lymphoblastic leukemia (ALL) with pre-pre-B-ALL immunophenotype, presenting as diarrhea, organomegaly, hyperleucocytosis of 1434 G/L, and tumor lysis syndrome. The lymphoblasts showed low proliferative activity and high in vitro drug sensitivity measured by the MTT assay. An excellent response to therapy was observed, but relapse ocurred 3 months later. On relapse, blasts showed extremely high drug resistance, high expression of P-glycoprotein, and high proliferative activity. The response to therapy was again positive, but a second relapse occurred in 1 month. The MTT assay indicated increasing drug resistance to all drugs. Cytogenetic analysis revealed deletion in 11q23 locus. This unfavorable case shows complex biology and differential drug resistance in congenital leukemia.
...
PMID:Differential chemosensitivity in a child with congenital relapsing acute lymphoblastic leukemia. 1207 67

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.
...
PMID:Pharmacogenetics of irinotecan. 1276 80

EPO906 (epothilone B) is a potent member of a new class of microtubule-stabilizing cytotoxic agents known as epothilones. Although structurally unrelated to the clinically validated taxanes, EPO906 acts similarly to promote the formation and stabilization of microtubules, arresting proliferating cells in mitosis, and eventually causing cell demise by apoptosis. In preclinical studies, EPO906 has shown anticancer activity both in vitro and in vivo against several cancer types, including models that are paclitaxel-resistant. Importantly, in contrast to the taxanes, EPO906 retained activity against cancer cells either overexpressing the P-glycoprotein efflux pump or bearing tubulin mutations. Two phase I studies with EPO906 were conducted to determine the safety and maximal tolerated dose on two different dosing schedules: weekly and every 3 weeks. Diarrhea was the dose-limiting toxicity on both schedules. Tumor responses were seen in colorectal cancer as well as a variety of other tumor types, such as breast, ovarian, lung, and carcinoid in these two phase I trials. Based on the promising results from phase I studies, phase II studies in numerous indications are ongoing.
...
PMID:EPO906 (epothilone B): a promising novel microtubule stabilizer. 1280 95


1 2 3 4 5 Next >>

---