Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hybridomas obtained by the fusion of spleen cells from rat cytochrome b5-immunized mice with mouse myeloma cells produced five groups of monoclonal antibodies (MAbs) with three mouse immunoglobulin subtypes: IgG1, IgG2b and IgM. All of the MAbs bound strongly to rat cytochrome b5 as measured by radioimmunoassay (RIA). Four clones of MAbs were also strongly immunoreactive with cytochrome b5 when tested by Western blotting, but only one of the MAbs (1-39-2) weakly immunoprecipitated cytochrome b5 in an Ouchterlony double-immunodiffusion test. Two of the MAbs partially inhibited cytochrome b5-mediated NADH cytochrome c reduction catalyzed by liver microsomes (24-36%). Expression of immunodetectable cytochrome b5 was highest in the liver, next highest in the kidney, and quite low in the other tissues examined with MAb 1-17-1 by Western blotting. This MAb recognized homologous cytochrome b5 of human liver microsomes and in homogenates of TK- cells infected with recombinant vaccinia virus encoding human cytochrome b5. These MAbs to cytochrome b5 will be useful for the identification, quantification, and purification of cytochrome b5 from animal and human tissues, and for understanding its role in cytochrome P450 catalyzed drug metabolism and carcinogen activation with respect to tissue, organ and individual differences.
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PMID:Monoclonal antibodies to rat liver microsomal cytochrome b5. 159 6

Benzene, a common industrial chemical and a component of gasoline, is radiomimetic and exposure may lead progressively to aplastic anaemia, leukaemia, and multiple myeloma. Although benzene has been shown to cause many types of genetic damage, it has consistently been classified as a non-mutagen in the Ames test, possibly because of the inadequacy of the S9 microsomal activation system. The metabolism of benzene is complex, yielding glucuronide and sulphate conjugates of phenol, quinol, and catechol, L-phenylmercapturic acid, and muconaldehyde and trans, trans-muconic acid by ring scission. Quinol is oxidised to p-benzoquinone, which binds to vital cellular components or undergoes redox cycling to generate oxygen radicals; muconaldehyde, like p-benzoquinone, is toxic through depletion of intracellular glutathione. Exposure to benzene may also induce the microsomal mixed function oxidase, cytochrome P450 IIE1, which is probably responsible for the oxygenation of benzene, but also has a propensity to generate oxygen radicals. The radiomimetic nature of benzene and its ability to induce different sites of neoplasia indicate that formation of oxygen radicals is a major cause of benzene toxicity, which involves multiple mechanisms including synergism between arylating and glutathione-depleting reactive metabolites and oxygen radicals. The occupational exposure limit in the United Kingdom (MEL) and the United States (PEL) was 10 ppm based on the association of benzene exposure with aplastic anaemia, but recently was lowered to 5 ppm and 1 ppm respectively, reflecting a concern for the risk of neoplasia. The American Conference of Governmental Industrial Hygienists (ACGIH) has even more recently recommended that, as benzene is considered an A1 carcinogen, the threshold limit value (TLV) should be decreased to 0.1 ppm. Only one study in man, based on nine cases of benzene associated fatal neoplasia, has been considered suitable for risk assessment. Recent re-evaluation of these data indicated that past assessments may have overestimated the risk, and different authors have considered that lifetime exposure to benzene at 1 ppm would result in an excess of leukaemia deaths of 9.5 to 1.0 per 1000. Although in this study, deaths at low levels of benzene exposure were associated with multiple myeloma and a long latency period, instead of leukaemia, which might justify further lowering of the exposure limit, the risk assessment model has been found to be non-significant for response at low levels of exposure. The paucity of data for man, the complexity of the metabolic activation of benzene, the interactive and synergistic mechanisms of benzene toxicity and carcinogenicity, the different disease endpoints (aplastic anaemia, leukaemia, and multiple myeloma), and different individual susceptibilities, all indicate that in such a complex scenario, regulators should proceed with caution before making further changes to the exposure limit for this chemical.
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PMID:The toxicity of benzene and its metabolism and molecular pathology in human risk assessment. 185 46

Over the past two decades, marked shifts have occurred in cancer mortality in the United States, the United Kingdom, and the Federal Republic of Germany. Stomach cancer mortality has declined sharply, while brain cancer and multiple myeloma increased nearly twofold for persons ages 75 to 84. Total cancer incidence in the United States, excluding lung cancer, has risen 27% since 1950, adjusted to the aging of the population. The origins of these trends are not known. The diet in the developed countries includes a number of naturally occurring, powerful anticarcinogens and carcinogens. To evaluate the role of these substances in the prevention and causation of human cancer, this paper reviews existing toxicologic and epidemiologic data. These data indicate that naturally occurring substances in food influence cancer initiation, promotion, progression, and demotion by a number of mechanisms, including (1) covalent binding to DNA of naturally occurring anticarcinogenic compounds to block the initiation of carcinogenesis; (2) induction of biotransforming enzymes such as cytochrome P450 and mixed-function oxidase (MFO) which can reduce carcinogenicity; (3) inhibition of tumor promotion by compounds such as retinol, tocopherol, and organosulfates found in garlic, onions, fruits, and vegetables; and (4) physical alteration of carcinogens by food constituents or by food preparation and handling so as to alter carcinogenicity. Systems have been proposed for estimating the relative ranking for humans of individually tested, experimental carcinogens, including some constituents of food. While qualitatively useful, such systems as the HERP Index do not take into account important interactions among naturally occurring and synthetic constituents in foods, nor do they permit examination of the possible role of evolved resistance. Common mixtures in food must be tested for carcinogenicity in human tissue cultures and in long-term rodent bioassays. Such studies need to examine whether the action of synthetic organic carcinogens may be inhibited by potent naturally occurring anticarcinogens.
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PMID:Natural anticarcinogens, carcinogens, and changing patterns in cancer: some speculation. 268 27

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.
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PMID:Technology evaluation: Valspodar, Novartis AG. 1124 78

Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies. Based on the results of phase II clinical trials, bortezomib received accelerated US Food and Drug Administration approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies. The results of phase III studies evaluating bortezomib as first- or second-line therapy, or in combination with other commonly prescribed therapies in multiple myeloma patients, are eagerly awaited. Studies assessing the antitumor effects of bortezomib in other hematologic malignancies and solid tumors are also under way. A thorough understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of this novel compound is essential for appropriate prescribing and monitoring of bortezomib therapy. Bortezomib is rapidly distributed into tissues after administration of a single dose, with an initial plasma distribution half-life of less than 10 minutes, followed by a terminal elimination half-life of more than 40 hours. Maximum proteasome inhibition occurs within 1 hour and recovers close to baseline within 72 to 96 hours after administration. Bortezomib is primarily metabolized by oxidative deboronation to one of two inactive enantiomers that are further processed and eliminated, both renally and in bile. Bortezomib has been shown to be a substrate of several cytochrome P450 isoenzymes using in vitro systems. Adverse effects of bortezomib are generally mild and effectively managed with supportive care. Bortezomib should be administered with caution to patients with preexisting fluid retention and patients with baseline platelet counts of less than 70,000/microL. Dose reductions are recommended for patients experiencing peripheral neuropathy, grade 3 or higher nonhematologic toxicities, or grade 4 hematologic toxicities. Formal drug interaction studies have not been performed, but bortezomib has been administered in combination with a variety of antitumor agents without significant alterations to its pharmacokinetic or pharmacodynamic profile.
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PMID:Pharmacology, pharmacokinetics, and practical applications of bortezomib. 1568 98

Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.
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PMID:Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. 1576 13

Human exposure to benzene in work environment is a global occupational health problem. After inhalation or absorption, benzene targets organs viz. liver, kidney, lung, heart and brain etc. It is metabolized mainly in the liver by cytochrome P450 multifunctional oxygenase system. Benzene causes haematotoxicity through its phenolic metabolites that act in concert to produce DNA strand breaks, chromosomal damage, sister chromatid exchange, inhibition of topoisomerase II and damage to mitotic spindle. The carcinogenic and myelotoxic effects of benzene are associated with free radical formation either as benzene metabolites or lipid peroxidation products. Benzene oxide and phenol have been considered as proheptons. Liver microsomes play an important role in biotransformation of benzene whereas in kidney, it produces degenerative intracellular changes. Cohort studies made in different countries suggest that benzene induces multiple myeloma in petrochemical workers. Though extensive studies have been performed on its toxicity, endocrinal disruption caused by benzene remains poorly known. Transgenic cytochrome P450 IIE1 mice may help in understanding further toxic manifestations of benzene.
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PMID:Biochemical toxicity of benzene. 1616 67

Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a first-in-class proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. In a preclinical toxicology study, bortezomib-treated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A beta-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC(50) approximately 18.0, 10.0, and 13.2 microM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC(50) approximately 11.5 microM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC(50) values > 30 microM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. To our knowledge, this is the first report on P450-mediated drug-drug interaction potential of proteasome inhibitors or boronic acid containing therapeutics.
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PMID:Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes. 1644 66

Bortezomib (1) is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor employed in the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. The potency of 1 is owed primarily to the presence of the boronic acid moiety, one which is suited to establish a tetrahedral intermediate with the active site N-terminal threonine residue of the proteasome. Hence, deboronation of 1 represents a deactivation pathway for this chemotherapeutic agent. Deboronation of 1 affords a near equal mixture of diastereomeric carbinolamide metabolites (M1/M2) and represents the principal metabolic pathway observed in humans. In vitro results from human liver microsomes and human cDNA-expressed cytochrome P450 enzymes (P450) indicate a role for P450 in the deboronation of 1. Use of 18O-labeled oxygen under controlled atmospheres confirmed an oxidative mechanism in the P450-mediated deboronation of 1, as 18O was found incorporated in both M1 and M2. Chemically generated reactive oxygen species (ROS), such as those generated as byproducts during P450 catalysis, were also found to deboronate 1 resulting in the formation of M1 and M2. Known to undergo efficient redox cycling, P450 2E1 was found to catalyze the deboronation of 1 predominantly to the carbinolamide metabolites M1 and M2, as well as to a pair of peroxycarbinolamides, 2 and 3. The presence of superoxide dismutase (SOD) and catalase prevented the deboronation of 1, thus, supporting the involvement of ROS in the P450 2E1-catalyzed deboronation reaction. The presence of SOD and catalase also protected 1 against P450 3A4-catalyzed deboronation, albeit to a lesser extent. The remaining deboronation activity observed in the P450 3A4 reaction may suggest the involvement of the more conventional activated enzyme-oxidants previously described for P450. Our present findings indicate that the oxidase activity of P450 (i.e., formation of ROS) represents a mechanism of deboronation.
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PMID:Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. 1660 65

(1) When multiple myeloma relapses more than one year after initial treatment, the median survival time is only 12 to 15 months. (2) Bortezomib is a cytotoxic agent that inhibits the 26S proteasome, a complex involved in intracellular protein breakdown in mammals. Bortezomib was initially licensed for the treatment of myeloma after multiple treatment failure; its indications were subsequently modified to include second-line treatment. (3) Second-line bortezomib therapy has not been compared with haematopoietic stem cell grafting, a treatment with documented efficacy. (4) An unblinded comparative trial involving 54 patients requiring second-line treatment showed that bortezomib at a dose of 1.3 mg/m to the 2nd power (twice a week for two weeks, followed by a 10 day rest period) was significantly more effective than a dose of 1 mg/m to the 2nd power in terms of the median survival time (not determined in the 1.3 mg group, versus 26.7 months in the 1 mg group) and the median time to disease progression (11.7 versus 4.2 months). (5) Among 251 patients in whom first-line treatment had failed, bortezomib was significantly more effective than dexamethasone: the one-year survival rate was 80% versus 66% on dexamethasone, and the progression-free survival time was 6.2 months versus 3.5 months. (6) Adverse effects occurred in 30% to 60% of patients enrolled in clinical trials, and were severe in about 10% to 20% of patients. They mainly included fatigue, nausea and vomiting, diarrhoea, anaemia, thrombocytopenia, and peripheral neuropathy. Animal studies indicated a possible risk of cardiotoxicity, and cases of cardiac arrhythmias and conduction disorders were observed in clinical trials. (7) Bortezomib is metabolised by the cytochrome P450 isoenzyme CYP3A4, with a high risk of interactions. (8) The vials contain an excessive amount of this costly drug, creating a risk of inadvertent overdose and leading to unnecessary waste. (9) In practice, bortezomib is an alternative to steroid therapy for patients with multiple myeloma in whom first-line treatment has failed and who do not qualify for stem cell grafting. The choice of treatment must be discussed with the patient, after providing thorough information on the likely benefits and risks
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PMID:Bortezomib: new indication. Second-line treatment of myeloma: limited efficacy, major risks. 1676 98


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