Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While cancer drug resistance has been extensively studied in cell culture, little is known about more clinically relevant in vivo resistance. The in vivo resistance of a murine mammary carcinoma EMT-6 to alkylating agents was demonstrated in the present study to be associated with multiple biochemical changes. These included an up to 1.5-fold increase in activity of phase II drug metabolizing enzymes (DMEs), such as glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), and an up to 88% decrease of phase I DME activity [7-ethoxycumarin O-deethylase (ECOD), P450 reductase (PR)] in the resistant tumors compared with the parental tumor. Transplant of either parental or resistant tumors to mice was accompanied by a decrease of both phase I and phase II DME activity in the livers of female Balb/C mice compared with the non-tumor mice. Moreover, at the protein level, while cytochrome P450 (CYP) IIB1/2 in the liver of mouse bearing both the sensitive and the resistant tumor was significantly diminished compared to that in the liver of non-tumor control mouse in Western analysis, there was actually an increase of this protein in the liver of the host bearing either of the two resistant tumors compared to that of the sensitive tumor-bearing animal. Although this in vivo resistance phenotype is not expressed in cell culture, the profile of most of the enzyme changes in the resistant tumors remained similar in in vitro culture of the isolated tumor cells. Collectively, these results demonstrate that this in vivo alkylating agent resistance is associated with multiple changes of both phase I and phase II DMEs in the resistant tumors, and some of these, such as CYP IIB1/2 protein are further altered in the resistant tumor-bearing mouse liver, suggesting a potential role of systemic factors in this resistance phenotype.
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PMID:Biochemical characterization of in vivo alkylating agent resistance of a murine EMT-6 mammary carcinoma. Implication for systemic involvement in the resistance phenotype. 992 73

The widely used anticancer prodrug cyclophosphamide (CPA) is activated in liver by a 4-hydroxylation reaction primarily catalyzed by cytochrome P-4502B and P-4502C enzymes. An alternative metabolic pathway involves CPA N-dechloroethylation to yield chloroacetaldehyde (CA), a P-4503A-catalyzed deactivation/neurotoxication reaction. The in vivo modulation of these alternative, competing pathways of P-450 metabolism was investigated in pharmacokinetic studies carried out in the rat model. Peak plasma concentrations (Cmax) for 4-OH-CPA and CA were increased by 3- to 4-fold, and apparent plasma half-lives of both metabolites were correspondingly shortened in rats pretreated with phenobarbital (PB), an inducer of P-4502B and P-4503A enzymes. However, PB had no net impact on the extent of drug activation or its partitioning between these alternative metabolic pathways, as judged from AUC values (area-under-the-plasma concentration x time curve) for 4-OH-CPA and CA. The P-4503A inhibitor troleandomycin (TAO) decreased plasma Cmax and AUC of CA (80-85% decrease) without changing the Cmax or AUC of 4-OH-CPA in uninduced rats. In PB-induced rats, TAO decreased AUCCA by 73%, whereas it increased AUC4-OH-CPA by 93%. TAO thus selectively suppresses CPA N-dechloroethylation, thereby increasing the availability of drug for P-450 activation via 4-hydroxylation. By contrast, dexamethasone, a P-4503A inducer and antiemetic widely used in patients with cancer, stimulated large, undesirable increases in the Cmax and AUC of CA (8- and 4-fold, respectively) while reducing the AUC of the 4-hydroxylation pathway by approximately 60%. Tumor excision/in vitro colony formation and tumor growth delay assays using an in vivo 9L gliosarcoma solid tumor model revealed that TAO suppression of CPA N-dechloroethylation could be achieved without compromising the antitumor effect of CPA. The combination of PB with TAO did not, however, enhance the antitumor activity of CPA, despite the approximately 2-fold increase in AUC4-OH-CPA, suggesting that other PB-inducible activities, such as aldehyde dehydrogenase, may counter this increase through enhanced deactivation of the 4-hydroxy metabolite. Together, these studies demonstrate that the P-4503A inhibitor TAO can be used to effectively modulate CPA metabolism and pharmacokinetics in vivo in a manner that decreases the formation of toxic metabolites that do not contribute to antitumor activity.
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PMID:In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity. 1002 28

Polyunsaturated fatty acids (PUFA) are important constituents of membrane phospholipids, whose levels are decreased in some tumor cells. This deficiency may cause alterations in signal transduction and an interruption of normal cellular events. The enrichment of tumor cells with PUFA may stimulate or inhibit tumor growth, probably depending on the type of PUFA and the cellular concentration of aldehydes derived from restored lipid peroxidation. We examined the effect of several doses of prooxidant on the growth of hepatoma cells with different aldehyde dehydrogenase activities, enriched with arachidonic acid. Two doses of prooxidant were sufficient to reduce growth of hepatoma cells with low aldehyde dehydrogenase activity, whereas three doses were necessary for those with high enzyme activity. In both cases, lipid peroxidation products blocked the cells in the S phase.
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PMID:Dose-dependent inhibition of cell proliferation induced by lipid peroxidation products in rat hepatoma cells after enrichment with arachidonic acid. 1047 28

Tumors resistant to chemotherapeutic oxazaphosphorines such as cyclophosphamide often overexpress aldehyde dehydrogenase (ALDH), some isozymes of which catalyze the oxidization of aldophosphamide, an intermediate of cyclophosphamide activation, with formation of inert carboxyphosphamide. Since resistance to oxazaphosphorines can be produced in mammalian cells by transfecting them with the gene for human ALDH isozyme 3 (hALDH3), it seems possible that patients receiving therapy for solid tumors with cyclophosphamide might be protected from myelosuppression by their prior transplantation with autologous bone marrow that has been transduced with a retroviral vector causing overexpression of hALDH3. We investigated whether retroviral introduction of hALDH3 into a human leukemia cell line confers resistance to oxazaphosphorines. This was examined in the polyclonal transduced population, that is, without selecting out high expression clones. hALDH3 activity was 0.016 IU/mg protein in the transduced cells (compared with 2x10(-5) IU/mg in untransduced cells), but there was no detectable resistance to aldophosphamide-generating compounds (mafosfamide or 4-hydroperoxycyclophosphamide). The lack of protection was due, in part, to low catalytic activity of hALDH3 towards aldophosphamide, since, with NAD as cofactor, the catalytic efficiency of homogeneous, recombinant hALDH3 for aldophosphamide oxidation was shown to be about seven times lower than that of recombinant hALDH1. The two polymorphic forms of hALDH3 had identical kinetics with either benzaldehyde or aldophosphamide as substrate. Results of initial velocity measurements were consistent with an ordered sequential mechanism for ALDH1 but not for hALDH3; a kinetic mechanism for the latter is proposed, and the corresponding rate equation is presented.
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PMID:Inactivation of aldophosphamide by human aldehyde dehydrogenase isozyme 3. 1085 27

Tumor-associated aldehyde dehydrogenase (T-ALDH) is strongly expressed in hepatocellular carcinoma (HCC) but undetectable in normal liver. In the present study, this enzyme from human HCC, HCC T-ALDH, was purified and the partial amino acid sequences (384 residues) determined by direct protein sequencing matched the amino acid sequence (453 residues) deduced from cloned HCC T-ALDH cDNAs with an open reading frame. The coding sequences of HCC T-ALDH cDNA, human stomach ALDH3A1 cDNA [Hsu et al., J. Biol. Chem. 267 (1992) 3030-3037] and human squamous cell carcinoma (SCC) T-ALDH cDNA (Schuuring et al., GenBank I.D. M74542) matched one another except for discrepancies at four positions, with consequent P12R, I27F and S134A substitutions. R and A were found in HCC and SCC T-ALDHs, whereas P and S were present in stomach ALDH3A1. To confirm that these discrepancies would have general occurrence, coding sequences of HCC T-ALDH cDNAs from six patients and stomach ALDH3A1 cDNAs from two individuals were examined and all were found to encode ALDH3A1 having R, I and A at protein positions 12, 27 and 134, respectively, indicating HCC T-ALDH to be variant ALDH3A1 which is common in human stomach tissues.
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PMID:Primary structure of human hepatocellular carcinoma-associated aldehyde dehydrogenase. 1101 24

New neoplastic models such as orthotopic solitary hepatic tumor (cholangiocellular cancer PC-1) as well as different strains of malignant pleuritis (hemoblastosis and ascitic tumors) have been evolved by transplanting tumor cell suspension to rat liver or murine pleural cavity. Intrahepatic cancer PC-1 has a solid mucosa-excreting structure and is characterized by low activity of detoxication enzymes of such xenobiotics as glutathione-S-transferase, NAD(p)N-chinonoxyreductase and aldehyde dehydrogenase. Orthotopic hepatic tumor PC-1 may be used for evaluating systemic and regional therapy. Models of tumorous pleuritis described with respect to their response to chemotherapy, may have an application in screening and preclinical examination of newly-developed antitumor drugs.
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PMID:[New models of experimental chemotherapy of tumors]. 1182 92

To explore whether human umbilical cord blood CD34+ cells transduced with human aldehyde dehydrogenase class-1 (ALDH1) and multidrug resistance gene (MDR1) increase resistance to 4-Hyaroxycyclophosphophamide (4-HC) and P-Glycoprotein Effluxed Drugs, a bicistronic Retroviral vector G1Na-ALDH1-IRES-MDR1 was constructed. The vector was transduced into the packaging cell lines GP + E86 and PA317 by LipofectAMINE. Using the medium containing VCR and 4-HC for cloning selection and pingponging supernatant infection between ecotropic producer clone and amphotropic producer clone, we obtained high titer amphotropic PA317 producer clone with the highest titer up to 5.6 x 10(5) CFU/ml. Cord blood CD34+ cells were transfectced repeatedly with supernatant of retrovirus containing human ALDH1 and MDR1cDNA under stimulation of hemopoietie growth factors. PCR, RT-PCR, Southern blot, Northern blot, FACS and MTT method analyses show that dual drug resistance genes have been integrated into the genomic DNA of cord blood CD34+ cells and expressed efficiently. The transgenes recipient cells confered 4- to 7.2-folds stronger resistance to cyclophospsphamede and P-Glycoprotein Effluxes drug in comparison with the nontransduced cells. This study provided a foundation for the application of combination chemotherapy in tumor clinical trial.
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PMID:[Study on expression and resistance of the double drug resistance genes transduced into human umbilical cord blood CD34+ cells mediated by bicistronic retroviral vector]. 1254 73

The study of the influence of genotype on drug activity and efficacy (pharmacogenetics) and the genome-wide approach to drug discovery and interpretation of complex pharmacological responses (pharmacogenomics) are gaining momentum in current molecular medicine. The reasons of the variable activity and tolerability of cancer chemotherapy are being unraveled by the discovery of genotypic alterations affecting pharmacokinetics and pharmacodynamics of drugs. Indeed, genetic variability may alter drug catabolism (i.e. dihydropyrimidine dehydrogenase for 5-fluorouracil, thiopurine-S-methyl transferase for thiopurines, aldehyde dehydrogenase for cyclophosphamide) and anabolism (i.e. thymidine phosphorylase for capecitabine, deoxycitidine kinase for gemcitabine). Moreover, increased expression of transporter systems (i.e. the ATP binding cassette (ABC) superfamily) is associated with reduction of the cytoplasmic levels of drugs which may be unable to exert a cytotoxic effect. Additional systems could protect tumor cells from drug cytotoxicity, including the DNA repair machinery (nucleotide excision repair (NER) and DNA alkyltransferases) and antiapoptotic systems (i.e. bcl-2). Finally, alterations of drug targets may be associated with a decrease in the effectiveness of chemotherapy (i.e. mutations affecting tubulin and topoisomerase I for taxanes and irinotecan, respectively, and increased expression of thymidilate synthase for 5-fluorouracil). Therefore, genetic analysis has the potential to predict treatment efficacy and tolerability. However, major problems encountered in pharmacogenetic and pharmacogenomic studies are the need of extensive validation of available technology, the difficulties in obtaining a suitable amount of tissue from patients during the course of their disease and the extremely complex regulation of gene function. From this perspective, the evaluation of the cellular effect of drugs in relation to protein expression and function (pharmacoproteomics) may be able to overcome these obstacles, and allow the optimisation of cancer chemotherapy in association with a pharmacogenetic approach.
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PMID:Pharmacogenetics of neoplastic diseases: new trends. 1520 12

Multidrug resistance (MDR) has been studied extensively because it is one of major problems in cancer chemotherapy. The MDR phenotype is often due to overexpression of P-glycoprotein (P-gp), that acting as an energy-dependent drug efflux pump exports various anticancer drugs out of cells. The major goal of our investigation is to establish whether bovine serum amine oxidase (BSAO), which generates the products H(2)O(2) and aldehyde(s), from the polyamine spermine, is able to overcome MDR of human cancer cells. The cytotoxicity of the products was evaluated in both drug-sensitive (LoVo WT) and drug-resistant (LoVo DX) colon adenocarcinoma cells. A clonogenic cell survival assay demonstrated that LoVo DX cells were more sensitive than LoVo WT cells. Exogenous catalase protected cells against cytotoxicity mainly due to the formation of H(2)O(2). However, spermine-derived aldehyde(s) still induced some cytotoxicity. The cytotoxic effect was totally inhibited in the presence of both enzymes, catalase and NAD-dependent aldehyde dehydrogenase (ALDH). Transmission electron microscopy investigations showed that BSAO and spermine induced evident mitochondria alterations, more pronounced in MDR than in LoVo WT cells. The mitochondrial activity was checked by flow cytometry studies, labelling cells with the probe JC1, that displayed a basal hyperpolarized status of the mitochondria in multidrug-resistant cells. After treatment with amine oxidase in the presence of polyamine-spermine, the cells showed a marked increase in mitochondrial membrane depolarization higher in LoVo DX than in LoVo WT cells. Our findings suggest that toxic oxidation products formed from spermine and BSAO could be a powerful tool in the development of new anticancer treatments, mainly against MDR tumor cells.
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PMID:Mitochondrial alterations induced by serum amine oxidase and spermine on human multidrug resistant tumor cells. 1522 8

The goal of chemotherapy is the elimination of tumor cells from the host. This is achieved by the use of therapeutic agents that are often more harmful to normal tissues than to the targeted tumor. Many chemotherapeutic agents are designed to damage cell replication machinery either directly at the level of DNA or indirectly, by inhibiting enzymes involved with DNA repair and synthesis. Novel therapeutic agents that exert their effects at signal transduction pathways have advanced chemotherapy; however, a role for the classic chemotherapeutic agents remains. These classic agents are associated with tumor cell resistance, toxicity, and occasionally secondary neoplasia. Current practices for the dosing of therapeutic agents rely on height and body surface measurements or drug monitoring and Bayesian adaptive control. Pharmacogenetics is emerging as an alternate approach to managing chemotherapy that may prevent undertreatment while avoiding overtreatment and associated toxicities. By determining the polymorphic genetic makeup of the host and, in some instances, the altered genetic expression of the tumor, chemotherapy can be tailored for interindividual response and toxicity avoidance. Chemotherapy is particularly applicable to the pharmacogenetic approach to tailored therapy for a number of reasons. The margin of safety is low with chemotherapeutic agents. Some drugs require biotransformation for activation. Drug activation correlates with toxicity. The pathways of drug clearance or inactivation exhibit polymorphic differences. Interindividual, race-specific, and age-related responses to chemotherapeutic agents are common. Last, drug resistance can be inherent to the tumor as a result of the suppression of apoptosis. Variations in response and toxicity to a specific drug can be caused by alterations in drug-metabolizing enzymes or receptor expression. These effects can be classed as pharmacokinetic and pharmacogenetic differences. Some of the genes known to display polymorphic differences include FLT3 receptor tyrosine kinase, FCG3RA IgG FC receptor, thymidylate synthase, methylenetetrahydrofolate reductase, thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, aldehyde dehydrogenase, glutathione S-transferase, uridine diphosphate glyuronosyl transferases, N-acetyl transferases, cytochrome P450, and the DNA repair enzymes XPD and XRCC1. To be successful a pharmacogenetic approach to individualized chemotherapy must selectively take advantage of a determination of direct enzyme activity, gene expression, and genotype.
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PMID:Pharmacogenetics in cancer chemotherapy: balancing toxicity and response. 1522 71


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