Cytochrome P450 pharmacogenetics and cancer

Rodríguez‐Antona, Cristina; Ingelman‐Sundberg, Magnus

doi:10.1038/sj.onc.1209377

Cited by 518 publications

(361 citation statements)

References 117 publications

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“…The resulting CYP2D6 phenotypes can be classified into poor metabolizers (PMs), with two nonfunctional genes; intermediate metabolizers (IMs), including one nonfunctional and one reduced activity, or two alleles with reduced activity; extensive metabolizers (EMs), with at least one normal allele and ultrarapid metabolizers (UMs) due to the presence of more than two functional alleles (http:// www.cypalleles.ki.se). 7,10,11 Two main CYP2C19 phenotypes have been described: poor (two nonfunctional genes, namely *2 and/or *3) and EMs (at least one functional allele, namely *1). Recently, a novel allele, CYP2C19*17, has been described: 12 this variant is associated with an increased enzyme activity due to enhanced gene expression.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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The role of pharmacogenomics and tamoxifen was investigated by analyzing several polymorphisms of cytochrome P450 and SULT1A1 gene in a nested case control study from the Italian Tamoxifen Prevention Trial. This study included 182 Caucasian subjects, 47 breast cancer (BC) cases and 135 matched controls. We used the AmpliChip CYP450 Test to screen 33 alleles of CYP2D6 and 3 of CYP2C19. One more variant for CYP2C19*17 and two single-nucleotide polymorphisms for the gene SULT1A1 were also performed. By using the AmpliChip CYP450 Test, out of 182 subjects, we identified 8 poor metabolizer (PM), 17 intermediate metabolizer (IM), 151 extensive metabolizer (EM) and 3 ultrarapid metabolizer (UM). PM women allocated to the tamoxifen arm showed a higher risk of developing BC compared to the remaining phenotypes (P ¼ 0.035). In an exploratory analysis, among 58 women with a CYP2D6*2A allele, 9 BCs were diagnosed in the placebo arm and only 1 in the tamoxifen arm (P ¼ 0.0001). CYP2C19 and SULT1A1 polymorphisms did not show any correlation with tamoxifen efficacy. Tamoxifen showed reduced efficacy in CYP2D6 PMs in the chemoprevention setting. Conversely, the CYP2D6*2A allele may be associated with increased efficacy of tamoxifen. These findings support the relevance of pharmacogenomics in tailoring tamoxifen treatment.

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Section: Introductionmentioning

confidence: 99%

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

et al. 2010

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“…In other words, the activity status of ALDH and cytochrome P450 isoforms implicated in CPA metabolism could have a detrimental effect on the long-term biological effects of LDM CPA protocols. Moreover, it is likely that consequences of modified CYP3A4 activity would go beyond CPA because many other compounds used in cancer therapy (and potentially coadministered with CPA) are metabolized by CYP3A4 (18,24,25).…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

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Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for z8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA. [Mol Cancer Ther 2007;6(8):2280 -9]

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“…This allowed construction of a calibration curve to correct the estimated size to the exact size (Figure 3). From the calibration curve, a correction equation (eq 1) was based on linear regression: (1) Figure 4 shows the electropherogram of a purified 5′-WellRedD4-tagged 20-base oligonucleotide. Its sequence is the same as the first 20 bases of the 5′-WellRedD4-tagged 147-bp DNA.…”

Section: Making Primary Standardsmentioning

confidence: 99%

“…1 However, some metabolites may be chemically reactive electrophiles. These reactive metabolites may damage DNA, proteins, and other biomolecules or be inactivated by metabolic bioconjugation enzymes.…”

Section: Introductionmentioning

confidence: 99%

Accurate DNA Fragment Sizing by Capillary Electrophoresis with Laser-Induced Fluorescence Array for Detection of Sequence Specificity of DNA Damage

et al. 2008

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Cancer has been linked to mutations within specific codons in genes that code for critical biomolecules such as tumor suppressor proteins (e.g., p53). Activated metabolites like benzo [a]pyrenediol epoxide act on preferred nucleotide sequences of DNA, and such mutations have been identified in cancers. DNA reaction site identification depends on accurate analysis of oligonucleotide fragment sizes produced by strand breakage at the damaged sites. Herein, we report a new method for DNA fragment sizing using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). Absolute sizing accuracy and speed are achieved by utilizing a CE-LIF array with two-color fluorescence detection. Accuracy depends on correcting results with commercial standards by referring them to primary standards with the same sequences and identical labels as sample fragments. The method is demonstrated by detection of a […GGCGCG-CAG…] G reaction site for styrene oxide on an oligonucleotide representing the CYP1B1 gene.This approach avoids the need for radioactive isotopes and is less labor intensive and faster than the alternative PAGE with 32 P end labeling.Cytochromes P450 in oxidative liver metabolism convert foreign hydrophobic substances into hydrophilic compounds that can be more readily excreted by the kidneys. 1 However, some metabolites may be chemically reactive electrophiles. These reactive metabolites may damage DNA, proteins, and other biomolecules or be inactivated by metabolic bioconjugation enzymes. 2 DNA damage often involves covalent binding of reactive metabolites to nucleobases, which may then lead to apoptosis (programmed cell death) or to neoplastic transformations.Cancer has been linked to specific changes within the amino acid sequence of certain proteins that control the movement of cells through the cell cycle, e.g., the p53 tumor suppressor protein. 3,4 These amino acid changes result from mutations in specific codons in the genes. The majority of human cancers are found to have mutations in the p53 gene. [5][6][7] These mutations do not occur at random within the gene but occur at specific positions with , adduct formation at the first guanine of codon 248 of the p53 gene causes G→T transversions. 3 This results in a point mutation in the p53 tumor suppressor protein, the substitution of an arginine for leucine at residue 248. The loss of the tumor suppressive capabilities of this mutated protein may contribute to uncontrolled cell growth or cancer. 11,12 Mapping the nucleobase sequence specificity for reaction of a reactive metabolite with DNA can be used as a predictive tool for carcinogenicity. There are two methods for detecting the sequence specificity of a DNA-damaging compound. The first involves isotopic 15 N or 13 C labeling of specific nucleobases within an oligonucleotide and determining the amount of damage at the site by mass spectrometry. [13][14][15][16] This method is rapid and also identifies the type of nucleobase adduct formed at the specific site. However, isotope-labele...

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Cytochrome P450 pharmacogenetics and cancer

Cited by 518 publications

References 117 publications

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Accurate DNA Fragment Sizing by Capillary Electrophoresis with Laser-Induced Fluorescence Array for Detection of Sequence Specificity of DNA Damage

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