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Pharmacology - Cardiovascular - Detailed Expression profiling and individualisation of treatment for ovarian cancer. Agarwal R, Kaye SB, 2006. Curr Opin Pharmacol. 6(4):345-9.
Abstract Ovarian cancer is the commonest cause of gynaecological cancer-related mortality. Patients with this disease generally undergo surgery followed by platinum-taxane chemotherapy, with additional chemotherapy at relapse. Although the prognosis for patients with advanced cancer is poor--a five-year survival of only 30-40%--there is a wide range of outcomes for individual patients. To date, clinico-pathological variables such as age, stage, grade, histology, debulking status and response to chemotherapy continue to provide the basis on which treatment decisions are made for individual patients. Immunohistochemical markers and information on p53 mutation status have been extensively evaluated in ovarian cancer, but have not yet been shown to be sufficiently informative to influence clinical decisions on a routine basis. The recent advent of expression profiling has provided a new impetus to identifying clinically useful prognostic markers. The ambition of personalised medicine through microarray-based profiling appears to be realistic, but further studies on large uniform cohorts are needed before this potential is fully realised. Journal link: Available through Science Direct | PMID Neonatal phenobarbital imprints overexpression of cytochromes P450 with associated increase in tumorigenesis and reduced life span. Agrawal AK, Shapiro BH, 2005. FASEB J. 19(3):470-2.
Abstract Perinatal exposure to phenobarbital produces a range of permanent reproductive, growth, locomoter, and learning dysfunctions in animals as well as humans. In addition, the affected individuals exhibit latently expressed (i.e., postpubertal) above normal activity levels of hepatic multicytochrome P450-dependent drug metabolizing enzymes. We report that in spite of apparent normal health for the better part of their lives, daily administration of therapeutic-like doses of phenobarbital to male and female rat pups during the first postpartum week reduced life expectancy by approximately 20%. Necropsy at the time of natural death revealed an associated two- to threefold increase in the incidence of tumors in barbiturate-exposed rats of both sexes and a three- to fourfold increase in urinary tract pathologies in male rats. At 2 yr of age, in agreement with an overexpression of hepatic CYP2C6 and CYP2C7, both in vitro and in vivo drug metabolism was more rapid in the phenobarbital-imprinted male and female animals. Moreover, when the senescent rats were rechallenged with a nominal dose of the barbiturate, males and females neonatally exposed to phenobarbital exhibited a dramatic overinduction of multicytochrome P450-dependent drug metabolizing enzymes as well as an overexpression of individual isoforms of cytochrome P450 implicated in enhanced susceptibility to tumorigenesis. Our findings support the growing realization that many adult diseases have their origins in early life by emphasizing that unlike adults, the new born is "plastic," and even therapeutic drugs may produce "silent" programming defects that subtly, but irrevocably, jeopardize life-long well-being. Predicting the outcome of chemotherapy for colorectal cancer. Allen WL et al., 2006. Curr Opin Pharmacol. 6(4):332-6.
Abstract Colorectal cancer is the second leading cause of cancer-related deaths in the Western world. Recently, improvements have been made in treating patients with advanced colorectal cancer; however, response rates still remain low at only 40-50% following combination therapy. The major limitation in treating these patients is the development of drug resistance. Therefore, there is a need to identify which patients will respond to a given chemotherapy regime so that they will be spared the unnecessary time and toxicity of being placed on a regime from which they will derive no benefit. It is also widely accepted that exposure to these chemotherapies themselves can induced acute resistance. Recent developments have been made in predicting response to chemotherapy using global approaches, with the ultimate aim of individualising patient treatment and improving overall survival rates. Journal link: Available through Science Direct | PMID Long-acting octreotide and prolonged-release lanreotide formulations have different pharmacokinetic profiles. Astruc B et al., 2005. J Clin Pharmacol. 45(7):836-44.
Abstract Single-dose pharmacokinetic (PK) profiles and multiple-dose PK modeling were compared for long-acting octreotide (20 or 60 mg) and prolonged-release lanreotide (90 or 120 mg) over 91 days; steady-state profiles were simulated. All treatments were well tolerated. Octreotide 20-mg profile showed increased concentration on day 1, lag from days 2 to 6, then prolonged plateau phase (days 11-41); 60-mg PK was dose proportional. Lanreotide 90-mg profile showed C(max) on day 1 then elimination (apparent t1/2 25.5 days); 120-mg profile was underproportional. Steady-state PK of octreotide 20 mg/28 d suggested a C(mean) of 1216 rhog/mL (range, 1065-1585) with low fluctuation index (43%). Steady-state PK of lanreotide 90 mg/28 d suggested a C(mean) of 4455 rhog/mL (range, 2499-9279) with high fluctuation index (152%). Long-acting octreotide had more predictable PK than prolonged-release lanreotide. Simulated steady-state profiles suggest long-acting octreotide could be optimized to meet individual patient needs. In contrast, prolonged-release lanreotide requires exposure constantly above the therapeutic target to enable monthly long-term therapy. Proteomics in clinical trials and practice: present uses and future promise. Azad NS et al., 2006. Mol Cell Proteomics. 5(10):1819-29.
Abstract The study of clinical proteomics is a promising new field that has the potential to have many applications, including the identification of biomarkers and monitoring of disease, especially in the field of oncology. Expression proteomics evaluates the cellular production of proteins encoded by a particular gene and exploits the differential expression and post-translational modifications of proteins between healthy and diseased states. These biomarkers may be applied towards early diagnosis, prognosis, and prediction of response to therapy. Functional proteomics seeks to decipher protein-protein interactions and biochemical pathways involved in disease biology and targeted by newer molecular therapeutics. Advanced spectrometry technologies and new protein array formats have improved these analyses and are now being applied prospectively in clinical trials. Further advancement of proteomics technology could usher in an era of personalized molecular medicine, where diseases are diagnosed at earlier stages and where therapies are more effective because they are tailored to the protein expression of a patient's malignancy. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. Babenko AP et al., 2006. N Engl J Med. 355(5):456-66.
Abstract BACKGROUND: The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. METHODS: We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. RESULTS: We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONS: Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved. Copyright 2006 Massachusetts Medical Society. Estradiol increases platelet aggregation in Pl(A1/A1) individuals. Boudoulas KD et al., 2006. Am Heart J. 152(1):136-9. Abstract BACKGROUND: The platelet glycoprotein IIb/IIIa receptor is a key mediator of platelet aggregation and intracoronary thrombosis. Studies have suggested that hormone replacement therapy (HRT) may increase coronary events in postmenopausal women. OBJECTIVES: We sought to characterize the relationship between the estrogen concentration expected in HRT and platelet aggregation. DESIGN AND RESULTS: Platelet aggregation studies were performed using epinephrine on 30 healthy individuals (15 Pl(A1/A1) and 15 Pl(A1/A2)) before and after incubation with beta-estradiol (E2) (10(-11) mol/L). The effect of E2 10(-11) mol/L on Pl(A1/A1) platelets demonstrated a significant increase (P = .03) in aggregation compared with baseline. In contrast, with the same concentration of E2, aggregation of Pl(A1/A2) platelets decreased significantly compared with baseline (P < .0001). CONCLUSIONS: Estrogen concentration similar to that expected in HRT resulted in an increase in platelet aggregation in Pl(A1/A1) individuals, but not in Pl(A1/A2) individuals. The data may provide further insight for the increase in coronary events seen in HRT clinical trials and suggest that further evaluation is needed to better define the role of pharmacogenetics in HRT. Effect of genetic variations in platelet glycoproteins Ibalpha and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy. Bray PF et al., 2007. Blood. 109(5):1862-9. Abstract Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA -5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA -5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction P < .001). HT reduced the HR in patients with the GP6 13254TT genotype by 17% but increased the HR in patients with the TC+CC genotypes by 35% (adj interaction P < .001). Furthermore, HT increased the HR of CHD events in patients with the GP1BA -5TT plus GP6 13254TC+CC genotypes by 57% and reduced the HR in patients with the GP1BA -5TC+CC plus GP6 13254TT genotypes by 55% (adj interaction P < .001). In postmenopausal women with established CHD, these polymorphisms of platelet genes were predictors of CHD events and significantly modified the effects of HT on CHD risk. It will be important to replicate these findings in other studies. Challenges and opportunities in proteomics data analysis. Domon B, Aebersold R, 2006. Mol Cell Proteomics. 5(10):1921-6.
Abstract Accurate, consistent, and transparent data processing and analysis are integral and critical parts of proteomics workflows in general and for biomarker discovery in particular. Definition of common standards for data representation and analysis and the creation of data repositories are essential to compare, exchange, and share data within the community. Current issues in data processing, analysis, and validation are discussed together with opportunities for improving the process in the future and for defining alternative workflows. The mixed promise of genetic medicine. Elliott C, 2007. N Engl J Med. 17;356(20):2024-5.
This editorial presents the pros and cons of genomic medicine. Short overview of big clinical picture. Genetic testing. Burke W, 2002. N Engl J Med. 347(23):1867-75. Review article that discusses genetics, related pathology, and clinical testing. Discusses interpretation and application to preventive care. Further, brief discussion of informed consent and genetic counciling. Altered cAMP and Ca2+ signaling in mouse pancreatic islets with glucagon-like peptide-1 receptor null phenotype. Flamez D et al., 1999. Diabetes 48(10):1979-86.
Abstract 1-Cells from rodents and humans express different receptors recognizing hormones of the secretin-glucagon family, which--when activated--synergize with glucose in the control of insulin release. We have recently reported that isolated islets from mice homozygous for a GLP-1 receptor null mutation (GLP-1R(-/-)) exhibit a well-preserved insulin-secretory response to glucose. This observation can be interpreted in two different ways: 1) the presence of GLP-1R is not essential for the secretory response of isolated islets to glucose alone; 2) beta-cells in GLP-1R(-/-) pancreases underwent compensatory changes in response to the null mutation. To explore these possibilities, we studied islets from control GLP-IR(+/+) mice in the absence or presence of 1 pmol/l exendin (9-39)amide, a specific and potent GLP-1R antagonist. Exendin (9-39)amide (15-min exposure) reduced glucose-induced insulin secretion from both perifused and statically incubated GLP-1R(+/+) islets by 50% (P < 0.05), and reduced islet cAMP production in parallel (P < 0.001). Furthermore, GLP-1R(-/-) islets exhibited: 1) reduced cAMP accumulation in the presence of 20 mmol/l glucose (knockout islets versus control islets, 12 +/- 1 vs. 27 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001) and exaggerated acceleration of cAMP production by 10 nmol/l glucose-dependent insulinotropic peptide (GIP) (increase over 20 mmol/l glucose by GIP in knockout islets versus control islets: 66 +/- 5 vs. 14 +/- 3 fmol x islet(-1) x 15 min(-1); P < 0.001); 2) increased mean cytosolic [Ca2+] ([Ca2+]c) at 7, 10, and 15 mmol/l glucose in knockout islets versus control islets; and 3) signs of asynchrony of [Ca2+]c oscillations between different islet subregions. In conclusion, disruption of GLP-1R signaling is associated with reduced basal but enhanced GIP-stimulated cAMP production and abnormalities in basal and glucose-stimulated [Ca2+]c. These abnormalities suggest that GLP-1R signaling is an essential upstream component of multiple beta-cell signaling pathways. ACE inhibitors and congenital anomalies. Friedman JM, 2006. N Engl J Med. 354(23):2498-500.
This is an invited discussion of a paper by Cooper, WO et al. in same issue. Clinical pharmacology of multiple doses of lasofoxifene in postmenopausal women. Gardner M et al., 2006. J Clin Pharmacol. 46(1):52-8. Abstract Lasofoxifene, a next-generation selective estrogen receptor modulator, is undergoing phase 3 clinical development for osteoporosis. This study evaluated daily lasofoxifene for 14 days in healthy postmenopausal women. A loading dose of 5 times the daily dose was followed by daily doses of 0.01 mg (n = 8), 0.03 mg (n =8), 0.1 mg(n = 16), 0.3 mg (n =9), 1 mg (n = 8), or placebo (n = 16). Samples were collected for pharmacokinetic and pharmacodynamic assessments. Lasofoxifene was well tolerated; study drug-associated adverse events were mild and unrelated to dose. There was a predictable increase in plasma concentrations of lasofoxifene with dose. Pharmacokinetic parameters included mean half-life of 165 hours, mean area under the plasma concentration-time curve from time 0 to 24 hours ranging from 1.67 ng x h/mL to 137 ng x h/mL, and mean maximum observed plasma concentration ranging from 0.09 ng/mL to 6.43 ng/mL. Lasofoxifene partially suppressed luteinizing hormone, follicle-stimulating hormone, low-density lipoprotein, and N-telopeptide.
Estrogen replacement therapy, serum lipids, and polymorphism of the apolipoprotein E gene. Garry PJ et al., 1999. Clin Chem. 45(8 Pt 1):1214-23.
Abstract Pharmacogenomics, the study of genetic loci that modulate drug responsiveness, may help to explain why estrogen replacement therapy (ERT) has differential effects on serum lipid and lipoprotein concentrations in postmenopausal women who inherit distinct alleles of the apolipoprotein E gene (APOE). We compared total-cholesterol, triglyceride, and lipoprotein (LDL and HDL) concentrations in 66 postmenopausal women receiving ERT ([+]ERT) with 174 postmenopausal women not receiving ERT ([-]ERT), controlling for three APOE genotypes divided into three groups: E2 (epsilon2/epsilon3, n = 31), E3 (epsilon3/epsilon3, n = 160), and E4 (epsilon3/epsilon4 + epsilon4/epsilon4, n = 49). Mean total-cholesterol concentrations were lower in all three [+]ERT groups compared with their [-]ERT counterparts but were statistically significant only for women in group E4 (P = 0.014). The mean LDL-cholesterol concentrations were significantly lower in all three [+]ERT groups compared with their [-]ERT counterparts (P </=0.005). Although all three groups of [+]ERT women tended to have higher mean HDL-cholesterol concentrations compared with their [-]ERT counterparts, the differences were not statistically significant. [+]ERT women in groups E2 and E3 had significantly higher (P <0.05) triglyceride concentrations than their [-]ERT counterparts. In [+]ERT women, the ratios of total and LDL-cholesterol to HDL-cholesterol were significantly higher in group E3 and E4 women compared with E2 women (P <0.006). Group E4 [+]ERT women had ratios of total and LDL-cholesterol to HDL-cholesterol that were comparable to group E2 [-]ERT women. Triglyceride concentrations in group E2 [+]ERT women may need to be monitored more closely than those in E3 or E4 [+]ERT women. Group E4 women should probably be targeted for ERT. Results suggest that APOE genotypes have a differential effect on serum lipids and lipoproteins in [+]ERT postmenopausal women. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. Gearry RB, Barclay ML, 2005. J Gastroenterol Hepatol. 20(8):1149-57
Abstract The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD. The pharmacogenetics research network: from SNP discovery to clinical drug response. Giacomini KM et al., 2007.Clin Pharmacol Ther. 81(3):328-45
Abstract The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism. Identification of a dysfunctional missense single nucleotide variant of human adenylyl cyclase VI. Gros R et al., 2005. Clin Pharmacol Ther. 77(4):271-8
Abstract Genetic variants have been described for a range of G protein-coupled receptors (as well as for G proteins) linked to adenylyl cyclase. Furthermore, expression of these variants resulted in alterations in receptor-mediated activation of adenylyl cyclase, as well as alterations in more "downstream" effector pathways mediated by cyclic adenosine monophosphate. However, the identification of dysfunctional variants of adenylyl cyclase has been far more limited. Screening a region of the molecule that we recently demonstrated to be critical in regulation of enzyme activity, we have identified a missense single-nucleotide variant at amino acid 674 of human adenylyl cyclase isoform VI. In a population of 286 healthy white subjects, this variant has an allelic frequency of 3.1% (although 0/90 nonwhite subjects had this variant). Expression of this variant of adenylyl cyclase VI (whether expressed as the S674 human adenylyl cyclase VI [ADCY6] or the S686 ADCY6 rat analog) is characterized by a significant decrease in stimulated adenylyl cyclase activity (forskolin-stimulated activity of the S674 human ADCY6 variant was decreased to 56% +/- 6% of the activity of the A674 variant [mean +/- SEM]; n = 9; P = .004). Furthermore, subjects with the S674 variant demonstrated a significantly higher lymphocyte count (2.68 +/- 4.13 x 10(3)/mm3 versus 1.90 +/- 0.72 x 10(3)/mm3, P = .019). Paralleling this phenotype, expression of the variant was associated with attenuation of the forskolin-mediated reduction in cell growth rate to 64% +/- 5% of the effect seen with expression of the wild-type ADCY6 (n = 4; P = .001). In summary, these data demonstrate an unappreciated variant of adenylyl cyclase isoform VI that has a functional impact on both enzyme activity and cyclic adenosine monophosphate-mediated regulation of cell growth. Connecting the dots using gene-expression profiles. Gullans SR, 2006. N Engl J Med. 355(19):2042-4.
Discusses the use of the connectivity map of gene expression profiles in human cells and attempts to correlate profiles and disease. Realizing the promise of genomics in biomedical research. Guttmacher AE, Collins FS, 2005. JAMA 294(11):1399-402
Commentary on current and future genome initiatives, technologies, and effects on health care and society. Genomic medicine--a primer. Guttmacher AE, Collins FS, 2002. N Engl J Med. 347(19):1512-20
This is a review article by pioneers in the field that presents a history of genomic medicine, a glossary of commonly used terms, and an excellent summary of genetic variations, mutations, and the human genome. Lastly a short discussion of genes associated with common diseases. Toward individualized analgesic therapy: functional cyclooxygenase 1 and 2 haplotypes. Halushka MK, Halushka PV, 2006. Clin Pharmacol Ther. 79(5):404-6
This is a short commentary over a paper by Lee et al. in same issue. Succinctly discusses importance of genetic screening for COX-1 and COX-2 inhibitors and successful analgesic therapy. Invited review: Pharmacogenetics of estrogen replacement therapy. Herrington DM, Klein KP, 2001. J Appl Physiol. 91(6):2776-84.
There are a number of genetic factors that likely modulate both the beneficial and adverse effects of estrogen. An important domain of consideration is the relationship of estrogen and thrombosis risk. Gene polymorphisms among the key elements of the coagulation and fibrinolytic cascade appear to influence the effects of estrogen on risk for venous thromboembolic events and possibly arterial thrombosis as well. Emerging data also suggest that allelic variants in the estrogen receptor-alpha may modulate estrogen's effects, especially with respect to bone and lipid metabolism. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Herrington DM et al., 2002. Circulation 105(16):1879-82. Erratum in: Circulation. 2003, 108(4):5001.
Abstract The estrogen receptor-alpha (ER-alpha) IVS1-401 polymorphism identifies a group of women (approximately 20%) who have augmented effects of hormone replacement therapy (HRT) on levels of HDL cholesterol. This study sought to determine if this augmentation extends to HRT regulation of E-selectin and C-reactive protein (CRP) and to explore possible mechanisms by which this polymorphism might influence estrogen action. Serum levels of soluble E-selectin and CRP were measured at baseline and 1 year in 264 postmenopausal women randomized to treatment with oral conjugated equine estrogen (0.625 mg/d), estrogen plus progestin (medroxyprogesterone acetate 2.5 mg/d), or placebo. Women with the ER-alpha IVS1-401 C/C genotype receiving HRT had nearly a 2-fold greater reduction in E-selectin compared with C/T or T/T women (P for interaction=0.02). In contrast, there was no augmentation of the HRT-associated increase in CRP among the C/C women compared with C/T or T/T women (P for interaction=0.54). Of luciferase reporter constructs containing sequences spanning the IVS1-401 T/C polymorphism, expression of the construct containing the C allele was enhanced >10-fold, with cotransfection of a constitutively expressed B-myb vector. In contrast, B-myb resulted in only a 2.5-fold increase in expression of the T allele construct. Women with the ER-alpha IVS1-401 C/C genotype have greater reductions in E-selectin but no further increases in CRP with HRT. The C allele produces a functional binding site for the transcription factor B-myb. The impact of this polymorphism on ER-alpha transcription and other estrogen-sensitive intermediate and clinical end points has not yet been established. Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects. Heusser K et al., 2006. Clin Pharmacol Ther. 79(5):500-8
Abstract Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Hieronymus H et al., 2006. Cancer Cell. 10(4):321-30. Abstract Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy. Prohibiting genetic discrimination. Hudson KL, 2007. N Engl J Med. 356(20):2021-3
This article discusses the Genetic Information Nondiscrimination Act. Has the result of a survey responding to “How much do you trust your doctor, genetic researchers, heath insurer, and employer to have access to your genetic test results. Utah's Family High Risk Program: bridging the gap between genomics and public health. Johnson J et al., 2005. Prev Chronic Dis. 2(2):A24. Abstract Family history is a simple yet powerful genomic tool that can identify individuals and entire populations at risk for diseases such as heart disease, cancer, and diabetes. Despite its use for predicting disease, family history has traditionally been underused in the public health setting. CONTEXT: A program for identifying families at risk for a variety of chronic diseases was implemented in Utah. Utah has population characteristics that are unique among the United States. Although the land area is large, most residents live within a relatively small geographic area. The religion of 70% of the residents encourages the recording of detailed family histories, and many families have access to records dating back to the 1800s. METHODS: From 1983 through 1999, the Utah Department of Health, local health departments, school districts, the University of Utah, and the Baylor College of Medicine implemented and conducted the Family High Risk Program, which identified families at risk for chronic diseases using the Health Family Tree Questionnaire in Utah high schools. CONSEQUENCES: The collection of family history is a cost-effective method for identifying and intervening with high-risk populations. More than 80% of eligible families consented to fully participate in the program. A total of 80,611 usable trees were collected. Of the 151,188 Utah families who participated, 8546 families identified as high-risk for disease(s) were offered follow-up interventions. INTERPRETATION: The program was revolutionary in design and demonstrated that family history can bridge the gap between genetic advances and public health practice. Pharmacogenomics of statin responsiveness. Kajinami K et al., 2005. Am J Cardiol. 96(9A):65K-70K; discussion 34K-35K.
Abstract Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to interindividual variations in clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, >30 candidate genes related to pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of low-density lipoprotein cholesterol lowering. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E; adenosine triphosphate-binding cassette transporter G5 and G8; cholesterol production, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase; and lipoprotein catabolism, such as apoB and the low-density lipoprotein receptor, all may play a role in modulating responsivesness as well genes involved in metabolism of statins such as cytochrome P450. However, there is considerable variation in results reported, and the data suggest that combined analysis of multiple genetic variants in several genes, all of which have possible functional significance, is more likely to give significant results than single gene studies in small sample populations. In the future, pharmacogenomic studies with a greater number of participants (>2,000 participants) should provide a better picture as to who is most likely and who is least likely to benefit from statin therapy. Journal Link: Available through www.sciencedirect.com | PMID Do we need genomic research for the prevention of common diseases with environmental causes? Khoury MJ et al., 2005. Am J Epidemiol. 161(9):799-805.
Abstract Concerns have been raised about the value of genomic research for prevention and public health, especially for complex diseases with risk factors that are amenable to environmental modification. Given that gene-environment interactions underlie almost all human diseases, the public health significance of genomic research on common diseases with modifiable environmental risks is based not necessarily on finding new genetic "causes" but on improving existing approaches to identifying and modifying environmental risk factors to better prevent and treat disease. Such applied genomic research for environmentally caused diseases is important, because 1) it could help stratify disease risks and differentiate interventions for achieving population health benefits; 2) it could help identify new environmental risk factors for disease or help confirm suspected environmental risk factors; and 3) it could aid our understanding of disease occurrence in terms of transmission, natural history, severity, etiologic heterogeneity, and targets for intervention at the population level. While genomics is still in its infancy, opportunities exist for developing, testing, and applying the tools of genomics to clinical and public health research, especially for conditions with known or suspected environmental causes. This research is likely to lead to population-wide health promotion and disease prevention efforts, not only to interventions targeted according to genetic susceptibility. Population screening in the age of genomic medicine. Khoury MJ, et al., 2003. N Engl J Med. 348(1):50-8
This review article describes current and evolving principles of population screening in genetics. Also, ethical, legal, and social issues encompassing screening and genomic medicine are discussed. The emergence of epidemiology in the genomics age. Khoury MJ et al., 2004. Int J Epidemiol. 33(5):936-44.
This article discusses the complementary relationship of epidemiology and genomics. The authors focus on cross-fertilization of epidemiological principles and methods to characterize genomic trends and impact on populations. Effect of quercetin on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in healthy subjects. Kim KA et al., 2005. J Clin Pharmacol. 45(8):941-6
Abstract Previous in vitro studies have demonstrated that quercetin inhibits CYP2C8, but there are no available data to indicate that quercetin inhibits CYP2C8 in vivo. The effect of long-term use of quercetin on the pharmacokinetics of rosiglitazone was evaluated. After administration of quercetin or matched placebo for 3 weeks in a crossover manner, rosiglitazone 4 mg was administered, and the pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were determined. For AUCinfinity, AUClast, and Cmax, the geometric mean ratios (90% confidence interval) for (quercetin + rosiglitazone/placebo + rosiglitazone) were 0.98 (0.92, 1.05), 0.99 (0.92, 1.05), and 1.01 (0.88, 1.14), respectively. Metabolic conversion based on the AUC ratio of N-desmethylrosiglitazone/rosiglitazone in the quercetin phase (0.49 +/- 0.17) was similar to that of the placebo phase (0.47 +/- 0.14) (P = .574). Even though the acute interaction that would occur during the first few days of concurrent administration of quercetin cannot be excluded, these results indicate that long-term use of quercetin does not inhibit CYP2C8 activity, and the usage has little possibility of interacting with drugs that are metabolized by CYP2C8, including rosiglitazone. Using genotyping to predict responses to anti-hypertensive treatment. Kurland L et al., 2005. Trends Pharmacol Sci. 26(9):443-7.
Abstract Hypertension is prevalent and affects approximately 1 in every 4 adults in the Western world. Although many drugs are effective in treating hypertension, an individual's response to treatment is unpredictable. Pharmacogenetics holds the promise of becoming a tool to predict this response but obstacles and shortcomings need to be overcome. Significant developments in molecular biology, including the sequencing of the genome, the cataloguing of genetic variation and the development of microarray techniques, enable analysis of many genotypes simultaneously. However, despite these technical advances there are, as yet, no clinical applications of pharmacogenetics in anti-hypertensive treatment. It is therefore necessary to design prospective pharmacogenetic studies that aim to identify a genetic profile that will predict the response to anti-hypertensive treatment. Variations in the alpha2A-adrenergic receptor gene and their functional effects. Kurnik D et al. 2006. Clin Pharmacol Ther. 79(3):173-85.
Abstract The alpha2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3'-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 +/- 6.1 pg/mL versus 218.4 +/- 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Lamb J et al., 2006. Science 313(5795):1929-35
To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project. Heritability and expression of C-reactive protein in type 2 diabetes in the Diabetes Heart Study. Lange LA et al., 2006. Ann Hum Genet. 70(Pt 6):717-25. Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 +/- 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed. Journal Link: Available at Blackwell-Synergy | PMID Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Lee YS et al., 2006. Clin Pharmacol Ther. 79(5):407-18.
Wide inter-individual variation in responses to cyclooxygenase (COX) inhibitory drugs limits their clinical utility and safety. METHODS: To better understand the molecular responses to COX inhibition, we analyzed the gene expression level of the genes encoding enzymes related to prostaglandin production including the COX-1 gene (PTGS1) and the COX-2 gene (PTGS2), as well as their genetic polymorphisms, and the analgesic response to COX inhibitory drugs such as ibuprofen or rofecoxib or to placebo after minor surgery. Notable heterogeneity in global gene expression was evident between subjects. At 2 to 4 hours after surgery, PTGS1 expression was slightly decreased (36%, P < .001) and PTGS2 expression was markedly increased (300%, P < .001) with wide inter-individual variation; at 48 hours after surgery, little detectable change in PTGS1 and PTGS2 expression was found in the control group. However, ibuprofen and rofecoxib treatment significantly increased PTGS2 expression at 48 hours (P = .001 and P = .049, respectively). At 2 to 4 hours after surgery, patients with the G/G allele at the nucleotide position of -765G>C in PTGS2 showed a significantly higher increase in PTGS2 expression (P = .012) compared with G/C and C/C patients, although all of them showed an increase in PTGS2 expression (P < .001 and P = .043, respectively). Among G/G patients, rofecoxib administration resulted in significantly lower pain intensity on a visual analog scale (7.2 +/- 2.5 mm) (P = .008) at 48 hours after surgery, as compared with ibuprofen administration (31.3 +/- 6.7 mm). The finding regarding pain intensity at 48 hours in G/C and C/C patients was opposite (P = .002), being greater in the rofecoxib group (37 +/- 6.8 mm) compared with the ibuprofen group (7 +/- 1.9 mm). These results suggest that wide variability in gene expression and functional polymorphisms in PTGS2 may explain part of the interindividual variations in acute pain and the analgesic efficacy of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors; this may be useful to define individual responders on the basis of genetic variations to predict patient risk and benefit to drugs. Personalized medicine: elusive dream or imminent reality? Lesko LJ, 2007. Clin Pharmacol Ther. 81(6):807-16
The market for molecular diagnostic tests is predicted to grow at extraordinary rates over the next 10 years, fueled by pharmacogenetics and the elusive dream of personalized medicine. The challenge is managing the expectations of the medical community and the public at large that have already been set by speculation, promises, and the repeated exposure to headlines about genetic discoveries. Personalized medicine is a paradigm that exists more in conceptual terms than in reality, with only a few marketed drug-test companion products and not very many actual clinical practices set up to personalize medicine in the way that supporters have intended. Nevertheless, the reality of personalized medicine has become more imminent because of the increased awareness of the shortcomings in the delivery of drugs with adequate benefit/risk to patients, a better molecular understanding of how to optimize drug selection and dosing, and an increased demand for integrating more clinically relevant genetic information into the drug development process to improve both innovation and productivity. This paper focuses on personalized medicine by (1) looking at some converging changes taking place in the health-care landscape that are creating a scientific and social infrastructure to enable personalized medicine, (2) considering challenges that need to be addressed with regard to clinical evidence standards for validating genotype-phenotype associations, and (3) considering how clinical pharmacology can help construct a rational personalized medicine framework. As therapeutic experts, clinical pharmacologists can work to assure that "good therapeutics follows good diagnostics". They are well equipped to provide timely genetic education to others and to interpret genetic data so that actionable decisions, especially about drug dosing in individual patients, can be implemented in clinical practice. Proteomics-based development of biomarkers in cardiovascular disease: mechanistic, clinical, and therapeutic insights. Mayr M et al., 2006. Mol Cell Proteomics 5(10):1853-64.
This review article presents a discussion of the proteomic analysis of different pathological cardiovascular phenotypes. Further association of these proteomic phenotypes to biomarkers, and its impact on diagnosis are presented. Gene and cell-based therapies for heart disease. Melo LG et al., 2004. FASEB J. 18(6):648-63
Abstract Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent developments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection and rescue of the myocardium. Genetic therapies have been devised to treat complex diseases such as myocardial ischemia, heart failure, and inherited myopathies in various animal models. Some of these experimental therapies have made a successful transition to clinical trial and are being considered for use in human patients. The recent isolation of endothelial and cardiomyocyte precursor cells from adult bone marrow may permit the design of strategies for repair of the damaged heart. Cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium, in blood vessel reconstruction, and in bioengineering of artificial organs and prostheses. We expect that advances in the field will lead to the development of safer and more efficient vectors. The advent of genomic screening technology should allow the identification of novel therapeutic targets and facilitate the detection of disease-causing polymorphisms that may lead to the design of individualized gene and cell-based therapies. Estrogen-metabolizing gene polymorphisms in the assessment of female hormone-dependent cancer risk. Mikhailova ON et al., 2006. Pharmacogenomics J. 6(3):189-93
Abstract Allelic variants of cytochrome P450: CYP1A1, CYP1A2, CYP19 (Aromatase) and II-phase enzyme Sulfotransferase (SULT1A1) genes are associated with a high risk of hormone-dependent cancers. We estimated a frequency of these allelic variants in the female Caucasian population of the Novosibirsk region of Russia and their association with the elevated risk of ovarian and endometrial cancer. A DNA bank of gynecologic oncology patients, patients with benign gynecologic diseases and healthy women was created, and the following single nucleotide polymorphisms (SNPs) were examined: CYP1A1 M1 polymorphism, that is, T264 --> C transition in the 3'-noncoding region; CYP1A2*1F polymorphism, that is, C734 --> A transversion in CYP1A2 gene; C --> T transition (Arg264Cys) in exon 7 of CYP19; SULT1A1*2 polymorphism, that is, G638 --> A transition (Arg213His) in SULT1A1 gene. A positive correlation of C allele of CYP1A2*1F and G allele of SULT1A1*2 with hormone-dependent cancers in women was found. Thus, these genes are appropriate candidates for studying the contribution of genetic factors to endocrine disorder and environmentally determined diseases susceptibility. In contrast, no association of CYP19 and CYP1A1 polymorphisms with increased cancer risk was revealed. Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Modok S et al., 2006. Curr Opin Pharmacol. 6(4):350-4.
Abstract Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitize cancers? Can personalized drug therapy be achieved? A closer look at pharmaco-metabonomics. Nebert DW, Vesell ES, 2006. Trends Pharmacol Sci. 27(11):580-6. Erratum in: Trends Pharmacol Sci. 2007, 28(2):50. Abstract Between 1930 and 1990, several dozen high-penetrance, predominantly monogenic disorders were identified and characterized, which led some investigators to speculate that individualized drug treatment was just around the corner. Informative DNA tests were sought to determine genetic predisposition to toxicity and cancer, thereby identifying individuals in which a drug was likely to be effective and those at increased risk of drug toxicity. These assays represent the leading edge of phenotype-genotype association studies, which are a major goal of clinical pharmacology and pharmacogenomics. Because of the complexity of the genome, however, the task is more challenging than anticipated originally. In the past decade we have come to appreciate how difficult it is to determine unequivocally either an exact phenotype or genotype. In the near future it seems unlikely that, by themselves, either transcriptomics or proteomics will be particularly helpful in achieving individualized drug therapy. However, recent advances in metabonomics are exciting and show promise. In the future, and perhaps in combination with proteomics, metabonomics might complement genomics in achieving personalized drug therapy. Population proteomics: the concept, attributes, and potential for cancer biomarker research. Nedelkov D et al., 2006. Mol Cell Proteomics 5(10):1811-8.
Abstract This review outlines the concept of population proteomics and its implication in the discovery and validation of cancer-specific protein modulations. Population proteomics is an applied subdiscipline of proteomics engaging in the investigation of human proteins across and within populations to define and better understand protein diversity. Population proteomics focuses on interrogation of specific proteins from large number of individuals, utilizing top-down, targeted affinity mass spectrometry approaches to probe protein modifications. Deglycosylation, sequence truncations, side-chain residue modifications, and other modifications have been reported for myriad of proteins, yet little is know about their incidence rate in the general population. Such information can be gathered via population proteomics and would greatly aid the biomarker discovery efforts. Discovery of novel protein modifications is also expected from such large scale population proteomics, expanding the protein knowledge database. In regard to cancer protein biomarkers, their validation via population proteomics-based approaches is advantageous as mass spectrometry detection is used both in the discovery and validation process, which is essential for the detection of those structurally modified protein biomarkers. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. Pearson ER, et al., 2006. N Engl J Med. 355(5):467-77
Abstract Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. METHODS: We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society. The art and science of personalized medicine. Piquette-Miller M, Grant DM 2007. Clin Pharmacol Ther. 81(3):311-5
This editorial discusses the historical perspective of variation of human drug response and its impact on individualized medicine. Further, barriers to application of pharmacogenomic information to clinical practice is presented. Journal Link: Available through Nature | PMID Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. Postic C et al., 1999. J Biol Chem. 274(1):305-15.
Abstract Glucokinase (GK) gene mutations cause diabetes mellitus in both humans and mouse models, but the pathophysiological basis is only partially defined. We have used cre-loxP technology in combination with gene targeting to perform global, beta cell-, and hepatocyte-specific gene knock-outs of this enzyme in mice. Gene targeting was used to create a triple-loxed gk allele, which was converted by partial or total Cre-mediated recombination to a conditional allele lacking neomycin resistance, or to a null allele, respectively. beta cell- and hepatocyte-specific expression of Cre was achieved using transgenes that contain either insulin or albumin promoter/enhancer sequences. By intercrossing the transgenic mice that express Cre in a cell-specific manner with mice containing a conditional gk allele, we obtained animals with either a beta cell or hepatocyte-specific knock-out of GK. Animals either globally deficient in GK, or lacking GK just in beta cells, die within a few days of birth from severe diabetes. Mice that are heterozygous null for GK, either globally or just in the beta cell, survive but are moderately hyperglycemic. Mice that lack GK only in the liver are only mildly hyperglycemic but display pronounced defects in both glycogen synthesis and glucose turnover rates during a hyperglycemic clamp. Interestingly, hepatic GK knock-out mice also have impaired insulin secretion in response to glucose. These studies indicate that deficiencies in both beta cell and hepatic GK contribute to the hyperglycemia of MODY-2. A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. Potti A et al., 2006. N Engl J Med. 355(6):570-80. Erratum in: N Engl J Med. 2007, 356(2):201-2.
Abstract Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy. We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study. The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy. The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC. Copyright 2006 Massachusetts Medical Society. DNA testing, banking, and genetic privacy. Roche PA, Annas GJ, 2006. N Engl J Med. 355(6):545-6
This article presents a perspective of ethical issues associated with genomic profiling. Predicting the outcome of chemotherapy for lung cancer. Rosell R et al., 2006. Curr Opin Pharmacol. 6(4):323-31.Erratum in: Curr Opin Pharmacol. 2007, 7(1):119. Abstract Lung cancer is a worldwide problem. At the time of diagnosis, 50% of patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results despite the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes, whereas thioredoxin confers a broad spectrum of chemoresistance. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival in certain cisplatin-based regimens. Epidermal growth factor receptor tyrosine kinase mutations are the crux of targeted therapies, whereas epithelial-mesenchymal transitions and HER3 mRNA levels are promising ancillary markers for treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Cardiovascular genomics. Sabatine MS et al., 2006. Circulation 113(11):e450-5
This is a review of the effects of genetic variations on heart disease. Also, examples and limitations of using genetic approaches to characterizing and managing heart disease are discussed. Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in cancer therapy. Sabharwal A, Middleton MR, 2006. Curr Opin Pharmacol. 355-63.
Abstract Improving the efficacy of standard chemotherapy by targeting DNA repair mechanisms remains an important area of research. O6-methylguanine-DNA-methyltransferase (MGMT), which repairs alkylating agent damage, is one such target. Downregulation of the gene through epigenetic silencing has been shown to predict response to alkylating agent therapy in selected malignancies. Platinums have also been found to downregulate MGMT expression and this approach is currently under exploration. Another way to deplete O6-alkylguanine DNA alkyltransferase (AGT) levels is to modify methylating agent scheduling. Extended dosing has met with early favourable results. However, pseudosubstrates used to inhibit AGT activity have had limited success because of dose-limiting myelotoxicity. Topoisomerase I is 'trapped' on DNA by alteration of ligation kinetics following alkylating agent damage, leading to interest in combining AGT inhibitors or O6-alkylating agents with topoisomerase I inhibitors. DNA repair by AGT is an interesting target for cancer therapy that remains to be fully evaluated. The best results are likely to be achieved where its inhibition is part of treatment targeting multiple DNA damage processing pathways. Hormonal effects on drug metabolism through the CYP system: perspectives on their potential significance in the era of pharmacogenomics. Sarlis NJ, Gourgiotis L, 2005. Curr Drug Targets Immune Endocr Metabol Disord. 5(4):439-48
Abstract Cytochrome P450 (CYP) is a group of enzymes that metabolize drugs to a more water-soluble form, rendering them available for renal excretion. The major site of CYP expression is the liver. Nearly 50% of all medications currently on the market are metabolized by the enzyme CYP3A4, while metabolism of another 35-40% occurs through enzymes CYP1A2, CYP2C19, CYP2D6, CYP3A5 CYP3A6, and CYP3A7. Here, we summarize the current knowledge of the effects of hormones on the CYP family. The term "hormone" is used in its broad sense and includes products of the major endocrine glands (i.e., thyroid, adrenals, gonads, pancreas) and compounds that are not classically considered hormones, such as neurogenic amines, cytokines, interleukins, and eicosanoids. In addition, we comment on the effects on CYP expression of states associated with profound hormonal changes, such as pregnancy, malnutrition, obesity, diabetes mellitus, systemic inflammation, and conditions of altered extracellular fluid volume or osmolality. Available data are limited and are derived primarily from in vitro and animal studies. Moreover, the picture is obscured by conflicting results among studies and the complexity of the regulation of the expression and activity of elements of the CYP system. While the clinical significance of hormonal effects on the CYP system remains to be determined, we anticipate that such effects will be most pertinent to drugs with a narrow therapeutic range. Further research is needed to determine the scope and significance of these effects in view of rapid advances in the field of pharmacogenomics and the ever-increasing number of drugs available for therapeutic use. Causal models in epidemiology: past inheritance and genetic future. Vineis P, Kriebel D, 2006. Environ Health 5:21
Abstract The eruption of genetic research presents a tremendous opportunity to epidemiologists to improve our ability to identify causes of ill health. Epidemiologists have enthusiastically embraced the new tools of genomics and proteomics to investigate gene-environment interactions. We argue that neither the full import nor limitations of such studies can be appreciated without clarifying underlying theoretical models of interaction, etiologic fraction, and the fundamental concept of causality. We therefore explore different models of causality in the epidemiology of disease arising out of genes, environments, and the interplay between environments and genes. We begin from Rothman's "pie" model of necessary and sufficient causes, and then discuss newer approaches, which provide additional insights into multifactorial causal processes. These include directed acyclic graphs and structural equation models. Caution is urged in the application of two essential and closely related concepts found in many studies: interaction (effect modification) and the etiologic or attributable fraction. We review these concepts and present four important limitations. 1. Interaction is a fundamental characteristic of any causal process involving a series of probabilistic steps, and not a second-order phenomenon identified after first accounting for "main effects". 2. Standard methods of assessing interaction do not adequately consider the life course, and the temporal dynamics through which an individual's sufficient cause is completed. Different individuals may be at different stages of development along the path to disease, but this is not usually measurable. Thus, for example, acquired susceptibility in children can be an important source of variation. 3. A distinction must be made between individual-based and population-level models. Most epidemiologic discussions of causality fail to make this distinction. 4. At the population level, there is additional uncertainty in quantifying interaction and assigning etiologic fractions to different necessary causes because of ignorance about the components of the sufficient cause. Inheritance and drug response. Weinshilboum R, 2003. N Engl J Med. 348(6):529-37
This review article provides an excellent background to pharmacogenomics presenting mechanisms of alteration of drug metabolism Overview of the pharmacogenetics of asthma treatment. Weiss ST et al., 2006. Pharmacogenomics J. 6(5):311-26.
Asthma affects approximately 300 million individuals worldwide. Medications comprise a substantial portion of asthma expenditures. Despite the availability of three primary therapeutic classes of medications, there are a significant number of nonresponders to therapy. Available data, as well as previous pharmacogenetic studies, suggest that genetics may contribute as much as 60-80% to the interindividual variability in treatment response. In this methodologic review, after providing a broad overview of the asthma pharmacogenetics literature to date, we describe the application of a novel family-based screening algorithm to the analysis of pharmacogenetic data and highlight our approach to identifying and verifying loci influencing asthma treatment response. This approach seeks to address issues related to multiple comparisons, statistical power, population stratification, and failure to replicate from which previous population-based or case-control pharmacogenetic association studies may suffer. Identification of such replicable loci is the next step towards the goal of 'individualized therapy' for asthma. Genes on the Web--direct-to-consumer marketing of genetic testing. Wolfberg AJ, 2006. N Engl J Med. 355(6):543-5
This article describes advantages and disadvantages of commercialization of direct marketing of genetic testing to the consumer. Subtype-specific alpha1- and beta-adrenoceptor signaling in the heart. Xiao RP et al., 2006. Trends Pharmacol Sci. 27(6):330-7.
Recent studies of adrenoceptors have revealed subtype-specific signaling, promiscuous G-protein coupling, time-dependent switching of intracellular signaling pathways, intermolecular interactions within or between adrenoceptor subfamilies, and G-protein-independent signaling pathways. These findings have extended the classical linear paradigm of G-protein-coupled receptor signaling to a complex "signalome" in which an individual adrenoceptor initiates multiple signaling pathways in a temporally and spatially regulated manner. In particular, persistent stimulation of beta-adrenoceptor subtypes causes a time-dependent switch of signaling pathways and elicits different, even opposing, functional roles of these receptors in regulating cardiac structure and function. Recent progress in the understanding of subtype-specific functions and signaling mechanisms of cardiac adrenoceptor subtypes, particularly beta(1)-adrenoceptors, beta(2)-adrenoceptors, alpha(1A)-adrenoceptors and alpha(1B)-adrenoceptors, might have important pathogenic and therapeutic implications for heart disease. The proteomic search for diagnostic biomarkers: lost in translation? Zolg W, 2006. Mol Cell Proteomics 5(10):1720-6.
This article discusses the development and implementation of using proteomics as biomarkers to make a clinical diagnosis and management. |
