Pharmacogenetics of anticancer agents: lessons from amonafide and irinotecan.
(17/1551)
Amonafide and irinotecan are anticancer drugs representative of the clinical relevance of N-acetyltransferase (NAT) and uridine diphosphate glucuronosyltransferase (UGT) polymorphisms in cancer chemotherapy, respectively. Amonafide, a substrate for the polymorphic NAT2, has an active metabolite, N-acetyl-amonafide. Using caffeine as a probe, slow and rapid acetylators of amonafide were identified. Fast acetylators experienced greater myelosuppression than did slow acetylators, and a reduced dose of amonafide for fast acetylators has been recommended. A pharmacodynamic model based on acetylator phenotype, pretreatment white blood cell count, and gender has been proposed for dose individualization. The strategy adopted for amonafide is a model for future investigations in pharmacogenetics, although amonafide is no longer in clinical development. SN-38, the active metabolite of irinotecan, is glucuronidated to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Genetic defects in UGT1A1 determine Crigler-Najjar and Gilbert's syndromes characterized by unconjugated hyperbilirubinemia. Gilbert's syndrome often remains undiagnosed and occurs in up to 19% of individuals. Gilbert's syndrome is due to a homozygous TA insertion in the TATAA promoter of UGT1A1, leading to the mutated (TA)(7) allele. Irinotecan toxicity depends on the individual glucuronidation rate of SN-38. Decreased SN-38 glucuronidating activity has been found in livers obtained from individuals carrying the (TA)(7) allele. A phenotyping procedure for UGT1A1 has not been identified and genotyping of the UGT1A1 promoter in patients receiving irinotecan may identify patients at increased risk of toxicity. A clinical trial at the University of Chicago is ongoing to demonstrate the predictive significance of UGT1A1 genotyping for irinotecan pharmacodynamics. (+info)
Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase.
(18/1551)
Thiopurine drugs are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best examples of the potential importance of pharmacogenetics for clinical medicine. Specifically, it is now known that patients with inherited very low levels of TPMT activity are at greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of these drugs, while subjects with very high activity may be undertreated. Furthermore, recent reports indicate that TPMT may be the target for clinically significant drug interactions and that this common genetic polymorphism might be a risk factor for the occurrence of therapy-dependent secondary leukemia. In parallel with these clinical reports, the molecular basis for the TPMT polymorphism has been determined as a result of cloning and characterization of the human TPMT cDNA and gene. Those advances led to the description and characterization of a series of single nucleotide polymorphisms that result in low levels of enzyme activity as well as a polymorphic variable number tandem repeat within the 5'-flanking region of the TPMT gene that may "modulate" level of enzyme activity. As a result of these observations, the TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is developed and applied to clinical medicine. (+info)
Interethnic variability in human drug responses.
(19/1551)
The scientific study of interethnic differences in responses to drugs has been extant for 80 years. Many of these differences have been described at the phenotypic level, and some have been explained by genetic factors. However, it is frequently difficult to disentangle accurately the hereditary and environmental influences in phenotypic comparisons. This is where the recent developments in knowledge of the genes responsible for drug receptors are starting to make a big impact. The beta 2 adrenoceptor is described; it has three genetic polymorphisms. The different genotypes influence responses to agonists such as albuterol (Salbutamol). New gene frequency data including those for Saudi Arabians, Indians, and Africans are shown. The expanding body of knowledge about genetic (and interethnic) variability in drug receptors is likely to be important in clinical medicine. (+info)
Prospects for pharmacogenetics and ecogenetics in the new millennium.
(20/1551)
Genetics and genomics are certain to have a large impact in drug development and proper pharmaceutical treatment of subgroups of patients with many specific diseases. We should be able to increase the therapeutic margin for many agents. Genetic variation will also be important in refining estimates of risk from all kinds of environmental agents and in choosing more effective and more cost-effective risk reduction strategies. The linkage of information about genetic variation and information about environmental, nutritional, behavioral, metabolic, medical, and healthcare factors will be necessary to interpret the variation in clinical and public health terms. However, there is a great risk that present federal and state efforts to protect confidentiality and privacy of individual genetic information may make such research infeasible. In Michigan, a Governor's Commission has sought to strike an appropriate balance. (+info)
Pharmacogenetic interactions between beta-blocker therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure.
(21/1551)
BACKGROUND: Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele (ACE D) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with beta-blocker therapy have not been previously evaluated. METHODS AND RESULTS: We prospectively followed 328 patients (age, 56.1+/-11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24+/-0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n=120) and those without beta-blocker therapy (n=208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D: allele (1-year percent survival II/ID/DD=94/77/75; 2-year=78/65/60; ordered log-rank test, P:=0.044). In patients not treated with beta-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P:=0.005). In contrast, in patients receiving beta-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD=91/80/86; 2-year=70/71/77; P:=0.73). CONCLUSIONS: In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with beta-blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with beta-blockers in the determination of heart failure survival. (+info)
Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer.
(22/1551)
PURPOSE: TAS-103 is an inhibitor of both topoisomerase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103. PATIENTS AND METHODS: Thirty-two patients were treated with escalating doses (50 to 200 mg/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques. RESULTS: DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P <.05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P <.05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103. CONCLUSION: We recommend a dose of 130 to 160 mg/m(2), or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted. (+info)
Pharmacogenetics and drug-induced arrhythmias.
(23/1551)
Drugs are widely recognized to vary in the beneficial and undesirable effects they produce in human subjects. The understanding that variants (polymorphisms and mutations) in the human genome are common and may well modulate both disease and its response to drugs, is a critical new concept in understanding mechanisms of drug action and their variability in human subjects. Variability can arise because of variability in genes encoding molecules of drug disposition, in genes encoding molecules that drugs target, or in genes that modulate the overall activity of the complex biological systems within which drugs act. The evolving understanding of the genetic basis of variability in response to drugs used in the treatment of sudden cardiac death has important implications not only for the treatment of patients who have survived an episode, but also for helping formulate a framework for further understanding mechanisms of drug action at the genetic level. (+info)
The human genome, implications for oral health and diseases, and dental education.
(24/1551)
We are living in an extraordinary time in human history punctuated by the convergence of major scientific and technological progress in the physical, chemical, and biological ways of knowing. Equally extraordinary are the sparkling intellectual developments at the interface between fields of study. One major example of an emerging influence on the future of oral health education is at the interface between the human genome, information technology, and biotechnology with miniaturizations (nanotechnology), suggesting new oral health professional competencies for a new century. A great deal has recently been learned from human and non-human genomics. Genome databases are being "mined" to prompt hypothesis-driven "postgenomic" or functional genomic science in microbial models such as Candida albicans related to oral candidiasis and in human genomics related to biological processes found in craniofacial, oral, and dental diseases and disorders. This growing body of knowledge is already providing the gene content of many oral microbial and human genomes and the knowledge of genetic variants or polymorphisms related to disease, disease progression, and disease response to therapeutics (pharmacogenomics). The knowledge base from human and non-human genomics, functional genomics, biotechnology, and associated information technologies is serving to revolutionize oral health promotion, risk assessment using biomarkers and disease prevention, diagnostics, treatments, and the full range of therapeutics for craniofacial, oral, and dental diseases and disorders. Education, training, and research opportunities are already transforming the curriculum and pedagogy for undergraduate science majors, predoctoral health professional programs, residency and specialty programs, and graduate programs within the health professions. In the words of Bob Dylan, "the times they are a-changing." (+info)