Association Study Among Candidate Genetic Polymorphisms and Chemotherapy-Related Severe Toxicity in Testicular Cancer Patients

Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III–IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III–IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III–IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy

Factores genéticos relacionados con la variabilidad en la respuesta a la quimioterapia en pacientes con cáncer testicular

El cáncer testicular (CT) es un tumor maligno que en Chile presenta tasas de incidencia y mortalidad superiores a las tasas mundiales. La familia de genes de Citocromo P450 y Glutatión-S-Transferasas (GSTs) participan en la biotransformación y desintoxicación de fármacos y xenobióticos. Mutaciones en estos genes, y en enzimas de reparación del ADN, han sido asociadas a una mayor incidencia de diversos tipos de cáncer y a un mayor riesgo de presentar reacciones adversas a medicamentos (RAM). Los objetivos de esta tesis fueron: relacionar la presencia de polimorfismos genéticos en CYP1A1, CYP3A4, GST y ERCC, así como factores no genéticos, sobre el riesgo de desarrollar cáncer testicular y el análisis del impacto de los polimorfismos de CYP3A4, GST y BLMH en el riesgo de presentar RAM en pacientes con cáncer testicular. Metodología: Se reclutaron 539 voluntarios de población chilena (PCh) y 234 pacientes con CT. El análisis genotípico fue realizado mediante qPCR y PCR-RFLP. Resultados: Las variantes genéticas de CYP1A1*2C (OR=3,00), GSTT1 (OR=2,08) y GSTP1 (A/G OR=2,86 y G/G OR=4,00) aumentan el riesgo de desarrollar CT, además de los antecedentes familiares de cáncer (OR=2,53) o el hábito tabáquico (OR=2,04). Los resultados del análisis multivariable muestran que la presencia de polimorfismos en GSTP1 (A/G y G/G) en conjunto con el hábito tabáquico y los antecedentes familiares de cáncer explican un 12 % del riesgo de desarrollar cáncer testicular en población chilena. Conclusión:, Los resultados de este estudio han permitido identificar factores genéticos y no genéticos que se asocian a la aparición de cáncer testicular CT, y permiten disponer de una herramienta de predicción parcial del riesgo. No se observaron asociaciones significativas entre variantes genéticas y RAM.Testicular cancer (TC) is a malignant tumor that in Chile has incidence and mortality rates higher than the world rates. The family of genes of Cytochrome P450 and Glutathione-S-transferases (GSTs) participate in the biotransformation and detoxification of xenobiotics. Mutations in these genes and in DNA repair enzymes have been associated with a higher incidence of various types of cancer, and an increased risk of presenting adverse reactions to drugs (ADR). The objectives of this Thesis were: to relate the presence of genetic polymorphisms in CYP1A1, CYP3A4, GST and ERCC and non-genetic factors on the risk of developing testicular cancer. In addition, the analysis of the impact of CYP3A4, GST, and BLMH polymorphisms with the risk of presenting ADR in patients suffering from TC. Methods: We recruited 539 volunteers from the Chilean population (PCh) and 234 patients with TC. The genotypic analysis was performed by using qPCR and PCR-RFLP. Results: Variant alleles that increase the risk of developing TC are CYP1A1*2C (OR = 3.00), GSTT1(-) (OR = 2.08) and GSTP1 (A/G OR = 2.86; G/G OR = 4.00), besides family history of cancer (OR = 2.53) or smoking (OR = 2.04). The results of the multivariate analysis show that the presence of variant alleles in GSTP1 (A/G and G/G) together with smoking habit and family history of cancer explain 12% of the risk of developing testicular cancer in the Chilean population. Conclusions: In this study, we identified genetic and non-genetic factors associated to CT, which make constitute a tool for partial risk prediction. We did not identify significant associations between genetic variants and ADR

Cardiovascular pharmacogenomics: Clinical applications in Latin America

© 2011 by Nova Science Publishers, Inc. All rights reserved. Cardiovascular diseases (CVDs) are the number one cause of death globally. Most cardiovascular diseases can be prevented by addressing behavioral risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity and harmful use of alcohol using population-wide strategies. Various factors help the occurrence of cardiovascular diseases. There are not-modifiable factors such as genetic inheritance and other modifiable such as smoking, alcohol intake, diet and physical activity risk factors. The overall level of risk of an individual is the one that determines the probability of cardiovascular disease, such as acute myocardial infarction, stroke, among others. On the other hand, a number of medications, including: Antiarrhythmics, anticoagulants, beta-blockers, calcium channel blockers, angiotensin receptor blockers, digitalis, diuretics, angiotensin converting enzyme (ACE) are the pharmacotherapeutic arsenal ava

Role of cytochrome P450 enzymes in the metabolism of antineoplastic drugs Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: Situación actual y perspectivas terapéuticas

Cytochrome P450 enzymes are very important to metabolize anti-carcinogenic agents. Therefore, understanding the role of these enzymes and their allele variants in the bioactivation or detoxification of drugs could greatiy benefit antineoplastic pharmacotherapy. The aim of thís manuscrípt is to give information about metabohzing enzymes for antineoplastic agents and to relate the current situation in antitumoral pharmacotherapy with recent knowledge about cytochrome P450 enzymes. This is crucial for the future perspectives towards personalized pharmacotherapy. We summarize the role of cytochrome P450 enzymes in the resistance and bioactivation of several antitumor agents, their induction and repression mechanisms and the effect of genetic polymorphisms on variability of drug metabolization. The understanding of genetic variability will help to develop new research Unes on innovative therapeutic possibilities. © 2009 Sociedad Médica de Santiago

Anticoagulation Management With Coumarinic Drugs in Chilean Patients

Warfarin and acenocoumarol are used in various cardiovascular disorders to improve the prognosis of patients with thromboembolic disease. However, there is a lack of substantial efficacy and safety data on antithrombotic prophylaxis in several countries, particularly in Latin America. The aim of this study was to provide information about the efficacy of anticoagulants in Chilean patients. Data were collected from databases of the Western Metropolitan Health Service, Santiago, Chile. We identified 6280 records of patients receiving anticoagulant treatment. The three most common diagnoses were rhythm disorder (43.7%), venous thrombosis (22%), and valvular prosthesis (10.7%). The majority of patients (98.5%) received acenocoumarol while 1.5% of patients received warfarin, at weekly therapeutic doses of 13.6 mg and 30.4 mg, respectively. For total diagnoses, the median time in the therapeutic range was 50%. However, better results, 66.7%, were observed when a telemedicine strategy was used only in Santiago Province. Our findings emphasize that in Chile, where the number of patients receiving anticoagulant treatment increases every year, telemedicine, by committed teams, improves the use of oral anticoagulants and is able to increase quality indicators of anticoagulant treatment care

Influencia de polimorfismos genéticos de CYP3A4/5 en la farmacocinética de levonorgestrel: estudio piloto

Introduction. Levonorgestrel a synthetic progestagen used for endometriosis, dysmenorrhea and emergency contraception, is quickly and completely absorbed in the digestive tract. levonorgestrel is predominantly metabolised through hepatic routes that utilise the CYP3A system (CYP3A4 and CYP3A5). Objective. This study aimed to evaluate the association between variant alleles of CYP3A4*1B and CYP3A5*3 polymorphisms and the pharmacokinetics of levonorgestrel. Materials and methods. A group of 17 adult female healthy volunteers who signed an informed consent were genotyped for CYP3A4 and CYP3A5 through PCR-RFLP. Volunteers were submitted to pharmacokinetic analysis where, after a 12-hour overnight fast, they received a single oral dose of 0.75 mg of levonorgestrel. Serial blood samples were obtained (0 to 24 hours), and levonorgestrel concentrations were determined by UPLC-MS/MS to determine pharmacokinetic parameters. The procedures employed herein were performed according to the Declaration of Helsinki and Good Clinical Practices standards. Results. Observed genotype frequencies in the studied group for CYP3A4*1B were 11.8% for *1B/*1B, 5.8% for *1/*1B and 82.4% for *1/*1. CYP3A5*3 frequencies were 70.5% for *3/*3, 23.5% for *1/*3 and 6.5% for *1/*1. A high pharmacokinetic variability between volunteers was observed, but no statistical association of pharmacokinetic parameters was found within the studied CYP3A4/5 polymorphisms. Conclusions. Genetic polymorphisms could be important factors in determining inter-patient variability in plasma levonorgestrel concentrations, which in this study were not significantly associated with the presence of CYP3A4*1B and CYP3A5*3 polymorphisms. Therefore, due to the significant inter-patient variability that we observed during the course of this study, it is necessary to carry out studies with larger number of volunteer