Background: Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate theinfluence of platinum pathway polymorphisms on treatment outcome in patients with MM. Patients and Methods: In total, 133 patients with MM treatedwith (n = 97) or without (n = 36) platinum-based therapy were genotypedfor common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms. Results: GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-typegenotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis. Conclusions: Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.
F.21 Development of new health/diagnostic methods/procedures
COBISS.SI-ID: 28755417Documented by almost five hundred references the chapter provides a systematic overview of enzymes involved in the first phase of drug and xenobiotic metabolism (activation) and their corressponding genes. It describes their role in the metabolism of drugs and other xenobiotics, as well as in the metabolism of the endogenous substrates. The chapter also summarizes the current knowledge on the importance of genetic polymorphisms of Phase I enzymes, especially cytochromes P450 in clinical practice. The chapter on pharmacogenetics of enzymes involved in phase I of metabolism of drugs and xenobiotics is a part of the book "Pharmacogenetics and Individualized Medicine" which was published by John Wiley & Sons in 2012. The book was edited Anke-Hilse Maitland-van der Zee from the University of Utrecht and Ann K. Daly from the University of Newcastle. The book provides summarizes the current knowledge in the field of pharmacogenetics and comprehensivly covers the metabolism of drugs and xenobiotics, the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of the active substances and the importance of pharmacogenetics for specific clinical areas such as cardiac disease, psychiatric disease, cancer, asthma and chronic obstructive lung disease, and chronic inflammatory bowel disease. It also summarizes the developments in the field of new technological approaches in the field of pharmacogenetics and highlights the problems associated with the transfer into clinical practice and the development of new drugs.
F.30 Professional assessment of the situation
COBISS.SI-ID: 30003673Background: The genetic factors may modify the individual susceptibility to the development of asbestosis. This study investigated whether MnSOD, ECSOD, CAT, iNOS, GSTM1, GSTT1 and GSTP1 genetic polymorphisms represent risk factors for asbestosis in workers occupationally exposed to asbestos. Methods: The nested case-control study included 262 cases with asbestosis and 265 controls with no asbestos-related disease. Data on cumulative asbestos exposure and smoking were available for all subjects. PCR based methods were used to genotype MnSOD Ala –9Val, ECSOD Arg213Gly, CAT –262C)T, iNOS (CCTTT)n, GSTM1-null, GSTT1-null, GSTP1 Ile105Val and Ala114Val polymorphisms. To asses asbestosis risk, logistic regression analysis was used. Results: The key findings of this study were that the GSTP1 coding for an enzyme with high conjugation capacity and the MnSOD -9Ala/Ala significantly increase the risk of developing asbestosis, whereas a protective effect was found for the GSTT1-null genotype. This study also demonstrated a strong interaction between MnSOD Ala –9Val and CAT –262C)T polymorphisms, as well as between iNOS CCTTT and CAT –262C)T polymorphisms. Important findings of the current study show that the association between smoking and asbestosis is modified by GSTM1-null and iNOS CCTTT polymorphisms. Additional studies are needed to clarify whether MnSOD, ECSOD, CAT, and iNOS genotypes confound or modify the cumulative asbestos exposure – asbestosis associations. Conclusions :The findings of the current study suggest that, in addition to asbestos exposure, the genetic factors involved in the defense against ROS may also have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 30504665