Application of pharmacogenetics in oncology

Abstract

The term "pharmacogenetics" is used to describe the study of variability in drug response due to heredity. It is associated with "genedrug interactions". Later on, the term "pharmacogenomics" has been introduced and it comprises all genes in the genome that can define drug response. The application of pharmacogenetics in oncology is of a great significance because of the narrow therapeutic index of chemotherapeutic drugs and the risk for life-threatening adverse effects. Many cancer genomics studies have been focused on the acquired, somatic mutations; however, increasing evidence shows that inherited germline genetic variations play a key role in cancer risk and treatment outcome. The aim of this review is to summarize the state of pharmacogenomics in oncology, focusing only on germline mutations. Genetic polymorphisms can be found in the genes that code for the metabolic enzymes and cellular targets for most of the chemotherapy drugs. Nevertheless, predicting treatment outcome is still not possible for the majority of regimens. In this review, we discuss the most comprehensively studied drug-gene pairspresent knowledge and current limitations. However, further studies in larger groups of cancer patients are necessary to be conducted with precise validation of pharmacogenetic biomarkers before these markers could be routinely applied in clinical diagnosis and treatment.

Force Field Parameters for Fe2+4S2−4 Clusters of Dihydropyrimidine Dehydrogenase, the 5-Fluorouracil Cancer Drug Deactivation Protein: A Step towards In Silico Pharmacogenomics Studies

“…The enzyme is involved in the degradation of pyrimidine bases (thymine and uracil) via a NADPH-dependent reaction to 5,6-dihydrothymine and 5,6 dihydrouracil, respectively [1]. Besides its biological nucleotide catabolizing function, the enzyme is an adjunct anti-cancer drug target [3]. It is solely responsible for the phase 1 metabolism of 5-fluorouracil (5-FU), a commonly prescribed pyrimidine-like anti-cancer drug.…”

Force field parameters for Fe2+4S2-4 clusters of dihydropyrimidine dehydrogenase, the 5-fluorouracil cancer drug deactivation protein: a step towards in silico pharmacogenomics studies

“…The enzyme is involved in the degradation of pyrimidine bases (thymine and uracil) via a NADPH-dependent reaction to 5,6-dihydrothymine and 5,6 dihydrouracil, respectively [1]. Besides its biological nucleotide catabolizing function, the enzyme is an adjunct anti-cancer drug target [3]. It is solely responsible for phase 1 metabolism of 5fluorouracil (5-FU), a commonly prescribed pyrimidine-like anti-cancer drug.…”

“…Thus, understanding the implication of mutations on the catalytic mechanism of DPD can improve treatment approaches for oncology patients. Although there is a growing interest in molecular investigations on DPD enzyme, especially via computational approaches such as molecular dynamics (MD) simulations [7], a significant hindrance against the implementation of such studies is the presence of four iron-sulfur (Fe 2+ 4S [2][3][4] clusters in the homodimeric form of DPD structure, which require additional force field parameters.…”

“…Comparison of average bond length (Å) calculated with X-ray, 1 DFT 2 (B3LYP) and 3 (LSDA) method for the molecular cluster model ([Fe 2+ 4S 2-4 (S-Cys)3(S-Gln)]) and ([Fe 2+ 4S 2-4 (S-Cys)4]) of Native DPD protein. Comparison of average internal angles ( 0 ) calculated with X-ray, 1 DFT 2 (B3LYP) and 3 (LSDA) method for the molecular cluster model ([Fe 2+ 4S 2-4(S-Cys)3(S-Gln)]) and ([Fe 2+ 4S 2-4(S-Cys)4]) of Native DPD protein Comparison of average external angles ( 0 ) calculated with X-ray, 1 DFT 2 (B3LYP) and3 (GFN1-xTB) method for the molecular cluster model ([Fe 2+ 4S 2-4(S-Cys)3(S-Gln)]) and ([Fe 2+ 4S 2-4(S-Cys)4]) of Native DPD protein. DFT: density functional theory, 2 B3LYP: Becke, three-parameter, Lee Yang Parr, 3 GFN1-xTB: eXtended TB: 4 SD: standard deviation, 5 QM: quantum mechanics…”

“…DFT: density functional theory, 2 B3LYP: Becke, three-parameter, Lee Yang Parr,3 LSDA: local spin density approximation, 4 SD: standard deviation, 5 QM: quantum mechanics,6 MD: molecular dynamics…”