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Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

Roco A, Cayún J, Contreras S, Stojanova J, Quiñones L - Front Genet (2014)

Bottom Line: These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer.Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments.Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Salud Metropolitano Occidente Santiago, Chile ; Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Molecular and Clinical Pharmacology Program, ICBM - Insituto de Ciencias Biomédicas, Faculty of Medicine, University of Chile Santiago, Chile.

ABSTRACT
Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility.

No MeSH data available.


Related in: MedlinePlus

Potential sources of variability to clinical response to cisplatin treatment. Abbreviations: DNA, deoxyribonucleic acid; GSTs, glutathione S-Transferases; NER, nucleotide excision repair; LPR2, Low Phosphate Root2; SLC31A1 (CTR1), solute carrier family 31 (copper transporter), member 1; SLC22A2, solute carrier family 22 (organic cation transporter), member 2; ERCCs, Excision Repair Cross Complementing group of proteins; XPC, Xeroderma Pigmentosum Group C Protein.
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Figure 1: Potential sources of variability to clinical response to cisplatin treatment. Abbreviations: DNA, deoxyribonucleic acid; GSTs, glutathione S-Transferases; NER, nucleotide excision repair; LPR2, Low Phosphate Root2; SLC31A1 (CTR1), solute carrier family 31 (copper transporter), member 1; SLC22A2, solute carrier family 22 (organic cation transporter), member 2; ERCCs, Excision Repair Cross Complementing group of proteins; XPC, Xeroderma Pigmentosum Group C Protein.

Mentions: From the beginning, cisplatin has presented variations in therapeutic response. While some tumors are hypersensitive to anticancer therapy, other tumors have an intrinsic resistance. Investigations have sought an explanation of this variation and have suggested that the major resistance mechanisms include reduction in drug levels that reach the target DNA due to reduced uptake and/or increased efflux; increased cellular thiol levels; enhanced DNA repair and/or increased damage tolerance; and failure of cell-death pathways after the formation of platinum-DNA adducts (Fojo, 2001; Siddik, 2003; Wang and Lippard, 2005). In each of these processes there exist potential sites of pharmacogenetics variability (Figure 1). Changes at the genetic level causing modifications in cellular phenotype could explain some of the variability in response and toxicity to cisplatin-included chemotherapy. In this review, we discuss associations between genetic variants in the germ line and in outcomes following cisplatin-based chemotherapy. We mainly focus on DNA repair and cisplatin detoxification through Glutathione S-Transferases (GSTs).


Can pharmacogenetics explain efficacy and safety of cisplatin pharmacotherapy?

Roco A, Cayún J, Contreras S, Stojanova J, Quiñones L - Front Genet (2014)

Potential sources of variability to clinical response to cisplatin treatment. Abbreviations: DNA, deoxyribonucleic acid; GSTs, glutathione S-Transferases; NER, nucleotide excision repair; LPR2, Low Phosphate Root2; SLC31A1 (CTR1), solute carrier family 31 (copper transporter), member 1; SLC22A2, solute carrier family 22 (organic cation transporter), member 2; ERCCs, Excision Repair Cross Complementing group of proteins; XPC, Xeroderma Pigmentosum Group C Protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231946&req=5

Figure 1: Potential sources of variability to clinical response to cisplatin treatment. Abbreviations: DNA, deoxyribonucleic acid; GSTs, glutathione S-Transferases; NER, nucleotide excision repair; LPR2, Low Phosphate Root2; SLC31A1 (CTR1), solute carrier family 31 (copper transporter), member 1; SLC22A2, solute carrier family 22 (organic cation transporter), member 2; ERCCs, Excision Repair Cross Complementing group of proteins; XPC, Xeroderma Pigmentosum Group C Protein.
Mentions: From the beginning, cisplatin has presented variations in therapeutic response. While some tumors are hypersensitive to anticancer therapy, other tumors have an intrinsic resistance. Investigations have sought an explanation of this variation and have suggested that the major resistance mechanisms include reduction in drug levels that reach the target DNA due to reduced uptake and/or increased efflux; increased cellular thiol levels; enhanced DNA repair and/or increased damage tolerance; and failure of cell-death pathways after the formation of platinum-DNA adducts (Fojo, 2001; Siddik, 2003; Wang and Lippard, 2005). In each of these processes there exist potential sites of pharmacogenetics variability (Figure 1). Changes at the genetic level causing modifications in cellular phenotype could explain some of the variability in response and toxicity to cisplatin-included chemotherapy. In this review, we discuss associations between genetic variants in the germ line and in outcomes following cisplatin-based chemotherapy. We mainly focus on DNA repair and cisplatin detoxification through Glutathione S-Transferases (GSTs).

Bottom Line: These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer.Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments.Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility.

View Article: PubMed Central - PubMed

Affiliation: Servicio de Salud Metropolitano Occidente Santiago, Chile ; Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Molecular and Clinical Pharmacology Program, ICBM - Insituto de Ciencias Biomédicas, Faculty of Medicine, University of Chile Santiago, Chile.

ABSTRACT
Several recent pharmacogenetic studies have investigated the variability in both outcome and toxicity in cisplatin-based therapies. These studies have focused on the genetic variability of therapeutic targets that could affect cisplatin response and toxicity in diverse type of cancer including lung, gastric, ovarian, testicular, and esophageal cancer. In this review, we seek to update the reader in this area of investigation, focusing primarily on DNA reparation enzymes and cisplatin metabolism through Glutathione S-Transferases (GSTs). Current evidence indicates a potential application of pharmacogenetics in therapeutic schemes in which cisplatin is the cornerstone of these treatments. Therefore, a collaborative effort is required to study these molecular characteristics in order to generate a genetic panel with clinical utility.

No MeSH data available.


Related in: MedlinePlus