Pharmacogenetics and Stomach Cancer: An Update

Abstract

Although new drugs and association regimens have been used in recent years, the chemotherapeutic outcome for gastric cancer is still poor and improvement in patient survival is not satisfactory. Pharmacogenetics could represent a useful approach to optimize chemotherapeutic treatments in order to identify individuals that are true candidates for clinical benefits from therapy, avoiding the development of severe side effects. The most recent update regarding gastric cancer pharmacogenetics highlights a prominent role of genetic polymorphisms of thymidylate synthase and glutathione S-transferase in the pharmacological treatment with commonly used drugs, such as 5-fluorouracil and platinum derivatives. In order to validate the genetic markers, further larger scale and controlled studies are required. A future challenge is represented by the introduction of targeted therapy in gastric cancer treatment, with the potential emerging tool of pharmacogenetic impact on this field.

Docetaxel: its role in current and future treatments for advanced gastric cancer

“…At present, however, there is no FDA-approved biomarker for the agents commonly used in gastric cancer chemotherapy, with the exception of C-KIT expression for imatinib mesylate in gastrointestinal stromal tumors. Even so, advances in pharmacogenomics in gastric cancer have provided a number of putative candidate markers for the prediction of tumor response to chemotherapies, including docetaxel and docetaxelcontaining combination regimens [4,[72][73][74][75][76][77]. We look forward to obtaining more data from ongoing trials, and we believe that future large trials will provide the best chemotherapy and predictive biomarkers for indicating individual toxicity risks and therapeutic benefi ts in gastric cancer patients.…”

Personalizing chemotherapy dosing using pharmacological methods

“…Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme involved in the metabolism of 5-FU to 5,6-dihydrofluorouracil, has been shown to exhibit polymorphic potential [31]. Given that 80-85 % of 5-FU is metabolized by DPD, a loss of enzyme activity has the potential to extend the half-life of 5-FU by up to 100-fold, enhancing the prolonged cytotoxic effect of the drug and corresponding toxicity.…”

“…To date, over 30 functional variants of DPYD, the gene coding for DPD, have been identified [32]. The polymorphic variant most commonly associated with DPD deficiency is a splice-site mutation, IV14 + 1G > A (also referred to as DPYD*2A), located on exon 14-flanking region and causing skipping of 165 base pairs [31].…”

Gold Nanoparticle Based Systems in Genetics

“…Although radiotherapy and chemotherapy, alone or combined with surgery, have improved cancer patients' outcomes, it is impossible to identify in advance which patients will benefit from such treatments since cancer cells can acquire resistance to chemotherapy by a wide range of mechanisms, including upregulation of ABC drug transporters, compromised apoptotic pathways, alteration of levels and/or efficiency of drug inactivating enzymes or DNA repair en-zymes [Marsh et al, 2004;Toffoli et al, 2003]. Conventionally adjustments of the dose of chemotherapeutic treatment could be ineffective in preventing toxicity and response variability, so new strategies for individualization of treatment in cancer patients are becoming an emerging issue.…”

“…However, several polymorphisms have been described in genes encoding proteins involved in the metabolic fate of nucleotides and in the repair of DNA lesion induced by these compounds [Toffoli et al, 2003], and inherited variability has been suggested to be responsible, partially, for individual differences in response to cancer treatment [Evans et al, 1999]. doxorubicin, carmustine (BCNU) have as target the DNA molecule, inducing DNA lesion leading to neoplasic cell death.…”