Pharmacogenomics in colorectal cancer: The first step for individualized-therapy

Abstract

Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.

Combined 5-FU and ChoKα Inhibitors as a New Alternative Therapy of Colorectal Cancer: Evidence in Human Tumor-Derived Cell Lines and Mouse Xenografts

“…These initial experiments have been reproduced in additional cell types including colon cancer derived cell lines (data not shown). Additional evidence has been reported that indicates a clear inhibition of the PI3K/AKT and ERK signaling pathways by ChoK inhibitors [38], [39], [40]. However, in the cellar systems used in this study, neither MAPK nor AKT signaling or ceramides generation are significantly altered by 5-FU treatment alone.…”

Prospects of ‘Omics Based Molecular Approaches in Colorectal Cancer Diagnosis and Treatment in the Developing World: A Case Study in Cape Town, South Africa

“…This area of research has been comprehensively reviewed recently by Asghar et al [56], Bandrés et al [57], Benheim et al [58], Coate et al [59], De Roock et al [60], and Ross et al [61] and forms the basis of the rich pharmacogenetic resource, PharmGKB® (http://www.pharmgkb.org) which documents each therapeutic agent together with an aggregated list of SNPs reported in the literature to be associated with treatment outcome.…”

“…In the former group, a polymorphism in the X-ray repair cross-complementing group 1 enzyme (XRCC1) -which is part of the base excision repair system -has been associated with variable initiation of DNA repair. [57] In addition, a polymorphism in a component of the ubiquitous nucleotide excision repair pathway -the excision repair cross complementing group 2 (ERCC2) gene -has been significantly associated with a clinical response to platinum-based chemotherapy. [57] However, there are no known polymorphisms in the DNA mismatch repair pathway associated with variation in treatment response with Oxaliplatin.…”

“…[57] In addition, a polymorphism in a component of the ubiquitous nucleotide excision repair pathway -the excision repair cross complementing group 2 (ERCC2) gene -has been significantly associated with a clinical response to platinum-based chemotherapy. [57] However, there are no known polymorphisms in the DNA mismatch repair pathway associated with variation in treatment response with Oxaliplatin. In the second group, it has been reported that platinum compounds are inactivated by glutathione conjugation and therefore the enzymes responsible for catalyzing this reaction have been investigated.…”

MicroRNAs and Rectal Cancer

“…2.7 Potential role of microRNAs in modulating anticancer drug and radiation response Drug resistance and the comparative impact of radiation has been fairly frequently studied in cancer cells in vitro (Bandres, 2007;DiGennaro, 2009). However, our knowledge of the molecular events that take place in response to anticancer drugs and radiation in human tumours in vivo is very limited, and this is even more true of microRNA expression changes induced by these events.…”