Current Pharmacogenomics - Volume 5, Issue 3, 2007

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the drug of choice for the treatment of metastatic colorectal cancer, despite the fact that poor patient response to the drug due to acquired or inherent drug resistance is a major clinical problem. To be able to predict an individual patient's response to 5-FU would facilitate the design of chemotherapeutic regimens tailored according to the individual patient and tumor profile. Pharmacogenomic studies provide information as to how variability on a genome-wide scale influences drug response, and are facilitated by high throughput technologies such as genomic and expression microarrays and single nucleotide polymorphism (SNP) assays. Not surprisingly, such investigations are taking the place of genetic studies that investigate associations between drug response and genetic alterations for one individual gene. This reflects the growing awareness that cancer drug response is multi-faceted. The cellular mechanisms underlying drug resistance can involve alterations at the single gene and/or genomic level on multiple biological regulatory pathways, e.g., cell cycle progression, apoptotic, and DNA repair pathways. This review will provide an update on how pharmacogenomic studies are being used to dissect the cellular mechanisms underlying drug response and drug resistance in colorectal cancer in order to identify novel biomarkers of 5-FU response, and how knowledge gained from transcriptional profiling studies of colorectal tumors is serving as a guide for optimization of current chemotherapeutic strategies and for design of new treatment strategies.

Pharmacogenomic research into smoking behaviour and smoking cessation holds promise for understanding why people smoke and how we can better help people to quit. As smoking prevalence declines in the United States and Western Europe through social and clinical action, average level of tobacco and nicotine dependence amongst smokers may increase. The place of the pharmacogenomic contribution to understanding residual dependence and how to further lower smoking prevalence may increasingly come to the fore. This review examines the influence of genetic variation on smoking initiation, progression to dependence, and persistent regular smoking (including amount smoked) as well as response to smoking cessation pharmacotherapies. Although research is still at an early stage, a future in which individualised treatment is tailored to genotype now seems possible. However, there are substantial practical, ethical, and social considerations that must be addressed before such research can be translated into clinical practice.

Many lines of evidence demonstrate that certain dietary phytochemicals have cancer chemopreventive effects. These dietary phytochemicals or chemo-preventive agents can suppress or block carcinogenesis by (1) enhancing the biotransformation enzymatic activities for efficient elimination of carcinogens or reactive oxidative or nitrosative species (ROS/RNS); (2) suppressing the growth/inflammatory signaling pathways involved in cancer cell proliferation; and (3) modulating phase II detoxifying/antioxidant enzymes, e.g. glutathione S-transferases (GST), NAD(P)H-quinone reductase 1 (NQO1), UDP-glucuronosyltransferases (UGT), and antioxidant enzymes such as gamma-glutamylcysteine synthetase (γ-GCS) and heme oxygenase 1 (HO1). Comparison of gene expression profiles among Nrf2 wild type and Nrf2 knockout mice showed that these genes are induced in an Nrf2-dependent manner in response to phytochemical treatments. The potential roles of different types of polymorphisms or pharmacogenetics in carcinogenesis and prevention/treatment of some of these genes will be described in this review. Finally, the potential usage of these dietary compounds in combination with conventional cancer chemotherapy will also be considered. The applications of pharmacogenomics to dietary cancer chemopreventive studies will be essential for understanding the cancer protective mechanisms and could lead to individualized drug therapies in the future.

The treatment of Chronic Myelogenous Leukaemia (CML) has been revolutionized by the introduction of Tyrosine Kinase Inhibitors (TKIs) and represents a new paradigm for the treatment of cancer. Imatinib Mesylate (IM) specifically targets limited numbers of tyrosine kinases (BCR-ABL, PDGFRα, PDGFRβ, C-ABL, c-fms and c-Kit), which explains its specific anti-tumoural efficacy and limited toxicity. In CML, the pivotal phase III trial has demonstrated the high superiority of IM for progression-free survival among interferon-α + cytarabine. Despite this remarkable success, >90% of the patients show long-term persistence of limited numbers of malignant cells in their body raising the intriguing question of the persistence of BCR-ABL+ leukaemic stem cells serving as a reservoir for the disease. In addition, and maybe as a consequence, growing numbers of patients escape from IM-disease control and progressively or brutally relapse. Considerable progress has been made in understanding the mechanisms responsible for CML resistance to IM, and the onset of BCR-ABL oncogene point mutations remains the most frequent and investigated event in this setting. More than 50 mutations have been described in patients' samples to date, which have a major impact on disease behavior and on the management of disease control. Interestingly, the prognosis seems quite different according to the type of mutations identified, and moreover particular mutations are more frequent in advanced phases of CML where their identification represents a marker of progression. Second generation TKIs have reached the level of clinical trials, and it is likely that they would overcome the majority of BCR-ABL mutation-induced resistances. However, some patients harbouring BCRABL mutations do not respond to these new compounds either, suggesting the onset of other molecular mechanisms involved in the resistance of the disease to TKIs. The aim of this review is to summarize the knowledge accumulated recently on the impact of BCR-ABL mutations in the sensitivity/resistance of CML to TKIs.

Osteoporosis is a prevalent disease, particularly among postmenopausal women, characterized by low bone mass and increased skeletal fragility. It is a complex disease resulting from the interaction of hereditary and environmental factors. Many investigators have studied the genetic influence on bone mass. Although the results have been controversial and not reproduced consistently, some genes appear to be likely candidates, including those related to estrogen metabolism and activity. According to their effects on bone remodeling, anti-osteoporotic drugs can be classified as anticatabolic (estrogens, selective estrogen receptor modulators, bisphosphonates, calcitonin, vitamin D, calcium) or anabolic (parathyroid hormone and derivatives). These drugs increase bone mineral density and may reduce fracture rate. There are few data about the influence of the individual genetic characteristics on the response to anti-osteoporotic drug therapy. Nevertheless, a number of studies suggest that some polymorphisms of estrogen and vitamin D receptors may be associated with differences in the changes of bone mineral density induced by anticatabolic agents. However, there is a clear need of further investigations before genetic data can be used in clinical practice to individualize drug use in the prevention and treatment of osteoporosis.

Despite the availabilty of active chemotherapy combinations and novel targeted agents, the prognosis in advanced non-small cell cancer (NSCLC) remains poor. Similarly, although the efficacy of adjuvant chemotherpy has recently been established, the risk of disease recurrence after surgery for early stage disease remains high. Some patients enjoy sustained benefit from currently available drugs, but overall results in unselected patient groups are modest. This marked inter-patient variation reflects the molecular heterogeneity of NSCLC, a heterogeneity which is increasingly understood to arise at the level of the cancer genome. The wide range of somatic genetic and epigenetic events that drive the lung cancer phenotype is now beginning to inform the selection of patients for treatment with both cytotoxic and targeted therapies. Furthermore, it is becoming apparent that germline genomic variability may also need to be taken into account in making treatment decisions for NSCLC patients.

Recent expansion of pharmacotherapy of inflammatory bowel diseases (IBD) reflects an increasing understanding of the mechanisms involved in its pathogenesis. Individual variation in response to drugs is a major problem in clinical practice and is associated with various host factors, including sex, age, diet, alcohol consumption, smoking habits and genetic background. The study of the genetic determinants influencing interindividual differences in drug responses is known as pharmacogenetics. A common disease as IBD may be caused by different groups of genes in different people, showing smaller genetic variation than IBD patients globally considered. The classification of individuals based on sets of susceptibility alleles will make treatment more predictable and effective. Pharmacogenetics in IBD is developing in two main directions. One involves the identification and design of novel drug targets by exploiting current knowledge of the structure and function of IBD susceptibility genes. Another thrust of IBD pharmacogenetic research is directed at understanding how genetic variation determines the response to and the side effects of existing therapeutic agents. Pharmacogenetics holds the promise that drugs might one day be adapted to each person's own genetic background and therefore be more efficacious and safe. Therapies of future should put emphasis on the epidemiological, molecular and genetic basis of disease with the application to clinical practice, underscoring the final goal of personalized medicine. In this review, we focused on the basis of pharmacogenetics, on the recent advances of the field in the main therapies involved in IBD (Azathioprine / 6-Mercaptopurine, 5-Aminosalicylates, Glucocorticoids, Methotrexate, Infliximab) and speculate on the future of pharmacogenetics.