Overcoming Imatinib Resistance
The understanding of mechanisms of IM resistance and of the overall biology of the BCR-ABL1 gene and protein has stimulated interest in developing therapeutic strategies to overcome resistance. Because it remains difficult to define the precise mechanism of resistance in the vast majority of patients on a routine clinical basis, the choice of alternative therapy in patients who are failing IM remains empirical. The commonly used strategy is to escalate the dose of IM since no dose-limiting...
The Biochemistry And Signaling Properties Of Egfr
ErbB receptors exhibit conserved structural similarity and domain topography (Fig. 1). They contain an extracellular ligand-binding region, which consists of two cysteine-rich domains, and is responsible for ligand-induced receptor dimerization. This Fig. 1. The domain topography of EGFR. The receptor contains cysteine-rich domains (CRDs) in the extracellular region, which contribute to ligand binding. The transmembrane region contains hy-drophobic amino acids, as is the case with other cell...
Waldenstroms Macroglobulinemia
Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoid malignancy characterized by IgM monoclonal gammopathy and intertrabecular marrow infiltration by small lymphocytes expressing CD20 antigen. Currently, rituximab can be used for the treatment of WM with response rates between 20 and 50 (62,63). The impact of FCGR3A polymorphism on the response to rituximab for WM has been demonstrated by the work of Treon et al. (Table 3) (64). They reported that two polymorphisms, FCGR3A-43 and...
Conclusion
Since the identification of the minute Philadelphia chromosome in 1960 and its subsequent identification as a translocation with chromosome 9, our evolving understanding of the structure and function of the BCR-ABL1 aberrant tyrosine kinase has led to incredible advances in our understanding of the pathogenesis and treatment of CML. This understanding culminated in the development of IM, and this has been rapidly followed by second- and subsequent-generation agents that have built on the...
Conclusions
In the past half-century, pharmacogenetics and pharmacogenomics have rapidly incorporated advances in modern biology, genetics, and genomics. The field has evolved from focusing on monogenic traits to emphasizing polygenic pathways. These pathways encompass genes in all relevant drug-metabolizing enzymes, drug transporters, and drug targets, as well as signaling cascades that are upstream or downstream from the targets. Hypothesis-driven approaches have resulted in some striking examples of...
Self Organizing
In order to have an overall measure of similarities between all GI50 data vectors we have used a self-organizing map (SOM)(1< 5) to organize cellular growth inhibition data derived from the NCI60 tumor cell panels (14). The SOM algorithm identifies cluster vectors in the 60-dimensional data space by minimizing the deviation between the GI50 data vectors and the cluster vectors. Regions in the GI50-space that are dense with data vectors attract many cluster vectors and regions with few data...
UGT1A Gene Structure
UDP-glucuronosyltransferases (UGTs) catalyze the transfer of a glucuronoic acid from uridine diphosphoglucuronic acid to a variety of endogenous and exogenous compounds. The major function of these enzymes is to change hydrophobic compounds into soluble derivatives and thereby facilitate their detoxification and excretion into the bile or urine. Among four subfamilies of UGTs identified in humans (i.e., UGT1, UGT2, UGT3, and UGT8) (20), UGT1A isozymes, such as 1A1, 1A7, 1A9, and 1A10, are known...
References
Wasinger VC, Cordwell SJ, Cerpa-Poljak A et al. Progress with gene-product mapping of the Molli-cutes Mycoplasma genitalium. Electrophoresis 1995 16 1090-1094. 2. O'Farrell PH. High resolution two-dimensional electrophoresis of proteins., Biol Chem 1975 250 4007-4021. 3. Simpson RJ, Connolly LM, Eddes JS et al. Proteomic analysis of the human colon carcinoma cell line (LIM 1215) development of a membrane protein database. Electrophoresis 2000 21 1707-1732. 4. Ha GH, Lee SU, Kang DG et al....
Metabolism Of 6mercaptopurine And 6thioguanine
Anabolic and catabolic pathways are involved in the metabolism of thiopurines (Fig. 2) (90,91,92). The enzyme hypoxanthine guanine phosphoribosylferase, responsible for bio-activation of thiopurines, converts 6-MP into 6-thioinosine monophosphate, Fig. 2. Metabolic scheme of thiopurine metabolism. 6-MP, 6-mercaptopurine 6-TG, 6-thioguanine 6-MMP, 6-methyl-mercaptopurine XO, xanthine oxidase TPMT, thiopurine S-methyltransferase HPRT, hypoxanthine guanine phosphoribosyl transferase IMPDH, inosine...
Advantages of the SNP Array
The SNP array has several advantages over traditional methods such as karyotyping and allelotyping with microsatellite markers. First, it requires no cell cultures, eliminating some of the karyotyping problems that arise from passaging cells. Cultures from primary tumors are often contaminated with normal cells, which can proliferate and thus complicate the karyotyping results. Second, the SNP array has a high SNP density for genotyping and copy number measurements. For example, on the GeneChip...
Dpd Impairment Implication Of Dpyd Gene Polymorphism And Genetic Downregulation
Erratic DPD activity is a major cause of the marked pharmacokinetic variability of 5-FU. Drug-drug interactions (47,48), circadian patterns (12,49,50), and inter-gender (7,8) inter-ethnic differences (51,52,53,54,55) have been identified as putative causes for profound variations in DPD activities. Consequently, population studies of DPD activities displayed extremely wide ranges of values (17,56,57). Genetic mutations are a major cause of DPD impairment (24,58). Polymorphism of the DPYD gene...
National Cancer Institute Ncis 60cell Screening And Gene Expression Data
The National Cancer Institute's (NCI's) 60-cell line drug discovery panel (NCI60) was developed as a tool to assess anti-cancer activity of compounds against a range of cell lines derived from different cancers, including lung, renal, colorectal, ovarian, breast, prostate, central nervous system, melanoma, and hematological malignancies (12). Chemicals that reduce the viability of the cell are tagged as potential leads for affecting particular pathways characteristic of each tumor cell's...
MTHFD1 Studies
To date, Krajinovic et al. have reported the only association between genetic variation in MTHFD1 and ALL treatment outcome (5) (Table 1). Specifically, the MTHFD1 A1958A allele was associated with a lower event-free survival that was statistically significant, p 0.02. Although statistical significance was lost in multivariate analysis, an a priori planned subgroup analysis of MTHFD1 A1958 allele and TS 28 bp promoter insertion polymorphism demonstrated a significant decrease in EFS in patients...
Methylenetetrahydrofolate Reductase Mthfr
Methylenetetrahydrofolate reductase is an approximately 19,301 base pair gene with 11 exons and located on chromosome 1p36.3 (2). Multiple polymorphic sites have been described, with the C677T and A1298G most often studied. As expected, allele frequency data varies by ethnicity The MTHFR C677T variant allele is present in 34 of Caucasians, 20 of Italians and Hispanics, 14 of African-Americans, and < 1 of Africans (3,4). The MTHFR A1298G allele is present in 27 -36 of Western Europeans (4)....
Basic Premises Pipelines And Timelines
The pharmaceutical industry's goal of developing beneficial drugs is achieved through a well-organized process termed the pharmaceutical pipeline (Fig. 1). An outline of this process facilitates an understanding of both opportunities and challenges presented by pharmacogenomics. Compounds are selected (i.e., candidate selection, CS) based on promising chemical and biological properties that predict developability, a process that lasts anywhere from 12 months to several years. Following this,...
Pros and Cons of Candidate Gene Approach
Besides the examples listed above, there are numerous exploratory association studies that have identified many potential polymorphism biomarkers for treatment response in membrane transporter, drug-metabolizing enzyme, and drug target genes. The methodology and statistical analysis for the candidate gene approach are simple the results are easy to interpret. Fig. 1. An example of power calculation to detect the indicated odds ratio for a range of risk factor prevalence and event rate with a...
Thiopurine Smethyltransferase
Another approach to optimize pharmacotherapy of leukemia with thiopurines is phenotyping and or genotyping of TPMT. TPMT is a ubiquitously expressed cytoso-lic methyltransferase that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds (130, 131). Neither the biological function of TPMT nor its endogenous substrates are known. In thiopurine-treated patients, the activity of TPMT determines the balance between 6-TGN and 6-MMPR. As already described above, high 6-TGN...
Relevance To Drug Toxicities In Humans
While the use of immortalized cell lines has the obvious benefits of convenience for high-throughput analysis, ability to replicate, and avoiding exposure of toxic molecules to patients or volunteers, cell lines are not human patients. The cells only represent one of many cellular constituents of a human (B-lymphocytes), and one that is not a major concern for life-threatening toxicity. This cell lineage may not adequately represent GI tract, nerves, and the complete bone marrow milieu. The...
Interpatient Variability in Response to Drugs and Toxicity
The main prognostic factors in cancer are age, tumor size, stage of disease, histologic type of the tumor, pathological grade, and in some cases hormone-receptor status. There are suggestions that the same genes that are implicated in cancer risk may also be involved in a person's propensity to carcinogenic exposure and or to modulation of therapeutic outcome (1). Therefore, constructing genetic profiles that can be used to individualize therapy may also increase our understanding of cancer...
FCGR3A Gene Polymorphism
Fc RIIIa is expressed on macrophages, natural killer cells, and some dendritic cells as a transmembrane receptor. The major polymorphism of Fc RIIIa gene is a single nucleotide substitution at position 559 resulting in the presence of either valine (V158) or phenylalanine (F158) at position 158 in the extracellular domain (41,42). It is known that valine (V) allele of the Fc Rllla gene has a higher affinity to human IgG1 and IgG3 than the phenylalanine (F) allele. Cells bearing the Fc RIIIa V...
Selective Egfr Tkis and the Discovery of Sensitizing EGFR Mutations
There have been frenzied efforts to develop anti-EGFR agents that might provide benefit to cancer patients with progressive and advanced disease who were refractory to traditional chemotherapeutic agents. Prior to these efforts, the use of a specific Abl tyrosine kinase inhibitor, imatinib, had proved very effective in the treatment of BCR-Abl positive chronic myelogenous leukemia (CML) (41). This target-based drug discovery strategy, that is, blocking the aberrant activity of a specific...
Roles of UGT1A7 1A9 and 1A10 for Irnotecan Pharmacogenetics
UGT1A7, 1A9, and 1A10, which are expressed in the gastrointestinal tract, are assumed to more or less contribute to irinotecan PK PD. The common polymorphism 1A9*1b(*22) -118(T)10 was shown to enhance in vitro transcription (33). However, a correlation between 1A9*1b(*22) and hepatic 1A9 protein levels was not observed (51), and association of 1A9*1b(*22) with hepatic SN-38 glucuronidation was inconsistent between two studies (44, 45). Recently, the 1A9 3'-flanking SNP I399C> T has been...
Roles ofUGT1A1 Genotypes Haplotypes
Until now, much attention has focused on the possible relevance of UGT1A1 polymorphisms to irinotecan toxicities (Table 3). The first clinical evidence showing a role for UGT1A1*28 in irinotecan toxicities was reported by Ando et al. (14). In this study, associations of UGT1A1 genotypes with irinotecan severe toxicities (grade 4 leucopenia and or grade 3 or 4 diarrhea) were retrospectively evaluated in 118 Japanese cancer patients who received irinotecan therapy with various regimens. Among 26...
Haplotype Structures Covering the UGT1A Gene and Ethnic Differences
As the importance of haplotype analysis in pharmacogenetic studies has been recognized, the analysis of UGT1A genes, particularly the 1A1 segment, has been conducted for irinotecan-pharmacogenetics in several ethnic populations. The first haplotype analysis of the UGT1A1 enhancer (PBREM) promoter region was conducted by Innocenti et al. using hepatic samples from 55 Caucasians and 37 African-Americans (37). This UGTlA Genetic Variations Described in this Chapter Nucleotide change Amino acid...
Anticancer Drug References
Recent advances in the systemic management of colorectal cancer. Future Oncol 2006 2 643-650. 2. Kopetz S, Hoff PM. Cytotoxic chemotherapy for advanced colorectal cancer recent advances in management. Oncology (Williston Park) 2005 19 11-17. 3. Sommadossi JP, Gewirtz DA, Diasio RB et al. Rapid catabolism of 5-fluorouracil in freshly isolated rat hepatocytes as analyzed by high performance liquid chromatography. J Biol Chem 1982 257 8171-8176. 4. Mentre F, Steimer...
Contributors
Richard Aplenc, MD, MS CE Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA Luigi Calzolai, PhD Medway School of Pharmacy University of Kent, Kent, UK Vincent Castranova, PhD The Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute of Occupational Safety and Health, Morgantown, West Virginia, USA Joseph Ciccolini, PharmD, PhD Pharmacokinetics Medical Oncology Universit de la M diterran e, Marseille, France David G. Covell, PhD...
Sensitivity of EGFR Mutants to TKIs The Oncogenic Shock Model
EGFR mutants are able to promote in vitro cellular transformation when expressed ectopically (62). The growth of these mutant EGFR-transformed cells can be potently inhibited with gefitinib and erlotinib. By a similar token, mice harboring human EGFR mutant transgenes, whose expression is under the control of doxycycline-dependent transcription, rapidly develop lung tumors with features reminiscent of human brochioalveolar adenocarcinoma, when given oral doses of doxycycline (63,64). When...
Thiopurines In The Treatment Of Childhood Acute Lymphoblastic Leukemia
The thiopurines 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were synthesized by Elion and Hitchings in the 1950s, and they play an important part in treatment protocols for leukemia (61,62,63,64). For no other than historical reasons, 6-MP is used in ALL while 6-TG is mainly used in acute myeloid leukemia (AML) or relapsed ALL. First-line treatment for childhood ALL usually includes several cycles of 6-MP at doses of 50-75 mg m2 d, starting as early as in consolidation early...
Pros and Cons of the Genome Wide Scan Approach
There are several distinct advantages of the genome-wide scanning approach. It is a hypothesis-generating and discovery-driven approach and no prior knowledge of the disease or drug action mechanisms is necessary. It can identify novel disease susceptibility genes or outcome-predicting genes and also confirm previously described genes. It gives a global assessment of each individual gene and may uncover the role of gene-gene interactions in complex genetic traits. The major limitations are the...
FCGR2A Gene Polymorphism
Fc RIIa is expressed on macrophages, neutrophils, dendritic cells, and some mast cells. The major Fc RIIa receptor polymorphism is a single nucleotide change affecting amino acid position at 131, coding for either arginine R131 or histidine H131 41 . FCGR2A-H131 has a higher affinity for human IgG3. Functionally, phagocytes obtained from individuals with homozygous HH 131 of FCGR2A showed much more effective phagocytic activity compared with those with RR 131 of FCGR2A. The FCGR2A gene contains...
Methotrexate Mechanism Of Action
Methotrexate inhibits folate metabolism by preventing methylenetetrahydrofolate reductase from converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate thus inhibiting thymidylate synthase conversion of dUMP to dTMP. DNA replication is effectively decreased by the diminution of dTMP availability. As shown in Fig. 2, multiple enzymes mediate the folate cycle. Thus, genetic variation in these enzymes may Fig. 1. Genetic factors impacting chemotherapy efficacy and toxicity. Fig. 1....
Statistical Consideration and Power Calculation
Statistical analyses in pharmacogenetic studies using the candidate gene approach are fairly simple and straightforward. Several generic methods, such as logistic regression, Cox proportional hazards model, Kaplan-Meier estimates and log-rank test, are commonly used to determine the association between individual genetic polymorphism and treatment response, toxicity, and survival. The major concern for the candidate gene approach in pharmacogenetic study is whether it has sufficient power to...
