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...

References

Atlanta, GA American Cancer Society, 2007. 2. Peto R, Boreham J, Clarke M et al. UK and USA breast cancer deaths down 25 in year 2000 at ages 20-69 years. Lancet 2000 355 1822. 3. Giordano SH, Buzdar AU, Smith TL et al. Is breast cancer survival improving Cancer 2004 100 44-52. 4. Kallioniemi A. Molecular signatures of breast cancer predicting the future. N Engl J Med 2002 347 2067-2068. 5. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000 100 57-70. 6....

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...