Genotypes and Chemotherapy Toxicity
Evaluation of: Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD: Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin. Pharmacogenet. Genomics 18, 1009–1015 (2008).
– Mariano Monzo & Alfons Navarro
It is well known that individual patients respond differently to the same treatment. After identical doses of the same drug, some patients will attain a therapeutic response while others will have an adverse drug reaction (ADR) Citation[1], such as hematological, digestive, cardiac or neurotoxicity. In the USA, 6–7% of all hospital admissions and 100,000 deaths a year are due to ADRs. ADRs are also a major problem in drug development, and it is estimated that approximately 4% of new drugs are withdrawn from the market due to ADRs Citation[2]. Therefore, one of the primary objectives of drug research is to identify factors responsible for ADRs in order to select sensitive patients, adjust dosage, reduce toxicities and cut costs.
There is a wealth of evidence that interindividual differences in drug efficacy and toxicity are the result of hereditary variations in genes encoding the enzymes that transport, metabolize and excrete the drug. Through microarray analysis, the study of gene mutations, proteomics and the analysis of SNPs, investigators have begun to define the genetic profiles of patients and to determine who can best benefit from different therapies Citation[3].
When an anticancer drug is captured and transported to the interior of a cell, many biochemical processes intervene in the metabolism of the drug. First, the Phase I and Phase II enzymes produce metabolites; these metabolites are then excreted via the ABC-transporter enzymes; and finally, the remaining drug binds to its molecular target. Polymorphisms in any of the proteins that intervene in these processes can affect the efficacy of treatment. Interestingly, these polymorphisms can be detected in both normal and tumor cells.
The anticancer agent cyclophosphamide is metabolized by cytochrome P450 (CYP), glutathione S-transferase (GST) and aldehyde dehydrogenase (ALDH) enzymes. In order to investigate the potential effect of polymorphisms of these enzymes on the activity and toxicity of cyclophosphamide, Ekhart et al. examined SNPs in the CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1 genes in peripheral blood cells from 113 patients with different types of tumors who had received a high-dose combination of cyclophosphamide, thiotepa and carboplatin (CTC) Citation[4]. Patients with the ALDH3A1*1/*2 genotype had an 11.95-times greater risk of cystic hemorrhage as those with wild-type ALDH3A1, and patients with the ALDH1A1*1/*2 genotype had a 5.13-times greater risk of hepatic toxicity as those with wild-type ALDH1A1. Interestingly, ALDH1A1 is expressed mainly in liver tissue, and ALDH1A1*2 was a 17-base-pair deletion in the promoter region Citation[5]. This deletion could lead to lower expression of the ALDH enzyme in the liver, resulting in an increase in metabolites, which may explain the increased risk of hepatic toxicity in patients harboring this SNP. No other SNP was associated with toxicity, perhaps because the SNPs examined do not influence metabolizing enzymes or perhaps because other epigenetic factors, such as microRNAs Citation[6], intervene.
References
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- Ekhart C , RodenhuisS, SmitsPH, BeijnenJH, HuitemaAD: Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin.Pharmacogenet. Genomics18 , 1009–1015 (2008).
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Genetic Predictors of Leukocytopenia Severity
Evaluation of: Tsuchiya N, Inoue T, Narita S et al.: Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer. J. Urol. 180, 2389–2395 (2008).
– Mariano Monzo & Alfons Navarro
It has been known for some time that genetic differences between individuals may affect chemotherapy response and that basing systemic therapy only on body surface area is not sufficient to avoid toxicity and treatment failure in some patients. Many biochemical processes intervene in the metabolism of an anticancer drug to enable it to bind to its molecular target, and polymorphisms in any of the proteins involved in these processes can affect the efficacy of treatment. These polymorphisms can be detected in both normal and tumor cells Citation[1], and many SNPs have been analyzed in tumor cells and in peripheral blood cells with a view to determining their effect on chemotherapy outcome. Tsuchiya et al. have reported that SNPs related to drug-metabolic pathways can be markers not only of treatment efficacy but also of chemotherapy-related adverse reactions Citation[2].
CYP3A5 has been related to the metabolism of vinblastine and doxorubicin, GSTP1 has been related to doxorubicin and cisplatin metabolism, MDR1 has been associated with blood concentrations of several drugs, and MTHFR is related to methotrexate sensitivity. Tsuchiya et al. examined the relationship of SNPs in these genes to toxicity in urothelial cancer patients treated with methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)-combination chemotherapy. When the authors analyzed the effect of SNPs and clinical parameters after the first cycle of chemotherapy, they found that the only factor associated with increased severity of leukocytopenia was the use of the classic MVAC regimen instead of high dose-intensity MVAC. However, when the analysis was performed throughout the chemotherapy period, two independent factors were associated with increased leukocytopenia severity: fewer treatment cycles and homozygosity for the CYP3A5*3 allele. Moreover the authors showed that CYP3A5*3/*3 patients had significantly lower white-blood counts than those with other genotypes and that the frequency of patients with this genotype increased with the grade of leukocytopenia.
Other authors have also found an association between adverse reactions and SNPs in CYP enzymes Citation[3], and between hematological toxicity and other SNPs related to drug-metabolic pathways Citation[4]. Pretreatment SNP analysis can offer new tools for individualizing treatment and reducing the risk of chemotherapy-related toxicity. The challenge is to reduce toxicity without decreasing the anti-tumor effect of chemotherapy. CYP3A5 A6986G analysis can identify those patients more at risk of hematological toxicity with the MVAC regimen, and increased doses of G-CSF can be administered to these patients to reduce this risk without the need for chemotherapy dose modification.
References
- Monzo M , NavarroA, FerrerG, ArtellsR: Pharmacogenomics: a tool for improving cancer chemotherapy.Clin. Transl. Oncol.10 , 628–637 (2008).
- Tsuchiya N , InoueT, NaritaS et al.: Drug related genetic polymorphisms affecting adverse reactions to methotrexate, vinblastine, doxorubicin and cisplatin in patients with urothelial cancer.J. Urol.180 , 2389–2395 (2008).
- Pirmohamed M , ParkBK: Cytochrome P450 enzyme polymorphisms and adverse drug reactions.Toxicology192 , 23–32 (2003).
- Kiyotani K , MushirodaT, KuboM et al.: Association of genetic polymorphisms in SLCO1B3 and ABCC2 with docetaxel-induced leukopenia.Cancer Sci.99 , 967–972 (2008).
Contribution of HMGCR Variation to Statin-Mediated Reduction in Low-Density Lipoprotein Cholesterol
Evaluation of: Noriega V, Pennanen C, Sánchez MP et al.: (TTA)n polymorphism in 3-hydroxy-3-methylglutaryl-coenzyme A and response to atorvastatin in coronary artery disease patients. Basic Clin. Pharmacol. Toxicol. 104(3), 211–215 (2008).
– Lara M Mangravite
Statins are prescribed for the reduction of low-density lipoprotein (LDL) cholesterol, a major risk factor for coronary artery disease (CAD). Statins act through competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in endogenous cholesterol biosynthesis. Although statins are widely effective, response is variable Citation[1]. Both LDL-cholesterol and CAD are influenced by genetic variation, suggesting that statin-mediated changes in these phenotypes may also be regulated by genetic determinants. Indeed, genetic variants that influence LDL-cholesterol metabolism have also been demonstrated to influence statin-mediated changes in LDL-cholesterol. Examples include the apolipoprotein E (APOE) variants (ε2, ε3, ε4) and mutations in the LDL receptor (LDLR), which are associated with familial hypercholesterolemia. These examples suggest that variation in other genes involved in lipoprotein metabolism may also influence statin efficacy.
Noriega et al. have assessed the association of the (TTA)nHMGCR polymorphism with the lipid-lowering effects of atorvastatin in 64 CAD patients Citation[2]. The HMGCR (TTA)n polymorphism was originally identified as a chromosome 5 marker for linkage mapping Citation[3]. While the (TTA)n polymorphism has been previously associated with hypercholesterolemia Citation[4] and CAD status Citation[5], neither association was supported by definitive evidence nor have they been replicated Citation[6]. In this report, the HMGCR (TTA)n polymorphism was not significantly associated with baseline or statin-mediated changes in either plasma lipids or C-reactive protein, a marker of inflammation.
In this era of consortiums that assess genetic determinants of lipid parameters across multiple populations totalling 40,000 individuals or more Citation[7], a negative association observed using a population of 64 individuals is clearly inadequate evidence of a null effect. However, the absence of definitive evidence associating this (TTA)n polymorphism with either treated or untreated LDL-cholesterol concentrations across multiple studies suggests that the contribution of this variant to cholesterol metabolism is negligible. Despite this report, genetic variation in the HMGCR gene may play a role in determining statin efficacy. Several studies utilizing gene-specific resequencing technologies to comprehensively assess HMGCR variation Citation[8,9] have identified an HMGCR haplotype (H7) that is associated with attenuated statin-mediated LDL-cholesterol reduction. Even the H7 association, which was independently identified in two populations, has not replicated in some studies Citation[10] suggesting that the influence of HMGCR H7 variation on statin efficacy may be dependent on additional population-specific factors. In support of this, the association of H7 with statin efficacy in the Cholesterol and Pharmacogenomics (CAP) study was dependent on the presence of a second HMGCR haplotype (H2) that was more prevalent in African–Americans than Caucasian Americans Citation[9]. In addition, variation in statin-mediated LDL-cholesterol reduction has also been associated with variable production of a statin-insensitive alternatively spliced HMGCR isoform, the production of which is also under genetic control Citation[11]. As such, it is likely that the compounded effect of multiple genetic variants including those identified in HMGCR may be more effective in predicting statin efficacy than any individual genetic variant.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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- Plat J , MensinkRP: Relationship of genetic variation in genes encoding apolipoprotein A-IV, scavenger receptor BI, HMG-CoA reductase, CETP and apolipoprotein E with cholesterol metabolism and the response to plant stanol ester consumption.Eur. J. Clin. Invest.32 , 242–250 (2002).
- Kathiresan S , WillerCJ, PelosoGM et al.: Common variants at 30 loci contribute to polygenic dyslipidemia.Nat. Genet.41 , 56–65 (2009).
- Chasman DI , PosadaD, SubrahmanyanL et al.: Pharmacogenetic study of statin therapy and cholesterol reduction.JAMA291 , 2821–2827 (2004).
- Krauss RM , MangraviteLM, SmithJD et al.: Variation in the 3-hydroxyl-3-methylglutaryl-coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment.Circulation117 , 1537–1544 (2008).
- Thompson JF , ManM, JohnsonKJ et al.: An association study of 43 SNPs in 16 candidate genes with atorvastatin response.Pharmacogenomics J.5 , 352–358 (2005).
- Medina MW , GaoF, RuanW et al.: Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin.Circulation118 , 355–362 (2008).