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Abstract: Cancer chemotherapy is characterized by a broad range of efficacy and ... on existing knowledge in clinical pharmacology, used to select the target(s).
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Current Drug Metabolism, 2007, 8, 554-562

Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing Anticancer Drugs for Personalized Cancer Chemotherapy Ken-ichi Fujita* and Yasutsuna Sasaki Department of Clinical Oncology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, 350-0495, Japan Abstract: Cancer chemotherapy is characterized by a broad range of efficacy and toxicity among patients. Most anticancer drugs show wide interindividual variability in pharmacokinetics and have narrow therapeutic windows. Since drug metabolism is often an essential determinant of interindividual variability in pharmacokinetics, pharmacogenomic studies of drug-metabolizing enzymes are expected to rationalize cancer chemotherapy in terms of patient, treatment, and dosage selection. Candidate gene approaches to pharmacogenomics are based on existing knowledge in clinical pharmacology, used to select the target(s) to be analyzed. So far, the candidate gene approach has provided important clues for pharmacogenomic-based personalized chemotherapy with 6-mercaptopurine (6-MP), solely metabolized by thiopurine S-methyltransferase (TPMT), and irinotecan, mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1). Reduced activity of TPMT caused by polymorphisms in the TPMT gene and decreased activity of UGT1A1 caused by UGT1A1*28 are related to severe toxic effects of 6-MP and irinotecan, respectively. In response to these findings, the Food and Drug Administration in the United States has supported clinical pharmacogenetic testing by revising the package inserts for these anticancer drugs. The genome wide approach to pharmacogenomics has gradually evolved with continued progress in genome sciences and technologies. This approach can disclose previously unknown relations of factors, as well as identify potential multigenetic associations. The genome wide approach can also identify genes underlying the phenotypic effects of anticancer drugs. This approach may play a complemental role to the candidate gene approach in the future of cancer pharmacogenomics. This review describes recent progress in pharmacogenomics in the field of cancer chemotherapy.

Keywords: Anticancer drug, candidate gene approach, drug-metabolizing enzymes, genome wide approach, irinotecan, 6-mercaptopurine, pharmacogenomics, pharmacokinetics. INTRODUCTION Cancer chemotherapy is usually associated with a broad range of drug responses relating to efficacy and toxicity [1,2]. Such diversity leads to several important questions in cancer chemotherapy: ‘Who is the right patient?’, ‘How can we select the best suited drug?’, and ‘What is the optimal dose?’. Unfortunately, at present it is generally difficult to identify patients who are most likely to benefit from a given treatment or have severe toxicity. Studies in clinical pharmacology have demonstrated that most anticancer drugs are characterized by wide interindividual variability in pharmacokinetics and narrow therapeutic windows; considerable pharmacodynamic variability has also been confirmed [3-5]. Systemic exposure to anticancer agents can vary up to 10-fold among patients receiving standard doses [6,7]. To decrease interpatient variability in pharmacokinetics, doses of anticancer drugs have traditionally been based on the body surface area of patients. Although straightforward, this method is inadequate for many anticancer drugs [8], since many factors can influence pharmacokinetics. Such factors can be genetic or acquired and include age, sex, malnutrition, polypharmacy, complex physiological changes due to concomitant disease, organ dysfunction, and tumor invasion. Among these factors, inherited differences in pharmacokinetics, especially drug metabolism, [9] are now known to influence the efficacy and toxicity of anticancer drugs. The science of pharmacogenetics is a relatively traditional concept. Inherited differences in drug metabolism were first demonstrated clinically in the 1950s. Genetic deficiency of plasma cholinesterase was found to cause prolonged muscle relaxation in some patients who received suxamethonium [10]. Subsequently, peripheral neuropathy due to isoniazid was shown to be related to reduced acetylation by N- acetyltransferase, caused by genetic polymorphisms [11,12]. The *Address correspondence to this author at the Department of Clinical Oncology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan; Tel: +81-49-276-2134, Fax: +81-49276-2134, E-mail: [email protected] 1389-2002/07 $50.00+.00

molecular genetic mechanisms of these inherited traits have been studied from the late 1980s, parallel to the development of molecular biology. A polymorphic human gene coding for the drugmetabolizing enzyme CYP2D6 (debrisoquin hydroxylase) was initially cloned and characterized [13]. To date, a wide variety of genetic polymorphisms have been demonstrated in most drugmetabolizing enzymes of anticancer agents (Table 1) [14,15]. Genetic polymorphisms can cause serious toxicity in patients given anticancer drugs that have narrow therapeutic windows and are inactivated by polymorphic drug-metabolizing enzyme(s). Pharmacogenetic research in cancer chemotherapy initially focused on single candidate genes related to the pharmacokinetics of a specific drug and variability in response. Genetic polymorphisms were clearly shown to be related to toxicity during chemotherapy with 6mercaptopurine (6-MP) and irinotecan, metabolically detoxified by thiopurine S-methyltransferase (TPMT) and UDP-glurucronosyltransferase (UGT1A1), respectively. As a result of these findings, the Food and Drug Administration (FDA) in the United States supported clinical pharmacogenetic testing and required revisions of the package inserts for 6-MP in 2004 and irinotecan in 2005. With recent advances in genomic sciences and technologies, pharmacogenomics has been used to identify entire sets of genes relevant to the pharmacological effects of drugs. Pharmacogenomic strategies attempt to identify the effects of genetic variations in entire genes, to examine interactions among gene products in pharmacological pathways, and to characterize drug-related phenotypes induced by polygenic traits [14]. Pharmacogenomic approaches can be broadly classified into two groups: the candidate gene approach and genome wide approach. The genome wide approach to pharmacogenomics (pharmacogenetics) will probably become a key strategy in the development of personalized treatments. This review describes recent progress in candidate gene pharmacogenomics in cancer chemotherapy mainly with 6-MP and irinotecan and discusses challenges in genome wide approaches that must be overcome to realize the routine clinical use of pharmacogenomic-guided personalized cancer chemotherapy. © 2007 Bentham Science Publishers Ltd.

Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing Table 1.

Current Drug Metabolism, 2007, Vol. 8, No. 6

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Polymorphic Drug-Metabolizing Enzymes and Anticancer Drugs

Drug-metabolizing enzyme

Anticancer Drug

Metabolic pathway

Web site for allele nomenclature

CYP2A6

Tegafur

5'-Hydroxylation

http://www.cypalleles.ki.se/cyp2a6.htm

CYP2B6

Cyclophosphamide

4-Hydroxylation

http://www.cypalleles.ki.se/cyp2b6.htm

Ifosfamide

4-Hydroxylation N-Dechloroethylation

CYP2C8

Paclitaxel

6-Hydroxylation

http://www.cypalleles.ki.se/cyp2c8.htm

CYP2C9

Cyclophosphamide

4-Hydroxylation

http://www.cypalleles.ki.se/cyp2c9.htm

CYP2C19

Thalidomide

5- and 5'-Hydroxylations

http://www.cypalleles.ki.se/cyp2c19.htm

CYP2D6

Tamoxifen

4-Hydroxylation

http://www.cypalleles.ki.se/cyp2d6.htm

Endoxifen formation CYP3A4/5

Cyclophosphamide

4-Hydroxylation

http://www.cypalleles.ki.se/cyp3a4.htm

N-Dechloroethylation

http://www.cypalleles.ki.se/cyp3a5.htm

Docetaxel

Hydroxylation

Etoposide

O-Demethylation

Gefitinib

O-Demethylation

Ifosfamide

4-Hydroxylation N-Dechloroethylation

Imatinib

N-Demethylation

Paclitaxel

3'-p-Hydroxylation

Tamoxifen

N-Demethylation

Teniposide

O-Demethylation

Vinca alkaloids

Unidentified

Dihdropyrimidine dehydrogenase

5-Fluorouracil

Reduction

Thiopurine S-methytransferase

6-Mercaptopurine

S-Methylation

UGT1A1

SN-38

O-Glucuronidation

http://galien.pha.ulaval.ca/alleles/UGT1A/UGT1A1.htm

These are from references [14, 15].

CANDIDATE GENE PHARMACOGENOMIC APPROACH 6-MP TPMT Variants and 6-MP Toxicity TPMT is a cytosolic drug-metabolizing enzyme that catalyzes the inactivation (S-methylation) of 6-MP, widely used to treat acute lymphoblastic leukemia (ALL), in hematopoietic tissues (Fig. 1) [16-19]. This enzyme is encoded by the TPMT gene, located on chromosome 6p22 and containing 10 exons and 9 introns spanning 34 kb [20]. The relation between TPMT variants and 6-MP toxicity is one of the best-studied examples in pharmacogenetics. The autosomal co-dominant inheritance of TPMT genetic polymorphisms was demonstrated to be related to the loss of erythrocyte TPMT activity and the hematopoietic toxicity of thiopurines [21,22]. Patients with reduced TPMT activity are exposed to much higher amounts of active drug in hematopoietic tissues after the administration of 6-MP in conventional doses. Excessively high concentrations of thioguanine nucleotide are thus produced, predisposing patients to severe hematopoietic toxicity [23-25]. Furthermore, the development of severe hematopoietic toxicity in TPMT-deficient patients given conventional doses of 6-MP might require the concurrent withdrawal of other cytotoxic agents until recovery of the absolute neutrophil count, thereby negatively affecting treatment efficacy for ALL. For example [23], myelosuppression and fever developed in a 6-year-old girl who received 6-MP, requiring hospitalization and discontinuation of all agents in her treatment regimen. The level of thioguanine nucleotide in the patient’s erythrocytes was seven times higher than the population median value. Subsequent therapy with 6% of the previously used dose did not induce prohibitive toxicity or require the cessation of other cyto-

toxic agents. TPMT activity is high in about 90% of individuals, intermediate in about 10%, and completely deficient in 0.3% [26]. Pharmacogenetic studies have revealed that inherited differences in TPMT activity are caused by polymorphisms in the TPMT gene [27-29]. Among 23 variant alleles identified thus far (wild-type *1 to *22) [30], 3 different variants, TPMT*2 (238G>C, A80P, exon 5) TPMT*3A (460G>A and 719A>G, T154A and C240Y, exons 7 and 10) and TPMT*3C (719A>G, C240Y, exon 10), account for more than 95% of dysfunctional TPMT alleles and are related to reduced enzyme activity in whites [16,17,27-29,31,32]. Individuals with high TPMT enzyme activity have TPMT*1/*1 genotype, those with intermediate activity inherit one TPMT*1 allele and one reducedfunction variant allele, and those who are completely TPMTdeficient possesses two non-functional variant alleles. More than 98% concordance between TPMT genotype and phenotype has been confirmed in German whites [31]. On the other hand, because nonrandom gains of chromosomes, trisomies, are present in many cases of leukemia and other malignances, Cheng et al. [32] examined chromosomal acquisition and its influence on genotype-phenotype concordance in cancer cells by using polymorphisms in genes encoding TPMT. Chromosomal gain can alter the concordance between germline genotype and cancer-cell phenotype. Allele-specific quantitative genotyping may thus be required to unequivocally define cancer pharmacogenomics. The past 20 years of research have hastened the development of genetic tests to identify patients who require clinically significant dose reductions to avoid the life-threatening hematopoietic toxicity of 6-MP [33]. In 2004, the FDA included a statement on clinical pharmacogenetic testing before 6-MP treatment in the package insert. Despite dose reductions of more than 90% and about 50%

556 Current Drug Metabolism, 2007, Vol. 8, No. 6 SH N

N H

N

N

N N TIMP

6-MP

S

SH

HPRT N

Fujita and Sasaki

N Ribose-P

N

HN O

SH

N H

N

N Ribose-P

TGMP

TXMP

N

N N

H2N

SCH3

TPMT N N Ribose-P

H2N

N

N

MethylTGMP

Ribose-P

TPMT

SCH3

SH

Cytotoxicity

N

N

N N

N H

Methyl6MP

H2N

N TGTP

N

RNA incorporation

N

DNA incorporation

Ribose-PPP

Fig. (1). Putative biotransformation pathway of 6-mercaptopurine. From references [18, 19]. 6-Mercaptopurine, 6-MP; Thioinosine monophosphate, TIMP; hypoxanthine guanine phosphoribosyl transferase, HPRT; thioxanthosine monophosphate, TXMP; thioguanosine monophosphate, TGMP; thioguanosine triphosphate, TGTP.

have been recommended for TPMT-deficient patients and patients heterozygous for TPMT, respectively [34], the recommended doses of 6-MP have yet to be approved by the FDA. TPMT Variants and 6-MP Efficacy The effects of variant TPMT alleles on the response to 6-MP as well as toxicity should be considered when deciding dosage recommendations. Recently, the TPMT genotype was reported to be associated with an early ALL treatment response [35]. Patients with 2 functional TPMT alleles were shown to have a 2.9-fold higher risk of positive minimal residual disease (MRD) than patients who were heterozygous for the TPMT allele, when the MRD on day 78 after remission-induction therapy, including 6-MP for 4 weeks, was measured to evaluate the ALL treatment response. This increased risk is consistent with the finding that heterozygous patients have higher systemic exposure to thiopurines because of poorer 6-MP metabolism. Patients with high TPMT activity might have a greater risk of treatment failure with 6-MP, since high TPMT activity results in greater drug inactivation and lower exposure of leukemia cells to active thiopurines, possibly requiring higher doses. It remains to be determined whether dose escalation in patients with wild-type TPMT would improve response. Irinotecan UGT1A1*28 and Irinotecan Toxicity Irinotecan is active against various solid tumors for which treatment options remain limited, most notably colorectal cancer [36]. This anticancer agent is a prodrug that is metabolized by carboxylesterase 2 to an active metabolite, SN-38. UGT1A1 is a microsomal phase II drug-metabolizing enzyme that catalyzes the detoxification of SN-38 to a polar inactive SN-38 glucuronide that is excreted in the bile (Fig. 2) [37,38]. Human UGT1A1 protein is encoded by the UGT1A gene on chromosome 2q37. This gene spans approximately 200 kb and contains 13 individual promoters/first exons and a shared set of exons 2 to 5 [39,40]. UGT1A isoforms, including UGT1A1, are produced by alternative splicing of the individual exon 1 with the common exons 2 to 5. Patients and oncologists have had grave concerns about the dose-limiting toxic effects of irinotecan, diarrhea and neutropenia [41]. Severe, occasionally life-threatening toxicity occurs sporadically, even in relatively low-risk patients enrolled in well-controlled clinical trials [42,43]. The co-occurrence of diarrhea and neutropenia places patients at greatest risk [43]. Interindividual variability in the pharmacokinetics (glucuronidation) of SN-38 resulting from glucuronide formation is at least one of the major causes of irinote-

can-induced severe toxicity [44-46]. Investigators have thus focused primarily on the polymorphic glucuronidation of SN-38 by UGT1A1, since UGT1A1 is the enzyme primarily involved in endogenous bilirubin glucuronidation as well as irinotecan glucuronidation. Decreased bilirubin glucuronidation capacity of UGT1A1 is clearly seen in patients with Gilbert’s syndrome, for which the genetic basis has been elucidated (http://galien.pha.ulaval.ca/ alleles/UGT1A/UGT1A1.htm). Gilbert’s syndrome is most commonly associated with homozygotes of the (TA)7 allele in the proximal promoter region of UGT1A1 (UGT1A1*28), causing the reduced expression of UGT1A1 mRNA and protein [47,48]. Previous studies have thus investigated the relations among UGT1A1*28, SN-38 glucuronidation, and irinotecan-related toxicity. Highly variable UGT1A1 expression caused by UGT1A1*28 results in up to 50-fold interpatient variability in the rate of SN-38 glucuronidation [37,38]. Case reports of irinotecan toxicity in patients with colorectal cancer and Gilbert’s syndrome who were homozygous for UGT1A1*28 [49,50] led to more detailed investigations. Several lines of evidence have linked UGT1A1*28 genotype to irinotecan toxicity [51-55]. In a retrospective study, severe toxicity, such as grade 4 leukopenia, grade 3 or 4 diarrhea, or both, developed in 26 of 118 Japanese patients with cancer who received various irinotecan-based regimens [51]. The genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%) of the 26 patients with severe toxicity, as compared with homozygous in 3 (3%) and heterozygous in 10 (11%) of the other 92 patients. These results suggested that UGT1A1*28 genotype is a clinically significant risk factor for severe irinotecan-related toxicity (pA, G71R), referred to as UGT1A1*6 (0.11 to 0.23) [47,58-60]. This mutation reduces catalytic activity by 60% in homozygotes [61,62]. Interestingly, this functional polymorphism is not found in whites [47,58-60]. The homozygous presence of UGT1A1*6 significantly impairs glucuronidation of SN-38 [63], but was not related to irinotecan toxicity in one study [51]. In contrast, a strikingly association with higher toxicity was found in Korean patients treated with irinotecan and cisplatin for advanced nonsmall-cell lung cancer [64]. About 2.5% to 4.6% of the Japanese population is estimated to have both UGT1A1*6 and UGT1A1*28 [60,62,65], which is similar to or slightly higher than the percent of individuals who are homozygous for UGT1A1*28. The coexistence of UGT1A1*6 and UGT1A1*28 in Japanese patients with cancer apparently lowers the SN-38 glucuronidase activity of UGT1A1, resulting in a phenotypic effect similar to that associated with homozygous UGT1A1*28 [66]. These results suggest that patients who are homozygous for UGT1A1*6 or who possess both UGT1A1*28 and UGT1A1*6 are at elevated risk for severe irinotecan-related toxicity due to increased exposure to SN-38. Further studies are necessary to more clearly delineate the roles of UGT1A1*6 in irinotecan-related toxicity and efficacy. UGT1A1 Variants and Irinotecan Efficacy Evidence linking polymorphisms to the therapeutic efficacy of irinotecan remains scare. Of interest, in a recent prospective study in 250 patients with metastatic colorectal cancer [67], the response rate was significantly higher in patients homozygous for UGT1A1*28 than those with wild-type alleles, which might be attributed to higher exposure to SN-38. Further systematic clinical studies are required to elucidate the roles of UGT1A1*28 not only in toxicity but also in efficacy in patients treated with irinotecan. In a study by Han et al. [64], patients homozygous for UGT1A1*6 had greater toxicity as well as lower response rates and poorer survival than the other patients. The poorer treatment outcomes in these patients apparently did not result from higher exposure to SN-38. The most plausible explanation for the negative effects of UGT1A1*6 on treatment outcomes is that the dose-intensity/density or cycle number might have been lower in patients with UGT1A1*6 because of toxicity occurring during the first cycle of chemotherapy [68].

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Roles of Other UGT1As in Irinotecan Pharmacokinetics UGT1A7 and UGT1A9 also participate in the glucuronidation of SN-38 [61,69,70]. However, the in vivo roles of these UGT enzymes are not as well understood as those of UGT1A1. Similar to UGT1A1, UGT1A7 and UGT1A9 are encoded by a single UGT1A gene located on chromosome 2q37. UGT1A7 is expressed in the oropharynx, esophagus, stomach, and pancreas [71-75]. Although UGT1A7 had been reported to be absent in the liver [76], a recent study [77] has demonstrated that treatment with 3methylcholanthrene induces UGT1A7 mRNA expression in human hepatocytes, despite no basal expression. UGT1A9 is expressed in the liver, kidney, small intestine, colon, and reproductive organs such as the testis and ovary [69-73]. Thus, both UGT1A7 and UGT1A9 might contribute to the glucuronidation of SN-38 in the liver, an important determinant of the systemic clearance of SN-38. Recent studies [64,78] in Japanese and Koreans have shown that genetic linkages of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 significantly reduce glucuronidation of SN-38. In detail, polymorphisms in the UGT1A7 and UGT1A9 genes are related to reduced transcriptional or catalytic activities closely linked to UGT1A1*6, which is frequently seen in Asians [47,58-60]. Perhaps UGT1A7 and UGT1A9 participate in the glucuronidation of SN-38 in addition to UGT1A1, although an alternative hypothesis is that UGT1A1 has a role in SN-38 glucuronidation, whereas UGT1A7 and UGT1A9 do not. Reduced glucuronidation capacity for SN-38 in patients may be principally caused by UGT1A1*6, whereas polymorphisms in the UGT1A7 and UGT1A9 genes may be linked to UGT1A1*6 only because of the close proximity of these loci (G related to TPMT*3 and/or four haplotypes including 719A>G were significantly correlated with reduced TPMT activity. If no candidate gene is known, HapMap single nucleotide polymorphisms are putatively dense enough that candidate gene can be identified with association studies. Therefore, they took an agnostic genome wide approach to evaluate genomic predictors of TPMT phenotype, with 1.1 million single nucleotide polymorphisms in 17,542 genes. In case including 719A>G genotypes, TPMT ranked at 198. Even when the analysis was done based on total whole genome haplotypes, TPMT ranked

Fujita and Sasaki

97 out of 17,542 genes evaluated. This implies that challenges remain for definitive gene identification with a genome wide approach. In 2002, Hetherington et al. [107] used a genome wide pharmacogenomic approach to investigate the mechanisms of lifethreatening immune reactions caused by the AIDS drug abacavir. They successfully identified three polymorphisms associated with immune-system genes that could be used to identify patients who should not receive abacavir. This work should encourage further genome wide pharmacogenomic studies in cancer chemotherapy, with the ultimate goal of establishing personalized treatments. CONCLUSION Pharmacogenomic approaches are expected to improve cancer chemotherapy by ensuring that the right patients receive the optimal treatment in the appropriate dosage. As illustrated by TPMT and UGT1A1, the candidate gene approach has successfully highlighted the value of pharmacogenomics in the design of personalized cancer therapy. The excellent results obtained so far emphasize the importance of focusing on candidate factor(s) that fundamentally contributes to the phenotypic effects of anticancer drugs. The genome wide approach offers the possibility of detecting previously unknown associations of factors as well as identifying potential multigenetic associations. This approach has been rapidly improved parallel to advances in genome sciences and technologies. The genome wide approach is expected to play a complemental role to the candidate gene approach in the future development of pharmacogenomic-based personalized cancer chemotherapy, although further challenges need to be performed. ABBREVIATIONS ALL = Acute lymphoblastic leukemia DPD = Dihydropyrimidine dehydrogenase DPYD = Dihydropyrimidine dehydrogenase gene ERCCI = Excision repair cross-Complementation group I 5-FU = 5-Fluorouracil FDA = Food and Drug Administration 6-MP = 6-Mercaptopurine MRD = Minimal residual disease TPMT = Thiopurine S-methyltransferase UGT1A1 = UDP-glucuronosyltransferase 1A1 REFERENCES [1] [2] [3]

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Received: March 23, 2007

Revised: April 14, 2007

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