Clinical Oncology UpdatePharmacogenetics and cancer chemotherapy
Introduction
Inter-subject variability in therapeutic drug responses and drug toxicities is a major problem in clinical practice. Such variability is largely due to genetic factors leading to altered drug metabolism and/or receptor expression[1]. Polymorphisms in drug-metabolising enzymes, which appear to be more extensive than those of receptors[2], result in altered pharmacokinetics of therapeutic agents. Since the discovery of debrisoquine hydroxylase deficiency in the 1970s[3], pharmacogenetic polymorphisms of several drug metabolising enzyme systems have been identified and characterised4, 5, 6, 7. Genetic variations in receptor expression systems, or pharmacodynamic polymorphisms, have been recently identified as major determinants of drug responses8, 9.
The relationship between an individual’s capacity to metabolise environmental carcinogens and other xenobiotics and susceptibility to cancer has been extensively studied10, 11, 12, 13. The applicability of pharmacogenetics in cancer chemotherapy is critical due to the following reasons:
- 1.
anticancer agents generally have a narrow margin of safety;
- 2.
many of these agents are prodrugs and are biotransformed to active counterparts by enzyme systems that exhibit genetic polymorphisms;
- 3.
the active forms are usually also associated with toxicity;
- 4.
certain anticancer agents are detoxified by polymorphic enzyme systems; and
- 5.
most cancer chemotherapeutic drugs exhibit significant inter-patient variability in pharmacokinetics and toxicity.
This review will focus on the role of genetic polymorphisms of well-known classes of drug-metabolising enzymes in cancer chemotherapy.
Section snippets
Thiopurine S-methyltransferase (TPMT)
TPMT catalyses the S-methylation of 6-mercaptopurine (6-MP) (also formed in vivo from the immunosuppressive prodrug, azathioprine), to form inactive metabolites. This competes with two other pathways of 6-MP metabolism that form inactive 6-thiouric acid and active 6-thioguanine nucleotides (6-TGN), catalysed by xanthine oxidase and hypoxanthine phosphoribosyltransferase (HPRT) enzymes, respectively[14]. 6-MP is commonly used as a component of maintenance therapy in acute lymphoblastic leukaemia
Dihydropyrimidine dehydrogenase (DPD)
DPD catalyses the initial, rate-limiting step in the catabolism of pyrimidines such as thymine and uracil and the fluoropyrimidine, 5-fluorouracil (5-FU). 5-FU is one of the most widely used anticancer agents in the treatment of breast, head and neck and colorectal cancers[32]. However, significant inter-individual variations in 5-FU clearance, tumour response and host toxicity have been reported after 5-FU therapy32, 33, 34. These variations may be due to genetic differences in the activity of
N-acetyltransferases (NAT)
Human acetylation polymorphism has been documented since the 1950s with the observation of slow and fast acetylators of isoniazid[60]. Two NAT genes (NAT1* and NAT2*) have been sequenced and located at distinct loci on chromosome 8, pter-q1161, 62. Substrates of NAT1 include p-aminobenzoic acid and p-aminosalicylic acid and those of NAT2 include isoniazid, procainamide, hydralazine and sulphonamide63, 64, 65. NAT1 was initially believed to be monomorphic, but recent reports indicate that the NAT
Glutathione S-transferases (GST)
GSTs are a superfamily of enzymes that conjugate xenobiotics, such as herbicides, insecticides, carcinogens and anticancer agents (cyclophosphamide) with glutathione80, 81, 82, 83. They have also been shown to play a role in multidrug resistance by direct binding to drugs and/or removing them from cells[84]. Increased levels of GST in tumour cells can contribute to the detoxification of the DNA-alkylating cytotoxic metabolite (phosphoramide mustard) of cyclophosphamide, resulting in the
Aldehyde dehydrogenase (ALDH)
The ALDH family comprises of at least seven members: ALDH1 to ALDH5, betaine aldehyde dehydrogenase (BADH) and succinic semialdehyde dehydrogenase (SSDH)[95]. Genetic polymorphisms have been described in ALDH2, which is involved in the metabolism of alcohol[96]. ALDH1, ALDH2 and SSDH have been reported to oxidise aldophosphamide[95]. ALDH1 variants are prevalent up to 10% in the population[97]. A phenotypic deficiency in the excretion of carboxyphosphamide arising from ALDH polymorphism98, 99
Uridine diphosphate glucuronosyltransferases (UGTs)
UGTs are a superfamily of enzymes that catalyse the transfer of glucuronic acid moiety to a variety of endogenous substrates and xenobiotics102, 103, 104, 105. Two major classes of UGT families have been identified: UGT1 and UGT2. UGT1 family members are formed by alternative splicing of exon 1 with the other exons2, 3, 4, 5, resulting in a conserved carboxyl region. UGT2 isoforms are separate gene products, eight of which have been identified so far103, 104, 105, 106. UGT1 enzymes catalyse the
CYP2D6
The CYP2D6 polymorphism was originally suggested in the inter-subject variations observed in debrisoquine metabolism3, 121. CYP2D6 activity is absent in 5–10% of European and North American Caucasian populations122, 123. Several alleles of CYP2D6 have been described, such as CYP2D6A, CYP2D6B, CYP2D6D, CYP2D6E and CYP2D6T[122]. Correlation of poor metabolism phenotype with CYP2D6 genotypes is being studied extensively for various therapeutic classes124, 125, 126, 127. However, most anticancer
Conclusions
A major problem in cancer pharmacology is the prediction of the outcome of therapy, both in terms of tumour response and host toxicity150, 151. Pharmacogenetic variability in drug metabolising enzyme systems is a major determinant of variations in these outcomes. Unpredictable disposition of drugs may result in an undertreatment failing to provide therapeutic effects, or an overtreatment leading to excessive toxicity[152]. The current practice in oncology is to dose patients based upon height
Acknowledgements
The authors would like to thank M. Mortell and H.Y. Tam for their assistance in the preparation of this manuscript. Supported in part by the Clinical Therapeutics Training grant, National Institutes of Health (T32-GM07019).
References (156)
- et al.
Altered mercaptopurine metabolism, toxic effects and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia
J Ped
(1991) - et al.
Genetic variation in response to 6-mercaptopurine for childhood acute leukaemia
Lancet
(1990) - et al.
Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia
Blood
(1995) - et al.
Correlation between catalytic activity and protein content for the polymorphically expressed dihydropyrimidine dehydrogenase in human lymphocytes
Biochem Pharmacol
(1995) - et al.
Assignment of the human dihydropyrimidine dehydrogenase gene (DYPD) to chromosome region 1p22 by fluorescence in situ hybridization
Genomics
(1994) - et al.
Structural heterogeneity of caucasian N-acetyltransferase at the NAT1 locus
Arch Biochem Biophys
(1993) - et al.
Multidrug resistance mediated by the multidrug resistance protein (MRP) gene
Biochem Pharmacol
(1996) - et al.
Gene deficiency of glutathione s-transferase μ isoform associated with susceptibility to lung cancer in a Chinese population
Cancer Lett
(1997) - et al.
Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde
Biochem Pharmacol
(1992) - et al.
The role of pharmacogenetics in chemotherapy: modulation of tumor response and host toxicity
Cancer Sur
(1993)
Pharmacogenetics: its biological roots and the medical challenge
Clin Pharmacol Ther
Polymorphisms and deficient drug metabolism as triggers of toxic reactions
Arzneimitt Forsch
The molecular basis of genetic polymorphisms of drug metabolism
J Pharm Pharmacol
Pharmacogenetic phenotyping and genotyping: present status and future potential
Clin Pharmacokin
Genetic polymorphisms of drug metabolism
Dev Pharmacol Ther
Genetic variation of CNS receptors—a new perspective for pharmacogenetics
Pharmacogenetics
Human drug-metabolizing enzyme polymorphisms—effects on risk of toxicity and cancer
DNA Cell Biol
Pharmacogenetics: detecting sensitive populations
Environ Health Perspect
Relevance of metabolic polymorphisms to human carcinogenesis: evaluation of epidemioloic evidence
Pharmacogenetics
The clinical pharmacology of 6-mercaptopurine
Eur J Clin Pharmacol
Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism
Clin Pharmacol Ther
Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity
Am J Hum Gen
Thiopurine methyltransferase activity in American white subjects and black subjects
Clin Pharmacol Ther
Higher activity of polymorphic thiopurine S-methyltransferase in erythrocytes from neonates compared to adults
Pharmacogenetics
Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver–erythrocyte correlation and presence of isozymes
Pharmacogenetics
Red blood cell hypoxanthine phosphoribosyltransferase activity measured using 6-mercaptopurine as a substrate: a population study in children with acute lymphoblastic leukaemia
Br J Clin Pharmacol
Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity
Proc Natl Acad Sci USA
Clinical pharmacology of 5-fluorouracil
Clin Pharmacokin
Dihydropyrimidine dehydrogenase activity and fluorouracil chemotherapy
J Clin Oncol
Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe averse reactions to 5-fluorouracil-based chemotherapy
Oncol Nurs Forum
Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients and clinical implication in 5-fluorouracil chemotherapy
Cancer Res
Population characteristics of hepatic dihydropyrimidine dehydrogenase activity, a key metabolic enzyme in 5-fluorouracil chemotherapy
Clin Pharmacol Ther
Familial deficiency of dihydropyrimidine dehydrogenase—biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity
J Clin Invest
Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase-deficiency—a potentially more common pharmacogenetic syndrome
Cancer
Severe 5-fluorouracil toxicity in a patient with decreased dihydropyrimidine dehydrogenase activity
Cancer Invest
Cited by (96)
Drug-Induced Liver Injury
2022, Comprehensive Pharmacology2D Germanane Derivative as a Vector for Overcoming Doxorubicin Resistance in Cancer Cells
2020, Applied Materials TodayCitation Excerpt :Several mechanisms responsible for a development of the drug resistance have been identified. These include the interpatient differences in drug pharmacokinetics [9, 10], a hypoxic tumour microenvironment affecting the cancer cell sensitivity, [9, 11] and more importantly, the specifics of the cancer cells themselves. [9] Besides other adaptive mechanisms of the cancer cells, the resistance is most frequently mediated by an overexpression of the drug efflux pumps from the ABC protein family.
In vitro evaluation of a biomaterial-based anticancer drug delivery system as an alternative to conventional post-surgery bone cancer treatment
2018, Materials Science and Engineering CChemotherapy Resistance
2018, Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy: Second EditionPharmacogenomics
2017, Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting