Pocket Oncology (Pocket Notebook Series), 1st Ed.

PHARMACOGENETICS AND PHARMACOGENOMICS

Mabel Rodriguez

Introduction

Pharmacogenetics: Effect of heritability on response to drugs. Study of single genes & their effects on interindividual differences in drug metabolizing enzymes.

Pharmacogenomics: Effect of inherited & acquired genetic variation on drug response. Study of the functions & interactions of all genes in the genome & how the overall variability of drug response may be used to predict the right tx in individual pts & to design new drugs.

Polymorphisms: Common variations in a DNA sequence that may lead to ↓ or ↑ activity of the encoded gene (SNP, micro- & minisatellites)

SNPs: Single base interchange that may cause an amino acid exchange in the encoded protein, account for >90% of genetic variation in the human genome

Phase I Drug Metabolizing Enzymes

Genetic polymorphisms have been reported for CYP450 isoforms 2C8, 2C9, 2C19, 2D6, & 3A4

CYP3A4/5

CYP3A isoenzymes account for ∼1/2 of the metabolic activity of all CYP450 enzymes

Substrates include etoposide, paclitaxel, & vincristine

SNP frequencies of CYP3A4 relatively low in most populations (14% in Caucasians & 10% in Japanese individuals) making it difficult to link genotype to PK or PD of CYP3A4 substrates

One study conducted by the National Children’s CA Group Pediatric ALL trial set out to correlate the association between relapse & tox of 1204 pts w/CYP3A41B,CYP3A5*3, & CYP3A5*6 SNPs

Trial results were negative, however the first two variants previously mentioned had a statistical risk of peripheral neuropathy

CYP2C8

A/w paclitaxel metabolism by 6α-hydroxylation; out of its six alleles

CYP2C8*3 in Caucasians is less efficient in the metabolism of this chemotherapeutic agent

CYP2C19

A/w thalidomide activation by hydroxylation

CYP2C19*2 homozygotes showed poor metabolizing phenotype, not responding to thalidomide tx

CYP2D6

Involved in the conversion of tamoxifen to 4OH-tamoxifen (more potent antiestrogen)

CYP2D6 homozygous variant or heterozygous genotype individuals have ↓ plasma endoxifen conc. (a metabolite of tamoxifen) than homozygous wild-type subjects after 4 mos of Rx

Non-P450 Phase I Metabolizing Enzymes

Dihydropyrimidine dehydrogenase (DPD)

Represents the first & rate limiting step in the catabolism of pyrimidine bases, uracil & thymidine

DPD degradates the majority of 5-FU to 5–6-dihydro-5-FU in the liver

DPD deficiency: Prolonged 5-FU T1/2 → sev., fatal GI & neurologic tox

Thirty nine polymorphisms & Mt of the DPD gene are known. DPD*2A: Most common polymorphism → causes inactive protein in 0.9% of Caucasian pts.

Phase II Drug Metabolizing Enzymes

Thiopurine methyltransferase (TPMT)

Involved in the methylation rxns of 6-MP & its prodrug, AZA

Out of the 8 alleles identified, three specific ones (TMPT*2, TMPT*3A, & TMPT*3C), account for 95% of TMPT deficiency cases

Pts who carry TMPT polymorphisms are at a risk of sev. hematologic tox

Appropriate 6-MP dose reductions for TMPT-deficient pts have allowed for similar tox & survival outcomes when compared to pts w/nl levels

Tests for TMPT genotype & phenotype are commercially available

Uridine Diphosphate Glucuronosyltransferase 1A1 (UGT1A1)

A microsatellite Mt results in UGT1A1*28 polymorphism, & ↓ UGT1A1 expression levels & activity

UGT1A1*28 polymorphism: Typically found in pts w/Gilbert syndrome; frequency 40–43% in Africans, 32–39% in Caucasians, 16–33% in Asians

Important role in the metabolism of etoposide, epirubicin, & most importantly irinotecan

Irinotecan: Prodrug activated to ethyl-10 hydroxycampothecin (SN-38) via carboxyl esterase. SN-38 undergoes UGT1A1-catalyzed glucuronide conjugation to form inactive SN-38 glucuronide (SN-38G). ↑ exposure to SN-38 in pts w/this genetic variation → ↑ tox (diarrhea, myelosuppression) limiting optimal clinical use

Drug Transporters

P-gp (MDR-1)

P-gp & its encoding gene MDR-1 (ABCB1) are expressed in high levels in brain vessels, adrenal glands, kidney, liver, & GI tract

P-gp is involved in the transport of hydrophobic drugs including doxorubicin, paclitaxel, irinotecan, hormones, & carcinogens

Multidrug resistance proteins act as drug efflux pumps rendering cells resistant to cytostatic drugs

Three most common SNPs are P-gp*6 (22–56% in Caucasians), P-gp*7, & P-gp*8

Drug Targets

5,10 Methylenetetrahydrofolate reductase (MTHFR)

Reduces 5, 10 methylenetetrahydrofolate to 5-methyltetrafolate, methyl donor for the methylation of DNA, homocysteine, & DNA synthesis

Reduced MTHFR activity affects intracellular folate pools → ↑ tox in pts treated w/antifolates

Thymidylate synthase (TS)

Essential enzyme in de novo synthesis of thymidylate, precursor of thymidine triphosphate, essential for DNA synthesis & repair

TS gene promoter is polymorphic & has 2 (TSER*2) or 3 (TSER*3) 28 bp tandem repeat sequences

In vitro studies show TS promoters w/the TSER*3 sequence generate 3× higher mRNA than those w/the TSER*2 sequence

Inhibition of TS by 5-fluorodeoxyuridine monophosphate (FdUMP) of TS is one of the 1° mechanisms of action of 5-FU

TS expression levels inversely correlate w/the Sn of tumors to 5-FU, therefore TSER*2 homozygotes respond better to 5-FU than TSER*3 homozygotes or heterozygotes