39 Personalized Medicine in Cancer Treatment Flashcards
What is pharmacogenetics?
The study of the genetic determinants of drug response variability
Germline or constitutional variants can impact disease treatments
What can polymorphic variant alleles do to the drug metabolism?
- activate a prodrug to its active form
- catalyze the inactivation and elimination of a drug or metabolite
What is the most important enzyme complex in drug metabolism?
cytochrome P450 superfamily (CYP)
It directly affect the pharmacokinetics of many drugs.
What is Cytochrome P450?
Cytochrome P450 is a hemeprotein
Plays a key role in the metabolism of drugs and other xenobiotics
It directly affect the pharmacokinetics of many drugs.
Besides CYP450 and enzymes, what other proteins are important for drug metabolism?
Cell receptors –> play a role in pharmacodynamics
Genetic variants in cell receptors can influence drug transport
What are the phases of drug metabolism?
phase I reactions
phase II reactions
What is the phase I of drug metabolism?
introduce reactive or polar groups
(-OH, -COOH, -NH2, -SH, etc.) into drugs, including oxidation, reduction, and hydrolysis,
where drugs cannot be excreted from bodies.
What is the phase II of drug metabolism?
The phase I modified drugs are conjugated to polar compounds by a variety of transferase enzymes, such as
uridine diphosphate (UDP)-glucuronosyltransferases,
sulfotransferases,
glutathione S-transferases
General pathways of drug metabolism
Phase I reactions –> Phase II reactions –> The conjugated drugs may be further processed, before being recognized by efflux transporters and pumped out of cells.
See the figure.
Contribution of different enzymes to drug metabolism:
CYP450
UGT, UDG glucuronosyl transferase;
FMO, flavin-containing monooxygenase;
NAT, N-acetyltransferase;
MAO, monoamine oxidase.
see the figure:
73% by CYP450
15% by UGT
What drugs are Fluoropyrimidines?
Fluoropyrimidines are a class of anti-cancer drugs, or more specifically antimetabolites.
Examples:
Capecitabine
Fluorouracil (5-FU)
Tegafur (Ftorafur®)
What type of cancers are treated by Fluoropyrimidines?
Solid tumors, such as breast and colorectal cancers.
What is an antineoplastic agent?
An antineoplastic agent is a chemotherapeutic agent that controls or kills cancer cells.
1) They are cytotoxic (inhibit or prevent cell function)
2) They are generally more damaging to dividing cells than resting cells.
3) Antineoplastic drugs are a subset of hazardous drugs.
What are the inactive prodrugs of 5-FU?
Capecitabine
Tegafur
What is the main mechanism of 5-FU activation?
Conversion from 5-FU to fluorodeoxyuridine monophosphate –>
inhibits thymidylate synthase
What is thymidylate synthase?
an important part of the folate-homocysteine cycle
and
purine and pyrimidine synthesis
What is the effect of 5-FU?
increased base excision repair damage–>DNA fragmentation and cell death.
the fluorouridine triphosphate metabolite can be incorporated into RNA in place of uridine triphosphate –> interfering with RNA processing and protein synthesis
What is the rate-limiting step of 5-FU catabolism?
Dihydropyrimindine dehydrogenase (DPD) conversion of 5-FU to dihydrofluorouracil
DPYD gene
1) Gene name for dihydropyrimidine dehydrogenase (DPD)
2) located at chr. 1p21.3
DPYD gene mutations
1) decrease DPD activity
2) increase drug half-life
3) severe or fatal 5-FU toxicity
What are the recommendations made by Clinical Pharmacogenetics Implementation Consortium (CPIC) for the DPYD gene mutations and 5-FU dosing?
1) 50% reduction in starting dose for patients who are heterozygous for a nonfunctional DPYD variant
2) an alternate therapy for patients with two nonfunctional DPYD variants (homozygous or compound heterozygous)
DPD deficiency
– homozygous loss-of-function
– an autosomal recessive disorder
– can be symptomatic and asymptomatic
– characterized by a wide range of severity : can have severe convulsive disorders with motor and mental retardation
– >50 mutations identified for DPD deficiency
– 3-5% Caucasian population has partial DPD deficiency
DPYD*2A
The mutation IVS14 + 1 G > A, DPYD*2A, is the most common mutation associated with DPD deficiency.
A G > A base change at the splice recognition sequence of intron 14, leads to exon skipping and results in a 165-bp deletion in the DPD mRNA
DPYD mutations detection
– Specimen: whole blood or tissues
– genotyping target: DPYD*2A decreased activity allele
– sequencing
Effect of heterozygous loss-of-function DPYD alleles
– reduction of 5-FU clearances: 40% to 80% reduction
Alternatives to DPYD genotyping are?
1) assessing DPD enzyme activity by dihydrouracil to uracil ratio in plasma
2) uracil breath test
3) measure DPD activity in peripheral mononuclear cells
Other genes influence 5-FU response:
1) ABCB1
2) MTHFR
3) TYMS
Which cancer is Irinotecan used for?
Irinotecan is used to treat metastatic colorectal cancer(CRC)
Irinotecan can be used with what anticancer agent to treat CRC?
5-FU
leucovorin leu-co-vo-rin
Irinotecan can be used with what anticancer agent to treat small cell lung cancer?
cisplatin
5-FU + Irinotecan are used to treat for what cancer?
colorectal cancer
leucovorin + Irinotecan are used to treat for what cancer?
colorectal cancer
cisplatin + Irinotecan are used to treat for what cancer
small cell lung cancer
How does Irinotecan works in treating cancers?
Binding to the topoisomerase I-DNA complex and prevent DNA replication
thus causes double strand DNA breakage and cell death
What is the active form of Irinotecan?
SN-38
How is the Irinotecan metabolized and eliminated?
SN-38 is glucoronized to SN-38 glucuronic acid (SN-38G)
and detoxified in the liver via conjugation by the UGT1A family, which releases SN-38G into the intestines for elimination.
what % of SN-38 is converted to SN-38G?
Approximately 70% of SN-38 becomes SN-38G, which has 1/100 of the antitumour activity and is virtually inactive.
What does UGT1A1 stand for?
the uridine diphosphate glucuronosyltransferase family 1 member A1
UGT1A1 gene is located on chr. 2q37.1
What are the symptoms of severe toxicities caused by impaired elimination of cytotoxic SN-38?
myelosuppression
diarrhea
neutropenia
chromosomal position of UGT1A1
chr. 2q37.1
What is the most important variant UGT1A1 allele?
UGT1A1*28
it is a promoter polymorphism comprised of 7 thymidine-adenine (TA) dinucleotide repeats:
[(TA)7TAA]
normal UGT1A1 allele
UGT1A1*1
it has 6 TA repeats: [(TA)6TAA]
How does the length of TA repeats affect UGT1A1 enzyme activity?
inversely correlated with UGT1A1 expression and activity
UGT1A1*28 heterozygotes has 25% reduction in enzyme activity
UGT1A1*28 homozygotes has 70% reduction in enzyme activity, and increased cytotoxicity
The function of the UGT family
it is responsible for the glucuronidation of hundreds of compounds:
– hormones,
– flavonoids,
– environmental mutagens,
– pharmaceutical drugs
Where the UGTs are expressed?
most in the liver
also in intestine, stomach, breast
Gilbert Syndrome
Caused by UGT1A1*28 or other UGT1A1 missense variants
An autosomal recessive unconjugated hyperbilirubinemia 高胆红素血症
No liver damage
can present with jaundice, mild abdominal pain, nausea triggered by fasting or infections
Classifications of G6PD mutations
most G6PD mutations are missense mutations that affect the protein stability
Classified by the level of enzyme activity
Class I: severe
Class II: <10% severely deficient
Class III: 10-60% moderate deficiency
Class IV: 60-150% normal activity
Class V: 150% enhanced activity
Enzyme involved in 4-hydroxylation of Tamoxifen to produce 4-hydroxy-Tamoxifen
CYP2D6
Enzyme involved in N-demethylation of Tamoxifen to produce N-desmethyltamoxifen
CYP3A4
Fig. 1. Metabolism of Tamoxifen and role of various cytochromes. The conversion of tamoxifen to N-desmethyl-tamoxifen is mainly mediated by cytochrome CYP3A 4/5. The cytochrome CYP2D6 has a major role in conversion of Tamoxifen to 4-hydroxy-tamoxifen. The 4-hydroxy-tamoxifen is converted to endoxifen by CYP3A4/5 while N-desmethyl-tamoxifen is converted to endoxifen by CYP2D6.
