Exam 1 Ch 5 Pharmacogenomics

Question 1

What is Phase I enzyme CYP2D6 responsible for?

Answer 1

Hepatic metabolism of 20% of commonly used drugs

& AMP; converting codeine to its active metabolite (morphine)

Question 2

Define the two types of chemotherapy.

Answer 2

cell-cycle phase specific- taregts one specific phase of the cell cycle
cell-cycle phase nonspecific- targeting all proliferating cells regardless of place in cell cycle

Question 3

What is irinotecan? What is its mechanism of action?

Answer 3

• chemotherapeutic agent used in treating colon cancer

- inhibits topoisomerase I

Question 4

What is thiopurine methyltransferase (TPMT) responsible for?

Answer 4

TPMT metabolizes chemotherapy for acute lymphoblastic leukemia.

Question 5

What happens when a patient has low or intermediate TPMT?

Answer 5

They accumulate higher concentrations of thioguanine cytotoxic metabolites which can result in unexpectedly high myelosuppression and occurence of seocndary malignancies.

Question 6

Elevated levels of dihydropyrimidine dehydrogenase (DPD) has what effect on fluorouracil (5-FU)?

Answer 6

Decreases bioavailability of 5-FU (DPD helps the body metabolize fluorouracil).

Question 7

Define Pharmacogenomics and Pharmacogenetics.

Answer 7

• Study of how genes affect the way a person responds to medications
• Used to determine ahead of time the best drug or dose for an individual patient

Question 8

What is the unfortunate consequence or adverse issue that comes up in chemotherapy used in cancer?

Answer 8

Most currently available anticancer drugs do not specifically recognize neoplastic cells, but rather affect all kinds of proliferating cells (both normal and abnormal)

Question 9

How do the dose-response curves for toxic and therapeutic effects of most currently available chemotherapy compare, and what does this mean?

Answer 9

They have steep dose-response curves for toxic and therapeutic effects, which reflects that most currently available anticancer drugs do not specifically recognize neoplastic cells, but, rather, affect all kinds of proliferating cells (normal and abnormal).

Question 10

How do inherited variations in enzymes affect how a given anticancer drug will work in an individual?

Answer 10

Variations affect how fast prodrugs are changed to their active form (e.g. some patients break down drug slowly, so standard doses of treatment may not work as well)

Question 11

Which populations tend to be fast acetylators of isoniazid? How would this affect dosing of this medication?

Answer 11

Proportion of fast acetylators is higher among people of Asian origin (and Native Americans) than those of European or African origin. Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effect.

Question 12

What is the mechanism of action of irinotecan (camptosar), commonly used to treat colon cancer? Which enzyme metabolizes it, what can lead to shortage of this enzyme, and what are the effects of this shortage? Are there any implications for the effectiveness of the drug in patients with the genetic variation?

Answer 12

Irinotecan inhibits topoisomerase I (involved in DNA replication and transcription).
In some people, genetic variations cause shortage of UGT1A1 enzyme (UDP glucuronosyltransferase 1 family, polypeptide A1, which metabolizes it.
Shortage of the enzyme can lead to severe adverse, life-threatening side effects including neutropenia or diarrhea.
Frequently, a lower dose is just as effective for these people.

Question 13

Which enzyme do clinicians test for when treating children with acute lymphoblastic leukemia, and why?

Answer 13

About 10% of people have genetic variations in thiopurine methyltransferase (TPMT), which is responsible for metabolizing chemotherapy for ALL. Testing for variations helps avoid severe side effects by giving lower dosages to children with the variations.

Question 14

State the type of drug that 6-thioguanine is, its mechanism of action, and potential side effects of patients who possess low or intermediate amounts of the enzyme that processes it?

Answer 14

6-thioguanine is an antimetabolite that is converted to S-methylation product, 2-amino-6-methylthiopurine, by thiopurine methyltransferase (TPMT). It inhibits purine ring biosynthesis. Patients with low or intermediate TPMT activity accumulate higher concentrations of thioguanine cytotoxic metabolites, which results in unexpectedly high myelosuppression (make less RBC’s, WBC’s and platelets), and is associated with the occurrence of secondary malignancies.

Question 15

TMPT genotyping is recommended before starting a patient on 6-thioguanine chemotherapy. What populations express homozygous versus heterozygous deletions in the TPMT gene?

Answer 15

Approximately 3% of whites and blacks express either homozygous deletion or mutation of TPMT gene.
About 10% of patients with a heterozygous deletion or mutation of TPMT, are at increased risk for toxicity.

Question 16

State the type of drug that fluorouracil (5-FU) is, its mechanism of action, and potential side effects of patients who possess high amounts of the enzyme that processes it?

Answer 16

It is an antimetabolite that inhibits thymidylate synthesis. Increased rate of 5-FU catabolism through elevated levels of dihydropyrimidine dehydrogenase (DPD), the enzyme that metabolizes 5-FU, can decrease the bioavailability of 5-FU, and increase the chances of side effects.

Question 17

What are some challenges in detecting somatic mutations in tumor samples?

Answer 17

Tumor samples are often small biopsies that are formalin-fixed and paraffin-embedded (FFPE), thus DNA is partially degraded. Extra care must be taken to determine whether the sample is amenable to genomic analysis. Mutations within the cancer cells may be heterogeneous, and different sections of tumor may be derived from different clonal expansions.

Question 18

What are the current treatment recommendations to address the heterogeneity of cancer cells in a tumor? Provide an example of a treatment that follows this.

Answer 18

Target ubiquitous alterations in the trunk of such phylogenetic tree if such targeted drugs are available. Targeted therapies have been developed against some of the the proteins (often tyrosine kinases) that are activated by somatic mutations.

Question 19

Why is understanding the mechanism of toxicities important in drugs?

Answer 19

Understanding the mechanism of toxicities can lead to more effective prevention & treatment of the toxicities

Question 20

What can the identification of genetic variations that affect activation and metabolism permit?

Answer 20

May permit development of individualized therapy that optimize effectiveness & minimize toxicity

Question 21

How can Pharmacogenomics be used for anticancer therapy?

Answer 21

By looking at studies of small variations within genes to see:

1) Whether targeted therapy is an option of not
2) Variations may affect whether genes can activate of deactivate specific anticancer drugs
3) Test results may help doctor to choose safest and most effective anticancer drug and dose

Question 22

When dealing with pharmacogenomics how does understanding how genetic variations in an individual can influence the response to anticancer treatments?

Answer 22

Understanding the genetic variation has potential to make anticancer therapy safer and more effective by determining selection and dosing of drugs for individual patient

Question 23

What are the 2 main reasons why anticancer drugs work differently in different patients?

Answer 23

Drug Activation

Drug Inactivation

Question 24

What kind of drug is Isoniazid (INH)? Where is it metabolized? Why do you have patients may be fast or slow inactivators?

Answer 24

Isoniazid (INH) is an antimycobacterial.
It is metabolized by the liver through acetylation.
Patients may be fast or slow inactivators due to genetic control, which would make them a fast or slow acetylator depending on genetics and origin.

Question 25

List the germline variants that could be predictors of drug response in a patient.

Answer 25

Codiene
Acute Lymphoblastic Leukemia (ALL)
6-Thioguanine
Isonaiazid
Fluorouracil (5-Fu) antimetabolite
Irinotecan

Question 26

List three important Somatic variants that could be predictors of drug response in patient

Answer 26

Cetuximab
Panitumumab
Crizotinaib

Question 27

What can somatic mutations in cancer pharmacogenomics tell us?

Answer 27

May be drivers that define cancer subtype or may be passengers

Question 28

How are heterogeneous somatic mutations within cancer cells treated in cancer pharmacogenomics?

Answer 28

Target ubiquitous alterations in trunk of phylogenetic tree if such targeted drugs are available

Question 29

What do Cetuximan and Panitumumab do and what is their main inefficiency?

Answer 29

Monoclonal antibodies designed to inhibit growth & survival of tumor cells with over expressed epidermal growth factor receptor (EGFR) in colon & head & neck cancer
Found to be inefficient in some mutated EGFR patients that have an association between resistance of cetuximab/panitumamb and KRAS mutations

Question 30

What does Crizotinib do and what happens when there is an EML4-ALK fusion?

Answer 30

• Crizotinib is an ALK inhibitor for treating non-small-cell lung cancer (NSCLC)
• Constitutively activated kinase and leads to carcinogenesis
• NSCLC caused by EML4-ALK had resistance to crizotinib