Cancer Agents

Question 1

Describe the mode of action of tamoxifen

Answer 1

Competitively block endogenous estrogen receptors in target tissue

Tamoxifen-ER alters estrogen responsive gene expression

Prevents cancer cell proliferation and activation

Question 2

What are some characteristics of Tamxoifen?

Answer 2

Stereoisomer has estrogenic and anti-estrogenic activity
- Cis isomer: estrogenic
- Trans isomer: anti-estrogenic

Tissue specific effect

Question 3

How is Tamoxifen absorbed?

Answer 3

Orally; rapid and extensive in the intestines

Question 4

What is the distribution of Tamoxifen like? Why so?

Answer 4

Plasma protein binding is high. High concentrations of tamoxifen are found to be concentrated in breast, uterus, liver, kidney, lung and pancreas

Question 5

How is Tamoxifen metabolized?

Answer 5

Phase I: Hydroxylation, N-oxidation and dealkylation

Phase II: Glucuronidation and sulfation

Question 6

What is the major metabolic pathway of Tamoxifen? What is formed?

Answer 6

N-demethylation which is catalyzed by CYP3A4 forms N-desmethyl-tamoxifen

Question 7

Upon metabolism, what is the active form of tamoxifen?

Answer 7

Endoxifen

Question 8

What is the minor metabolic pathway of Tamoxifen and what is formed?

Answer 8

Hydroxylation by CYP2D6 forms 4-OH-tamoxifen

Question 9

What are the CYP enzymes involved in metabolism of tamoxifen?

Answer 9

CYP2D6 and CYP3A4

Question 10

How is Tamoxifen eliminated?

Answer 10

Faeces

Question 11

What are some DDI to watch out for the metabolism of tamoxifen?

Answer 11

CYP2D6: Grapefruit juice

CYP3A4: Diphenhydramine

Question 12

List the clinical use of tamoxifen

Answer 12

Breast cancer: early and metastatic
Pre and postmenopausal women
Chemoprevention for breast cancer for those with high risk
Breast cancer + osteoporosis

Question 13

Name some of the minor adverse effects of Tamoxifen.

Answer 13

Hot flashes
Menstrual irregularities
Vaginal bleeding and discharge
N/V

Question 14

Name the major adverse effects of Tamoxifen

Answer 14

Endometrial cancer
VTE
Acute neurotoxicity

Question 15

Describe the mode of action of pembrolizumab

Answer 15

Binding to PD-L1 on cancer cells allow the release of PD-1 pathway mediated inhibition of T cell activities. Thus, allow T cell activation and killing of cancer cells to occur.

Question 16

How is pembrolizumab absorbed?

Answer 16

IV administration

Question 17

How is pembrolizumab’s distribution?

Answer 17

Limited extravascular distribution as limited binding to plasma protein

Question 18

How is pembrolizumab metabolized?

Answer 18

Metabolized by non-specific catabolism where larger molecules are broken down to smaller ones

Question 19

What are the factors that can affect pembrolizumab clearance?

Answer 19

Albumin
Bilirubin level
Type of cancer
Gender: lesser in females

Question 20

List the adverse drug reactions associated with pembrolizumab

Answer 20

Infusion related side effects such as rash or itchiness
Fatigue
Diarrhea
Nausea
Joint pain
Immune related inflammation on lungs, endocrine, liver and kidney

Question 21

Which groups of patient are contraindicated in the use of pembrolizumab?

Answer 21

Those on corticosteroids and immunosuppressants

Pregnant women

Patient with history of severe reaction to another antibody therapy or other illnesses

Question 22

Describe the mode of action of leuprorelin

Answer 22

Acts as GLP-1 agonist by mimicking GnRH

Decreases androgen production in testes

Minimal positive effect on androgen sensitive prostate cancer cells

Cancer cells undergo apoptosis

Question 23

What are the monitoring parameters for those on leuprorelin? How frequent should they be monitored?

Answer 23

PSA
FSH and LH
Testosterone levels

After 4 weeks of therapy

Question 24

How is leuprorelin absorbed? How frequent is it dosed?

Answer 24

SC/IM
At 1, 3 and 4 months interval

Question 25

How is leuprorelin metabolized?

Answer 25

Proteolytically by peptidases into inactive peptides

Question 26

How is leuprorelin excreted?

Answer 26

Small proportion of 5% by urine

Question 27

What are some of the adverse side effects of leuprorelin?

Answer 27

Local pain at injection site
Flushes
Headache
GI disturbances
Altered mood
Hyperglycemia
Hyperlipidemia
Loss of libido

Question 28

Which group of patients are contraindicated in the use of leuprorelin?

Answer 28

Hypersensitivity to GnRH agonist
Preexisting heart disease
Patient with risk of osteoporosis

Question 29

Why is Bicalutamide prohibited from use as monotherapy?

Answer 29

Bicalutamide act as androgen receptor inhibitor

Blocking it will cause LH to increase due to the shift in equilibrium and hence, cause an increase in testosterone

Not ideal for prostate cancer

Question 30

What is the mode of action of bicalutamide?

Answer 30

Act competitively to antagonize androgen receptors

Inhibit the nuclear translocation of androgen receptor with promoter at AR response element

Impairs cell proliferation and triggers apoptosis

Decreases prostate size as lesser amount of testosterone

Question 31

How should it be used?

Answer 31

With GnRH analogue (leuprorelin) to alleviate testosterone surge

Question 32

Name the clinical indications of bicalutamide

Answer 32

Prostate cancer
Androgen deprivation therapy
Locally advanced disease

Question 33

How is bicalutamide absorbed?

Answer 33

Orally

Question 34

How is the distribution of bicalutamide like?

Answer 34

Highly plasma protein bound

Question 35

How is bicalutamide metabolized?

Answer 35

Via the liver

Question 36

Which stereoisomer (R or S) is the active form of Bicalutamide? How is it formed?

Answer 36

R-Bicalutamide

Formed when bicalutamide undergoes hydroxylation then glucuronidation

Question 37

How is bicalutamide eliminated?

Answer 37

Bile and urine

Question 38

Name the adverse effects associated with bicalutamide

Answer 38

Gynecomastia
Sexual dysfunction
Fatigue
GI disturbance
RARE; Seizures