Targeted Chemotherapeutics 1

Question 1

Name some first generation cancer drugs?

Answer 1

First generation - cytotoxics e.g. nitrogen mustards (mainly limited to the treatment of lymphomas, especially Hodgkin’s disease)

Question 2

Name some second generation cancer drugs?

Answer 2

Second generation - DNA damaging agents, anti-metabolites, microtubule inhibitors

Question 3

Name some examples of targeted therapies?

Answer 3

Tyrosine kinase (imatinib - tyr kinase domain in Abl, c-kit and PDGF-R)
Growth factor receptors (EGFR, Her1, ErbB-1)

Question 4

Name some examples of immuno-therapies.

Answer 4

Immuno-modulation (interferons, cytokines), tumour antigenicity (tumour specific antigens, monoclonal antibodies), immunotherapy (CAR T cells, checkpoint inhibitors)

Question 5

How do targeted therapies differ from standard chemotherapy?

Answer 5

Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells. Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells

Question 6

What is the mechanism of action of asparaginase (L-ASP)?

Answer 6

L-ASP hydrolyses circulating asparagine to aspartic acid and ammonia, depriving malignant cells of asparagine, leading to cell death. (cells needs L-asparagine for protein synthesis)

Question 7

What’s pegaspargase?

Answer 7

L-Asp conjugated to 5000-Da units of monomethoxy-PEG. Reduced immunogenicity, slower clearance. Produces rapid and complete depletion of plasma asparagine

Question 8

How many translocations are associated with APL (Acute Promyelocytic Leukaemia)?

Answer 8

4

Question 9

How does ATRA kill malignant cells?

Answer 9

ATRA induces the terminal differentiation of the leukemic promyelocytes, which then undergo spontaneous apoptosis

Question 10

Name 2 therapeutic strategies in hormone targeted therapies?

Answer 10

1. Prevent hormone synthesis
2. Block hormone receptors

Question 11

Which other organ does tamoxifen target aside from breast cells?

Answer 11

Tamoxifen has partial agonist effects in the endometrium and has been linked to endometrial cancer. Tamoxifen is also an agonist in the bone, preventing bone loss by inhibiting osteoclasts, therefore they prevent osteoporosis.

Question 12

Where are clomiphene and fulvestrant pure antagonists for?

Answer 12

All tissues

Question 13

Where does cetuximab bind and what is it used for the treatment of?

Answer 13

binds to the EGF receptor. Used for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer

Question 14

Name a small molecule Tyr kinase inhibitor?

Answer 14

Gefitinib (only effective in cancers with mutated and overactive EGFR)

Question 15

Where does Herceptin bind?

Answer 15

HER2

Question 16

Explain the cellular abnormalitites in chronic myelogenous Leukemia?

Answer 16

Chromosomal translocation affecting the Abl gene (on chromosome 9) and the breakpoint cluster region (BCR) gene (Chromosome 22). The BCR/Abl fusion gene creates a constitutively active tyrosine kinase - uncontrolled cell proliferation and resistance to apoptosis.

Question 17

Does imatinib bind to the ATP binding site in an inactivate or activate conformation?

Answer 17

Inactive

Question 18

How does imatinib prevent tyrosine kinase inactivation?

Answer 18

Imatinib binds to and stabilises inactive form of tyrosine-kinase, thus prevents activation

Question 19

Which type of cancer is nitrogen mustard mostly limited to the treatment of?

Answer 19

Lymphoma, especially Hodgkin’s disease

Question 20

Name a hormone targeted therapy that is used for osteoporosis?

Answer 20

Raloxifene (agonist)

Question 21

Name a drug that is used to manage breast cancer disease progression after tamoxifen.

Answer 21

Fulvestran

Question 22

Name a drug targeting the EGF receptor.

Answer 22

Cetuximab

Question 23

Gefitinib is only used in which type of cancer genotypes?

Answer 23

Only effective in cancers with mutated and overactive EGFR

Question 24

Where does Imatinib bind?

Answer 24

Binds at ATP binding site in inactive confromation

Question 25

What drug can be used with imatinib to reduce resistance?

Answer 25

Verapamil