Chemotherapy Drugs: Cytotoxic Drugs

Question 1

Cancer Survival Rate?

Answer 1

See slide 3 for details.

Ppl are now surviving for longer periods of time

survival rate for pancreatic cancers still low

Question 2

List ways tumours can grow

Answer 2

• sustaining proliferative signaling
• evading growth suppressors
• activating invasion and metastasis
• enabling replicative immortality
• inducing angiogenesis
• resisting cell death

Question 3

Cancer Initiation

What are the 2 types of mutations?

Answer 3

• Genetic (i.e. Brca1)

- Environmental (i.e. Radiation)

Question 4

Cancer Initiation

Which 2 types of genes are affected by mutations?

Answer 4

• Activation of proto-oncogenes. Proto-oncogenes are
  genes that normally control cell division, apoptosis
  and differentiation.
• Suppression of Tumour Suppressor genes. Normal
  cells contain genes that suppress malignant change
  (i.e. apoptosis of normal cells).
  Tumor suppressor kills cells

Question 5

What is Single Nucleotide Polymorphism (SNP)?

What is Somatic Mutation?

Answer 5

A variation of a nucleotide that occurs at an appreciable degree within a population (>1%).

• Genetic predisposition for a disease or not getting a disease (Occurs in every cell)

A variation of a single nucleotide that can be passed to the progeny of the mutated cell in the course of cell division (<1%).
- only in tumor, not other cells

Question 6

What are the 2 types of BRCA mutations?

BRCA mutation is proto-oncogene or tumor suppressor gene?

Answer 6

BRCA mutations account for 5-10% of breast cancer and 10-15% of ovarian cancer in US each year

BRCA 1 and BRCA 2

tumor suppressor - normally expressed in breast and
ovarian tissues and function to repair damaged DNA
(error-free repair of DNA).

Question 7

See slide 10 for details

Answer 7

Rare to get a mutation to change your aa
Some aa look similar (hydrophobic, philic, small)
Protein mutated in cancer are usually kinases

Question 8

Pathogenesis of Cancer?

Answer 8

• Uncontrolled Proliferation
– mutations to proto-oncogenes (i.e. RAS) in certain areas that will turn it on constitutively (never turn off)

• De-differentiation and loss of function
– The multiplication of normal cells begins with
division of undifferentiated stem cells giving rise to
two daughter cells that differentiate to non-dividing
cells. Cancer cells have the ability to de-
differentiate to proliferative cells

• Invasiveness
– Tumours have the characteristic of invading into normal tissues
- epithelium chromosomal transition, now can penetrate vessels and other organs

• Metastasis
– The ability to form secondary tumours (EMT), dangerous

Question 9

Pathogenesis of Cancer flowchart

Answer 9

see slide 12

Question 10

Cytotoxic Anticancer Drugs are highly incorporated in and effective against highly ____ cells (i.e. cell division)

What are the 3 groups of Cytotoxic Drugs and their MOA?
which is worst to give?

Answer 10

• highly proliferative cells

1. Alkylating agents and related compounds:
   
   • form covalent bonds with DNA and thus impede
     replication
     Alkylating agents worst to give NOT SELECTIVE
2. Antimetabolites:
   
   • block or subvert one or more of the metabolic
     pathways involved in DNA synthesis.
     - affects intermediates required for making nucleotides
3. Antibiotics:
   
   • substances of microbial origin that prevent
     mammalian cell division (i.e. mitochondria), kills cells thru mitochond

Question 11

What are the 3 Alkylating Agents?

Which 2 are among the most commonly used anticancer agents?

What are the characteristics of Cyclophoshamide?

Answer 11

Alkylating Agents:
• Nitrogen Mustards
– Cyclophosphamide (Breast, Lymphoma)

• Triazines/Tetrazines
– Procarbazine (Lymphoma)

• Platinums
– Cisplatin (Lung)
– Carboplatin (Lung)
– Oxalipatin (Colon)

Most commonly used:
• Nitrogen Mustard
• Cisplatin

Characteristics of Cyclophoshamide:
• It is inactive until metabolized in the liver.
• It suppresses the immune system.
• It is given by intravenous injection.

Question 12

Alkylating Agents Common Side Effects?

what cells are highly proliferative in the body?

Answer 12

– Impaired wound healing
– Bone marrow toxicity (decreased leukocyte 
    production and decreased resistance to infection)
– Loss of hair (alopecia)
– Depression of growth in children
– Sterility
– Teratogenicity
– Carcinogenicity

reversible side effects after going off of these agents

Question 13

What are the 3 groups of Antimetabolites?

won’t be tested - referred to antimetabolites

Answer 13

1. Purine Analogs
   – Mercaptopurine (Leukemia)

2. Pyrimidine Analogs
    – Cytarabine (Leukemia)
    – Fluorouracil (Colon, Breast)
    – Capecitabine (Colon, Breast)
    – Gemcitabine (Lung)

3. Folate Antagonists
   – Methotrexate (Leukemia)
   – Pemetrexed (Lung)

Question 14

Antimetabolites

What is the MOA of

1. Methotrexate
2. Fluorouracil
3. Cytarabine

GENERAL

Answer 14

1. Prevents the synthesis of purine nucleotides and
   thymidylate, essential for DNA synthesis and cell
   division.
2. Is an analogue of uracil and is converted to
   fluorodexyuridine monophosphate which inhibits
   Thymidylate synthetase. This increases the levels of
   dUMP and causes DNA damage.
   JUST KNOW IT INHIBITS CRITICAL ENZYMES FOR NUCLEOTIDE SYNTH
3. A potent inhibitor of DNA Polymerase

Question 15

What are the Antimetabolites common side effects?

Answer 15

– Bone marrow toxicity (decreased leukocyte
production and decreased resistance to infection)

– Damage to the epithelium of the GI tract. (highly replicated)

Question 16

Cytotoxic Antibiotics are also referred to as Topoisomerase Inhibitors

How many types of Topoisomerase Inhibitors?

MOA of Topoisomerase Inhibitors?

Answer 16

Topoisomerase I Inhibitors
Topoisomerase II Inhibitors

MOA:
• Topoisomerase I Inhibitors
- ???
• Topoisomerase II Inhibitors
- Mechanistically can inhibit topoisomerase II, but are
potent inducers of the tumour suppressor protein
p53. (DOXORUBICIN)
- p53 targets many pathways (inhibit angiogenesis, cell cycle arrest, repair DNA, alternate metabolism)
- major tumor suppressor role but can be mutated

Question 17

Topoisomerase I Inhibitors agents?

Answer 17

Topoisomerase I Inhibitors agents:
• Camptothecin Derivatives
– Irinotecan (Colon)

Topoisomerase II Inhibitors agents:
  • Anthracyclines
    – Doxorubicin (Breast, Lymphoma)
    – Idarubicin (Leukemia)
    – Epirubicin (Breast)

• Epipodophyllotoxins
– Etoposide (Lung, Lymphoma)

Question 18

Topoisomerase Inhibitors common side effects?

Answer 18

– Cardiotoxicity (doesn’t have replicative cells, terminally diff and can lead to heart failure)
- pt seeing cardiologist at same time
– Loss of hair (alopecia)

Question 19

Cancer arises as a result of a series of genetic and
epigenetic changes:
1. ____
2. ____

Answer 19

1. Activation of oncogenes

2. Inactivation of tumour suppressor genes

Question 20

Cancer cells have many characteristics
distinguish them from normal cells, including
1. \_\_\_\_
2. \_\_\_\_
3. \_\_\_\_
4. \_\_\_\_

Answer 20

1. Uncontrolled Proliferation
2. Loss of function because of a lack of capacity to
   differentiate
3. Invasiveness
4. Metastasis

Question 21

driver vs passenger mutation

Answer 21

Driver mutation - enough to cause cancer
- some therapies may induce other driver mutations

Passenger mutation - can detect these mutations, won’t cause cancer

Question 22

what steps of cell cycle most vulnerable?

Answer 22

G1 and S, DNA replication

Question 23

Alkylating Agents

cisplatin MOA?

Answer 23

• passes thru cell membrane and that becomes activated and binds with specific nucleotides
• interpolates to become part of DNA at diff positions
• stops DNA from unravelling and replication

Question 24

cytotoxic anticancer drugs are fairly effective but are ________

Answer 24

NOT SPECIFIC