B33 CAN Pharmacology

Question 1

What is a cancer?

Answer 1

Cancer is a group of disease characterised by abnormal cell growth through which cells may acquire potential to metastasise from site of origin to secondary site

Question 2

Tumour growth is dependent on….?

Answer 2

Tumour growth is depedent upon delivery of nutrients and oxygen via increased vascular supply (angiogenesis)

Question 3

Types of tumours and descriptions

Answer 3

Benign

• Cells well-differentiated
• Slow growing
• Encapsulated & does not metastisize

Malignant

• Cells poorly differentiated
• Frequent cell divison
• Capable of intravastation at distant site and metastisi

Question 4

Classification of Cancer Pathology

Answer 4

• Carcinoma - Most common type, ectoderm e.g. breast
• Sarcoma - Cancer of embryonic mesoderm e.g. bone
• Lymphoma - cancer in lymphnodes and tissue immune system
• Leukamia - Cancer of WBC in bone marrow

Question 5

Properties of a metastatic cell

Answer 5

• Local invasion into vasculature
  (loss of cell adhesion (cadherins) and gain of alternate adhesion (intergrins)

Survival in a vessel
(platelet-enhanced metastatic spread)

Arrest at Distant site

Extravasation

Growth of secondary tumour and angiogensis

Question 6

Metastatic Cascade

Answer 6

1) primary tumour formation
2) localized invasion
3) intravasation
4) Transport through circulation
5) Arrest in microvessels of organs
6) Extravasation
7) formation of micrometastasis
8) colonisation

Question 7

Vascularisation is essential for?

Answer 7

Vessel formation is essential for optimal;
Gas exchange, nutrient delivery, disposal of metabolic waste

Vasculogenisis: Differentiation and activation of ECs with prolfieration, alignment branching tube formation

Angiogenisis:
Formation of new vessels from pre-exisiting vasculature

Question 8

Normal Vs pathological angiogensis

Answer 8

Controlled Vs Uncontrolled
Organisved Vs disorganized
Low interstital pressure vs High intersital pressure

Question 9

Normal angiogenesis

Answer 9

In normal angiogenisism VEGF is the stimulus causing tip cells to grow and stalk elongation

Question 10

Goals of cancer therapy

Answer 10

Curative
- Main goal is to cure the patient

Maintenance
- Secondary goal is maintenance to prolong progression-free survival

Pallitative

• Clear patient cannot be cured
• Focused on pain relief & comfort

Question 11

General problems with anti-cancer drugs?

Answer 11

• Selectivity and specificity
• Off target side effects
• Tumour cell heterogeneity
• Drug resistance

Question 12

Approaches to cancer treatment

Answer 12

Surgery

Radiotherapy: Damage DNA

Chemotherapy: Interfere with the cell cycle - Cytotoxic (S phase DNA rep, or M phase (mitosis)

Targeted Therapy : Interfere with specific pathway

Question 13

Targeted Therapy examples

Answer 13

Inhibit the interaction of a growth factor/hormone with its receptor (e.g Bevacizumab and VEGF)

Question 14

Bevacizumab and VEGF

Answer 14

VEGF binds to receptor
Phosphorylation occurs to tyrosine residues (autophosphorylation occurs T-arms coming together)

Stimulates series of downstream signalling processes

Leads to upregulation of signalling cascade molecules -ERK, PI3K

Bevacizumab inhibits interaction of Growth factor wirth receptor stopping the downstream signalling.

Question 15

HER-2 Signalling & Trastuzumab

Answer 15

Breast cancers that express HER-2 receptor can be treated with Trastuzumab
Antibody shape Mab
- Binds to external domain receptor
-Stops signalling mechanism(RAS & PI3K)

Question 16

History of chemotherapy

Answer 16

Era of modern chemotherapy during World War I - Soldiers exposed to mustard gas died because bone marrow destoyed -> compounds caused DNA alkylation, prevation cell divison -> APOPTOSIS

Question 17

Chemotherapy

Answer 17

Drugs interfere with DNA synthesis and mitotic porcesses
These cytotoxic agents dont distinguish between normal cells and cancer cells
ADR to chemotherapy is the cytotoxicity of normal cells

Question 18

Types of cytotoxic drugs (1-3 Sphase)

Answer 18

1) Alkylating-like agents
2) Antimetabolites
3) Topoisomerase Inhibitors
4) Microtubule poisons (M phase)

Question 19

General ADR associated with chemotherapy

Answer 19

1) cytotoxic chemotherapy drugs target cells that are actively multiplying
2) common toxicities include myelosuppression
Increased risk infection
N & V & D
Sterility

Question 20

Alkylating-like agents: Cisplatin

Answer 20

• Bind to DNA and cause cross-linking (prevent cell divison cause cell death)
  Cause conformational change in DNA making DNA repair difficult
  Impair DNA Replication and S
  Link to DNA via Pt atom cross linking the strand

ADR:
Nephrotoxicity
Neurotoxicity
Peripheral neuropathy

Question 21

Antimetabolites : Methotrextate MTX

Answer 21

Methotrexate is a DHFR inhibitor / Folate antagonist

MTX binds to DHFR preventing the production of thymidine (impairing nucleic acid synthesis therby inhibiting DNA RNA and protein production)

ADR:
Nephrotoxicity
Hepatic fibrosis and cirrhosis
Neurotoxicity

Question 22

Topoisomerase I inhibitor: Topotecan

Answer 22

Topoisomerase I are enzymes that regulate DNA supercoiling, causing single strand breaks & religation
Topotcan intercalates between DNA bases, interfering with DNA structure (imparing DNA replication and synthesis and repair, leading to apoptosis)

Question 23

Topoisomerase II inhibitor: Doxorubcin

Answer 23

Topoisomerase II are enzymes that regulate DNA supercoiiling causes cleavage of BOTH strands using hydroylsis and ATP

Doxorubicin inhibits activity TopoII

• Binds strongly to Duplex DNA by intercalation
• Generates free radicals
• Bind to cell membranes to alter fluidity and ion transport -> apoptosis

ADE:
Cardiotoxicity ; CHF can appear

Question 24

Microtubule Poisons: Vincristine

Answer 24

Vincristine

• Binds to tubuli strucutres and prevents polymerisation into microtubules
• Blocks critcal step in M phase

ADE:
Cardiovascular
Peripheral Neuropathy (motor nerver damage long term)
GI : constipation

Question 25

CV effects of Anti-VEGF Therapy

Answer 25

Hypertension (blockage of VEGF leads to vasoconstriction)

Arterial Thromboembolic Events
Prevents adherence of blood cells to Vasculature

CHF

Nephrotoxicity

Wound complications (inhibiton of VEGF disrupts normal healing)

Question 26

Mabs : Inhibiton HER2: Trastuzumab

Answer 26

ADE: Cardiac Toxicity

• > Previous exposure to anthracycline
• > Diabetes Mellitus
• > Hypertension

Question 27

Side effects Tamoxifen

Answer 27

Hot flushes
Sweating
Weight gain due to water retention

Question 28

Immunotherapy Vaccines

Answer 28

HPV Vaccines Side effects:
Headache and dizziness + sore muscles
Fever
N & V & D
Pruritis