Pharmacology - Cancer I Lecture

Question 1

What are the phases of the cell cycle?

Answer 1

A normal somatic cell may spend ~ 6-12 h in G1, ~ 6-8 h in S, ~ 3-4 h in G2 and ~ 1 h in M (timing could vary depending on cell type).

G0: Postmitotic cells exit the cell cycle and enter into a non-proliferative phase e.g., terminally differentiated nerve cells, or some cells that enter temporarily into G0 for weeks, months or years and later re-enter the cycle.

Question 2

What are the 2 major proteins that control cell cycle progression?

Answer 2

Cyclins: the regulatory proteins e.g., cyclins A, B, D or E.
Cyclin-dependent kinases (Cdks): the catalytic proteins e.g., Cdks 1, 2, 4 or 6.

Cdks have no kinase activity unless associate with a cyclin.
Each Cdk can associate with different cyclins.
The cyclin determines which proteins would get phosphorylated by the cyclin-Cdk complex.

Different cyclin-Cdk complexes function in different phases of the cell cycle e.g.,
• Cdk4-cyclin D in G1 phase
• Cdk2-cyclin A in S phase
• Cdk1-cyclin B in G2/M

Question 3

What part of the cell cycle is the Rb-E2F involved in?

Answer 3

Rb-E2F Pathway: progression from G1 to S phase.

• Cyclin D/Cdk4, Cyclin D/Cdk6 and Cyclin E/Cdk2 phosphorylate the retinoblastoma protein (Rb).
• Hypophsophorylated Rb is bound to E2F family of transcription factors. Heperphosphorylation of Rb results in the release of E2F.
• E2F activates the transcription of genes whose products control progression from G1 to S phase.

Question 4

T/F: Progression from S phase to G2 phase involves Cyclin A/Cdk2 but the targets remain unknown.

Answer 4

True

Question 5

What are the four checkpoints in the cell cycle?

Answer 5

Four key checkpoints
• G1 arrest
• S-phase arrest
• G2 arrest
• M arrest.
Mechanisms that control cell cycle progression implement these checkpoints to ensure that each stage of the cell cycle is properly completed before the next stage is initiated.

Examples
• If DNA is damaged, cells will arrest in G1 or G2, no progress to S or M phases
respectively.
• If DNA is not properly replicated, S phase arrest and no progress to G2.
• If improper spindle formation, M phase arrest.

Question 6

What are caspases?

Answer 6

Integral component of apoptotic machinery
• They are Cystein proteases and exist as inactive pro-enzymes named pro-caspases
• Activated in response to apoptotic insults e.g., anticancer drug treatment.
• They recognize specific cleavage sites within proteins (including caspases)

They are utilized in cascade known as ‘Caspase Cascade’
For example, upstream initiator caspases (caspase 8 or 9) cleave and activate downstream effector (executioner) caspases such as 3, 6 and 7.

Question 7

Two major apoptotic pathways responsible for activation of caspase cascade:

Answer 7

1. Death Receptor-dependent Pathway

2. Mitochondrial Pathway

Question 8

What is “intrinsic resistance?”

Answer 8

dysregulation in apoptotic/survival pathways, common in many cancer types, confers upon cancer cells the intrinsic (i) survival advantage and (ii) resistance to anticancer drugs, a sort of “double whammy”.

1. Dysregulation of one or both apoptotic pathways common in many types of cancer and occur due to: inactivation of apoptosis promoting genes/proteins (mutations, deletions or epigenetic mechanisms)
2. Hyperactivity of survival or anti-apoptotic genes/proteins.
3. Host Factors: poor absorption or rapid metabolism or excretion of drugs: low serum levels. Delivery failure e.g., bulky tumors or high molecular mass of drugs such as monoclonal antibodies.

Question 9

What is acquired resistance?

Answer 9

(i) Acquired drug resistance due to dysregulation of one or both apoptotic pathways during chemotherapy.
(ii) Many anticancer drugs induce DNA damage. During the course of chemotherapy, many cancer cells acquire the ability to rapidly and efficiently repair DNA damage. Consequence: reduced apoptosis.
(iii) Gene amplification: amplification of genes triggering overproduction of proteins that make anticancer drugs ineffective.
(iv) Increased expression of energy-dependent efflux pumps that confer multidrug resistance by ejecting drugs out of cells. Transporters of the ATP-binding cassette (ABC) family e.g., p-glycoprotein also known as p-gp or multidrug transporter, MRP1 through MRP6 (multidrug resistance associated protein) and some other less well characterized transporters.
(v) Decreased drug uptake because the protein molecules that facilitate drug transport inside the cells stop working.
(vi) Dysregulation in drug metabolism: some drugs are normally metabolized into active metabolites inside the cells but cancer cells can acquire mechanisms to block drug activation.
(vii) Acquisition of mechanisms by the cancer cells to inactivate drugs.

Question 10

T/F: Most Alkylating agents are Leukemogenic

Answer 10

True

risk of secondary neoplasia