Chemotherapy Lecture 21

Question 1

What are the objectives of cancer treatment

Answer 1

Cure the patient (kill or remove all cancer cells)
Prolong patient survival (kill most cancer cells)
Palliate symptoms (kill some cancer cells)

Question 2

What are the 2 types of drugs

Answer 2

Cell cycle specific drugs - acts on cells in the cell cycle and inhibits cell growth at specific phases. More effective against tumours with higher percentage of cells that are replicating
Cell cycle non specific drugs - acts on resting and cycling cells, useful against tumours with low of high percentage of replicating cells

Question 3

What is the Norton-Simon hypothesis?

Answer 3

• Delivering treatments at a greater rate could optimise chemotherapy efficacy
• Minimising regrowth of cancer between doses of therapy
• Increase cumulative cell kill -> greater clinical benefit

Question 4

What types of chemo agents are there?

Answer 4

• Alkylating agents
• Platinum agents
• Antimetabolites
• Topoisomerase inhibitors
• Antimicrotubular agents

Question 5

What do alkylating agents do?

Answer 5

Covalently transfer alkyl groups to DNA bases i.e. Ifosfamide
1. Base alkylation - monofunctional DNA adducts
Repair of these leads to SSBs in DNA
2. Two bases linked together by an alkylating agent forming cross-bridges
Cross-linking prevents DNA from being separated for DNA synthesis or transcription

Question 6

What do platinum agents do?

Answer 6

• Bind covalently to purine DNA bases
• Form bifunctional intra-strand crosslinks that prevent DNA double strand separating
  i. e. Cisplatin

Question 7

What do antimetabolites do?

Answer 7

• Interfere with incorporation of nucleic acid bases
• Are purine or pyrimidine analogues
• Inhibits formation of normal nucleotides
• Prevent formation of folate (essential for methyl groups in DNA synthesis)
• Usually S phase specific
  i. e. 5FU

Question 8

What do topoisomerase inhibitors do?

Answer 8

• Topoisomerases relax supercoiled dsDNA to allow DNA replication and RNA transcription
• Top1 - single strand nicks
• Top2 - double strand nicks
• Swivelling of supercoiled DNA occurs at nicks followed by re-ligation relieve torsional strain

Inhibitors

• Work by binding and stabilising top 1 adducts
• Inhibit re-ligation of DNA strands

Question 9

What are antimicrotubular agents?

Answer 9

Prevent spindle formation (mitosis phase)
Vinca alkaloids: (vincristine)
-Bind to tubulin, preventing polymerisation of microtubules (inhibits progression through cell cycle)
Taxanes:
-Prevent microtubular dissassembly
-Disrupts microtubule dynamics required for cell division

Question 10

What toxicities do chemotherapy agents cause?

Answer 10

Effects on dividing cell:

• Myelosuppression (reduction of WBCs)
• Mucositis (GI tract damage. Treatment includes mouth care, antiseptic mouth wash)
• Skin
• Alopecia
• Neutropenic (low neutrophil count)

Non-replicative toxicity

• Nausea
• Neuropathy

Question 11

Describe toxicity

Answer 11

Has to have a low therapeutic index due to targeting both normal and cancer cells.
Toxicity to normal cells is a major limiting factor
Careful dose calculation

Question 12

What are the different responses to chemotherapy?

Answer 12

Complete response:
-Prerequisite (but not sufficient) for cure
Partial response:
-Palliative value only, offset by drug toxicity effects
Stable response:
-Any impact on survival

Question 13

The use of combination therapy

Answer 13

Combination therapy is more effective and provides the maximum cell kill within the range of toxicity that can be tolerated for each drug.
Provides a broader range of coverage of resistant cells
Prevents or slows the development of drug resistanct cells

Select drugs with different mechanisms of action, in optimum dose,, minimum interval between cycles, with different dose-limiting toxicities to minimise damage to any one organism