L19: cancer chemotherapy

Question 1

What are the possible types of systemic chemotherapy?

Answer 1

‘carpet bombing’
- Cytotoxic chemotherapy
o Natural antibiotics/poisons
o Chemical warfare/WMDs
o All dividing cells

‘smart bombing’
- (tumour) targeted therapies
o Inhibiting pathways (e.g. hormones)
o Directing payloads (drug conjugates)
o Genetic weaknesses (DNA damage repair)

‘soft power’
- Infrastructure – metabolic/angiogenic
- Popular revolt – immunotherapy
- Restricted movement – bisphosphonates

Question 2

What are the aims of systemic chemotherapy?

Answer 2

• Curative (radical)
  o Primary treatment (SACT alone or as a radionsensitiser)
  o Accept high risks for reward of potential cure
  o SACT alone: germ cell, haematological
  o Combined chemo-radiotherapy: lung, rectal, head and neck
• Adjuvant (e.g. post-op)
  o To reduce risk of recurrence from microscopic disease after curative local therapy
  o Only moderate additional risk reduction c.f. surgery alone – so only moderate risks acceptable
  o Breast, colorectal, lung, ovarian
• Neo-adjuvant (e.g. pre-op)
  o To also shrink macroscopic disease down before local therapy and understand chemosensitivity
  o Breast oesophageal, rectal, ovarian, etx
• Palliative
  o To contorl an incurable cancer and relieve symptoms
  o Symptomatic relief must outweigh toxic side effects

Question 3

What are the classes of chemotherapy?

Answer 3

• Alkylating agents (sticky things which alkylate DNA molecules)
• Alkylating-like agents – platinum compounds
• Antimetabolites
• Plant alkaloids (microtubule agents / spindle poisons) (disrupts microtubule assembly)
• Topoisomerase inhibitors (important in unfolding DNA as part of DNA synthesis process)
• Anti-tumour antibiotics (esp anthracyclines)

Question 4

What are the sources of chemotherapy agents?

Answer 4

• Nature (natural poisons)
  o Plants e.g. vincas, taxanes
  o Other organisms e.g. marine, moulds (strong antibiotics)
• Labs (chemical poisons)
  o Chemicals that have been modified

Question 5

Describe mechanism of action of alkylating agents, provide examples and side effects

Answer 5

• Highly reactive chemicals that donate an alkyl group to DNA (esp guanine bases) and proteins. This (or any subsequent cross-linking) impairs DNA replication and can trigger apoptosis
• Work in all phases of the cell cycle
• Examples: mustard gas, cyclophosphamide, busulfan
• Side effects: haemorrhagic cystitis (causes blood in the bladder), metabolite acrolein causes it; Mesna protects it

Question 6

Describe alkylating-like agents

Answer 6

• Platinum drugs also cross-link DNA (again esp guanine)
• Most important agents
• Examples: cisplatin, carboplatin

Question 7

Describe anti-metabolites, provide examples

Answer 7

• False substrates that interfere with DNA/RNA synthesis
• Not unique to oncology
• Generally active during the S-phase of the cell cycle when DNA is being duplicated
• Pyrimidine analogues
  o 5-fluorouracil (5-FU), capecitabine
• Purines analogues
  o Gemcitabine
• Anti-folates: methotrexate
  5FU / capecitabine GI toxicity
• Dihydropyrimidine dehydrogenase – major toxicity diarrhoea

Question 8

Describe plant alkaloids / microtubule agents

Answer 8

• Generally derived from plants. Block cell division by interfering with microtubule function (the part of the cytoskeleton that binds centromeres and segregates chromosomes)
• Vinca alkaloids (periwinkle plant): bind tubulin to prevent microtubule assembly (vincristine, vinblastine, vinorelbine)
• Taxanes (from yew trees): bind tubulin to prevent microtubule disassembly (paclitaxel, docetaxel)

Question 9

What is Nab-Paclitaxel?

Answer 9

Nab-Paclitaxel
- Paclitaxel from yew tree is highly insoluble
- So it is dissolved in polysorbate and alcohol
- Problem: bodies react to solvents and not to chemo badly
- Nab-paclitaxel is the same drug but wrapped up in albumin, makes it more soluble, selectively taken up by cancer cells

Question 10

Describe topoisomerase inhibitors

Answer 10

• Topoisomerases cut one (type I) or both (type II) strands of the DNA double helix to allow it to uncoil when opening up to be read (transcription) or copied (replication)
• Examples: etoposide

Question 11

Describe antibiotics (anthracyclines)

Answer 11

Antibiotics (esp anthracyclines)
- Anthracyclines are derived from bacteria
- Intercalate between base pairs: interfere with DNA and RNA synthesis; and inhibit topoisomerase II
- Create oxygen free radicals which damage cell membranes and DNA (likely explains class-specific cumulative cardiac toxicity)
- Examples: epirubicin, doxorubicin

Question 12

What are the advantages of combination chemotherapy?

Answer 12

• Additive and synergistic activity
• Lower individual doses may limit specific side effects
• Better targets a heterogenous tumour population
• May prevent / slow the development of resistance