COMBINATION THERAPY IN MALIGNANCY

Question 1

principles of combination therapy

Answer 1

-drugs should have no overlapping toxicity
- drugs should have different mechanism of action
- drugs should have different mechanisms of resistance
- drugs should be given in optimum doses and schedules for efficacy
- drugs should not have greater toxicity when administered together

Question 2

concept of combination therapy

Answer 2

• it is less likely that a cell will have resistance mechanisms to more than one drug/treatment if they work on different pathways
• thus using a combination of drugs is more likely to kill all the tumour cells
• combination therapy may make other treatments work better such as radio-sensitisers enhancing tumour cell response to radiation

Question 3

drug synergism

Answer 3

facilitation of the effects of one drug by another when given together
- additive (summation)
- supra-additive (potentiation)

Question 4

3 rationales for combination cancer therapy

Answer 4

• additive or synergistic interactions
• within tumour heterogeneity
• between tumour heterogeneity (makes a quantitative prediction based on single-drug activities)

also
reduced drug associated side effects if can use less of each drug - less risk of multi drug resistance

Question 5

FOLFOX indication

Answer 5

used to treat bowel cancer and colorectal cancer

Question 6

FOLFOX

Answer 6

drugs:
FOL - folinic acid (leucovorin)
F - fluorouracil (5FU)
OX - oxaliplatin

health care team will decide how many cycles a patient needs

a cycle lasts 2 weeks

Question 7

leucovorin in FOLFOX

Answer 7

not a chemotherapy drug itself but used in addition to these chemo drugs to enhance anti-cancer effects or to help prevent or lessen side effects

Question 8

fluorouracil in FOLFOX

Answer 8

• when given alone stays in body for only a short time, when given in combination with Leucovorin, Leucovorin can enhance the binding of fluorouracil to an enzyme inside of the cancer cells
• as a result fluorouracil may stay in the cancer cell longer and exert its anti-cancer effect on the cells

Question 9

FOLFIRNOX

Answer 9

drugs:
FOL - folinic acid
F - fluorouracil (5FU)
IRIN - irinotecan
OX - oxaliplatin

improved survival in pancreatic cancer

Question 10

irinotecan/topotecan

Answer 10

• works by blocking an enzyme, topoisomerase I
• all cells need this enzyme to divide and grow by unwinding the DNA helix
• irinotecan blocks this enzyme so the helix can’t unwind cancer cells can’t divide

Question 11

radiosensitiser

Answer 11

a drugs that makes tumour cells more sensitive to radiation therapy

Question 12

radiotherapy and chemotherapy used together

Answer 12

conventional chemotherapeutics are currently being used in conjunction with radiation therapy to increase its effectiveness

ex: gemcitabine and platinum analogues

Question 13

gemcitabine and platinum analogues mode of action

Answer 13

disregulating cell cycle checkpoints in tumour cells
- gemcitabine causing cells in the S-phase to disrepair DNA damage caused by the radiation
- platinum analogues such as cisplatin inhibit DNA repair by cross linking strands, and so exacerbate the effects of DNA damage induced by radiation as these can’t be repaired

Question 14

radiotherapy and chemotherapy limitations

Answer 14

radiotherapy - cells of solid tumours become deficient in oxygen. solid tumours can outgrow their blood supply, causing a low-oxygen state (hypoxia). oxygen is a potent radiosensitiser, increasing the effectiveness of radiation by forming DNA- damaging free radicals. tumour cells in a hypoxic environment may be 2-3x more resistant to radiation damage than those in a normal oxygen environment.

Question 15

radiosensitisation of TKIs

Answer 15

TKIs down regulate the proliferate signals triggered by RT (such as radiation-induced autophosphorylation of EGFR) this suggests a potential radiosensitising effect of TKIs

Question 16

cancer cells responding to DNA damage

Answer 16

• cancer cells are much better at repairing damage than normal cells
• cancer cell repair is often flawed resulting in cells with DNA that has lots of damage
• cancer cells have ways to prevent apoptosis and cell cycle arrest and in response to damage by radiation will up regulate genes that make proteins to help them survive
• these can be targeted in combination therapy

Question 17

why is radiotherapy used in combination with drugs

Answer 17

• radiotherapy it more toxic to dividing cancer cells
• kills cells by causing DNA double strand breaks
• to ensure the cancer cells can’t be repaired after the DNA break, radiotherapy is used in combination with drugs which either stop the repair of the SBs or work in other ways

Question 18

radio sensitising agent - topotecan (TPT)

Answer 18

• TPT is an topoisomerase I inhibitor
• responsible for unwinding supercoiled DNA during DNA replication and transcription
• also involved in the cellular response to DNA damage

Question 19

PARP inhibitors

Answer 19

• convert single strand breaks into double strands breaks which are harder to repair
• used in BRCA mutations