Lecture 10 - combination therapy Flashcards
how do tumours differ?
No tumours are the same. even within a tumour there are different cells, different mutations, different oxygen, different nutrients
what are the principles of combination theory?
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
why is combination therapy used?
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. If one drug doesn’t work then the other will
Another reason for combinations is that many treatments may make other treatments work better such as radiosensitisers
Enhancing tumour cell response to radiation
what happens when drug interact?
Additive and synergistic good!
Additive good if toxicity less
Drug synergism: facilitation of the effects of one drug
By another when given together
- Additive ( summation)
- Supra-additive ( potentiation)
what are three rationales for combination cancer therapy?
additive or synergistic interactions
within tumour heterogeneity
between tumour heterogeneity- makes a quantile predictive based on single-drug activities
describe FOLFOX use
used to treat bowel cancer and colorectal cancer
FOLFOX is named after the initials of the drugs used
for treatment. The drugs are:
FOL – folinic acid (leucovorin)
F – fluorouracil (5FU)
OX – oxaliplatin.
cycle 1
FOLFOX 2 weeks
Cycle 2
FOLFOX 2 weeks
Reperat
FOLFOX 2 weeks
health team will advise how many cycles left
what is leucovorin?
Leucovorin is not a chemotherapy drug itself, however it is used in addition to these
chemotherapy drugs to enhance anti-cancer effects (with fluorouracil) or to help prevent or
lessen side effects (with methotrexate).
Fluorouracil when given alone stays in the 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
descried the use of FOLFIRNOX
FOLFIRINOX is named after the initials of the drugs used
for treatment. The drugs are:
FOL – folinic acid
F – fluorouracil (5FU)
IRIN – irinotecan
OX – oxaliplatin.
Irinotecan/topotecan works by blocking an enzyme, called topoisomerase I. All cells need this enzyme to divide and grow by unwinding the DNA helix. . Irinotecan blocks this enzyme so the helix cant unwind cancer cells can’t divide.
shown for improved survival in pancreatic cancer
what are radiotherapies and chemotherapies being used in conjunction?
A radiosensitiser is a drug that makes tumour cells more sensitive to radiation therapy.
conventional therapies are currently being used in conjunction with radiotherapies to increase efficacy
eg gemcitabine and platinum analogues.
gemcitabine casuists cells in the S phase to disrepair DNA damage caused by 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 the can not be repaired.
what are the limitations of radiotherapy and chemotherapy ?
major limitation of radiotherapy is cells of solid tumours become oxygen deficient. Solid tumours can outgrow their blood supply, causing a low-oxygen state known as 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 to 3 times more resistant to radiation damage than those in a normal oxygen environment.
Much research has been devoted to overcoming this problem including the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, hypoxic cell radiosensitisers such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine- Not been very succesful
what can targeted therapies do ?
Targeted therapies can also radiosensitise. this means they can enhance the sensitivity of cancer cells to radiotherapy
TKIs down-regulate the proliferative signals triggered by Radiotherapies (such as radiation-induced autophosphorylation of EGFR). This suggests a potential radiosensitising effect of TKIs
how can a cell respond to DNA damage?
Cancer cells are much better at
Repairing damage than normal cells
The type of repair cancer cells do
Is often flawed, resulting in cells
With DNA that has lots of damage
cancer cells also have ways to prevent the cell from undergoing apoptosis, have ways of stopping cell cycle arrest and in response to damage by radiation will up-regulate genes that make proteins to help them survive.
All these can be targeted by using
combination therapy
what are types of radiation induced lesion in DNA?
single breaks are easy to repair
double breaks are diffisuctl to repair
chemical change is easy to repair if small number
radiotherapy kills diving cells more than non-dividing cells. kills cells by causing double stranded DNA breaks that cannot be repaired properly. cancer cells are quite difficult treat, radiotherapy is used in combination with drugs which either stop the repair of the DSBs or work in other ways
what are PARP inhibitors?
treatment for BRCA mutant breast cancer.
in normal cells PARP binds to the single strand DNA damage and facilitates the repair process of DNA, leading to cell survival and proliferation. in tumour cells; there is a aisngle dna damage break. PAPR binds to it however PARP inhibitors cause trapping of PARP, leading to double DNA breaks. if there is mutated BRCA1/2 homologous recombinant repair is deficit and so there is cell death. If there is normal non-mutated BRCA 1/2 homologous recombination repair Is proficient, then the cell is repaired.
PARP is used by base excision repair whereas BRCA1/2 by homologous recombinant repair
PARP inhibitors have been shown to be excellent chemo and radio sensitisers.
what can be sued for neuroblastoma treatment?
131 MIBG and topotecan in neuroblastoma (MATIN) new approach for relapsed or refractory (not resposnign to normal treatment ) neuroblastoma.
Topotecan inhibits nuclear enzyme topoisomerase I. topoisomerase I is responsible for unwinding supercoiled DNA during DNA replication and transcription
may also be involved in the cellular response to DNA damage
