chemotherapy Flashcards
How long has chemotherapy been in use for?
50 years
What are common toxicities associated with chemotherapy?
It is usually toxic to other proliferating tissues as it targets DNA replication - usually myelosuppression and irritation to the GI tract occurs, as well as destruction of hair follicles.
Name examples of chemotherapy drugs.
Doxorubicin, epirubicin, cisplatin, carboplatin, 5-fluorouracil, methotrexate, cyclophosphamide, irinotecan, topotecan,
How do alkylating agents work? Name examples.
These inhibit DNA replication by cross-linking DNA preventing its replication. Cyclophosphamide and carboplatin are examples.
Discuss cyclophosphamide mechanism of action and uses.
Cyclophosphamide is an alkylating agent whose active metabolite directly binds DNA to form crosslinks and halt DNA replication. It becomes activated by CYP2B6 to form 4-hydroxycyclophosphamide. It then undergoes further tautomerisation and a spontaneous condensation reaction to form an active species called phosphor amide mustard. It is often used in lymphomas, leukaemia, breast cancer and is associated with alopecia, myelosuppression, nausea, lethargy.
What are the pharmacogenetics issues associated with cyclophosphamide?
There is vast variation in the CYP450 enzymes: these are involved in activation as well as parent drug inactivation. As a result, increased activity of CYP450 enzymes may cause an increased clearance, therefore requiring a higher dose. However, current studies are looking at P450 gene delivery to the tumour via adenovirus delivery. As a result, activation will occur at the tumour site instead of the liver, causing increased cytotoxic effect at the target site. This may allow reduced dosing and off-target cytotoxicity, as well as improved socioeconomic factors (cost, quality of life).
Discuss carboplatin mechanism of action and uses.
Carboplatin is a platinum compound which binds directly to DNA to form platinum DNA adducts, halting DNA replication. It is an analogue of cisplatin however it has a 100x slower interaction rate with DNA as the loss of its 2 bidentate ligands is much slower. This is often administered for germ cell tumours (e.g. excellent outcome in prostate cancer), as well as childhood cancers. However, it is associated with haematological toxicity, as well as nausea.
Discuss the kinetics of carboplatin and how therapeutic drug monitoring improves response.
Carboplatin follows simple linear kinetics and is eliminated by the kidneys. The AUC is directly related to the clinical effect and the toxicity observed in patients. As a result we can dose based on individual renal function to allow an AUC within the therapeutic window to be achieved, increasing clinical effect and reducing treatment deaths (AUC of 5-7 ug/mL/minute). This is particularly adopted in neonates, as their kidneys are still developing therefore it is hard to assess which dose is optimal. TDM is routinely used now, and studies have identified that without TDM, neonates are significantly undergoes, particularly at 6 weeks when the kidneys have rapidly developed, allowing increased renal elimination of the drug.
What are the mechanisms of resistance for alkylating agents?
- Decreased uptake into tumour cells (hypoxic tumours)
- Inactivation by intracellular GSH
- Increased DNA damage repair (usually NER)
- Cross-resistance with other alkylating agents.
Discuss topotecan mechanism of action and its uses.
Topotecan is a type 1 topoisomerase inhibitor, preventing DNA processing and causing cell death. It binds to the complex of Topo 1 to prevent relegation of the DNA strand break. This promotes DNA damage and cell death. It is considered an antimetabolite and is often used in ovarian, lung, and colorectal cancers. However, it is associated with myelosuppression, fatigue, and diarrhoea.
Discuss resistance mechanisms of topotecan and its optimisation.
Resistance can occur as it has binding affinity for P-glycoprotein, therefore the drug can be effluxes from the tumour, inhibiting its uptake and preventing the desired clinical effect. As a result, a similar drug irinotecan has been produced which is not a substrate for P-glycoprotein. Irinotecan is a prodrug which produces the active metabolite SN-38, which is used in colon cancer.
Discuss methotrexate mechanism of action and its uses.
Methotrexate is an antifolate drug which prevents DNA synthesis via competing with folate. It becomes polyglutanated to enhance the cellular retention, then targets dihydrofolate reductase (DHFR) preventing DHF being reduced to THF. It is used in breast cancer and ALL, however is associated with myelosuppression and nephrotoxicity.
Discuss optimisation methods of methotrexate and its kinetics.
High doses are sometimes required, e.g. for glioblastoma it is hard to get across the blood brain barrier. In this case, we can deliver a high dose of methotrexate, with folinic acid rescue, preventing severe toxicity. Rapid elimination of methotrexate occurs really, however no current individualised dosing occurs. A study looked at methotrexate individualised dosing in ALL - this caused significant increase in the proportion of children reaching target therapeutic window, compared to when conventional dose was given. This was achieved via therapeutic drug monitoring - the dose was increased if deemed too low, or decreased if too high. A 10% increase in number of ALL patients achieving continuous complete remission was achieved. Moreover, TDM can be used to identify patients at high risk of toxicity. As toxicity occurs a week later, we can undergo therapeutic drug monitoring to identify when plasma concentration levels indicate a high risk of toxicity. In these situations we can deliver colonic acid rescue to prevent this.
Discuss the mechanism of paclitaxel and its uses.
Paclitaxel is a taxane, part of the tubular binder family involved in cell division inhibition. It overstimulates microtubulin polymerisation causing formation of inappropriate structures at the G2M blockade. This promotes cell death at the checkpoint. This occurs independently of P53 therefore it is unaffected by P53 mutation. It occurs via BCL2 which activates BAX prop-apoptotic protein. It is metabolised via CYP2C8 and CYP3A4 and is used in breast, lung and ovarian cancer. It has associated myelosuppression, neurotoxicity and anaphylactic reactions.
Discuss optimisation methods of paclitaxel and its kinetics.
As doses increase, there is decreased clearance from the plasma as the tissues become saturated and cannot cope with the concentrations of the drug. At lower doses, clearance is high therefore less effect is achieved. Higher doses for short administration schedules are preferred for maximum effect. However, care should be taken when dosing as small increases could cause severe toxicity. Genotyping and profiling may be required to prevent this.
