W5.2_Cancer Treatments Flashcards
Name the different cancer treatments. What are the limitations of surgery? Apart from the original six hallmarks of cancer, what are the four additional emerging and enabling hallmarks?
- Surgery, radiotherapy, drugs, cell therapies
- Limitations for surgery: location, proximity to tissue, vascularisation, metastasis
- Deregulating cellular energetics: switches respiration/metabolism route to anaerobic to reduce oxygen demand -> allow rapid cell division
- Avoiding immune destruction: tumour cells produce strange antigens, shut down mechanism to elicit auto-immune response/actively producing molecules to prevent T cells from reaching
- Genome instability and mutation: allow tumour cells to find additional ways to induce angiogenesis
- Tumour-promoting inflammation: allow tumour to grow faster
Explain the principle of chemotherapy. Explain the mechanism of alkylating agents and name some examples.
- Chemotherapy prevents tumour cell division/growth
- ∵ Cancer cells grow much faster than normal cells
- ∴ Take advantage of that and use drug that target hyper-proliferating cells -> cell death
- Alkylating agents (derivatives of toxic gases)
- Cross-link by covalent bonds/fragmentation/abnormal base pairing of DNA (usually G&T) -> incorrect DNA copy/inhibit DNA synthesis -> cell death
- Body can repair by removing the alkylation by bypassing (but can cause secondary mutation)
- ex. cyclophosphamide, ifosfamide, chlorambucil, melphalan
Explain the mechanism of antimetabolites by using capecitabine as an exmaple. Why is folinic acid administered before 5-FU treatment?
- Block formation of metabolites (ex. stop DNA bases production) -> system breakdown/wrong substrates used
- ex. Capecitabine: pro-drug of 5-FU, which is metabolised into FDUMP and FTUP, where FDUMP prevents conversion of dUMP to dTMP to inhibit DNA synthesis, FTUP interfere with RNA and protein synthesis
- Folinic acid (Leucovorin) is usually administered before 5-FU treatment: stabilise bond between fluorouracil and thymidylate synthase -> strengthen inhibition of thymidylate production -> enhance anti-cancer effect
Explain the mechanism and give some examples of mitotic spindle inhibitors and topoisomerase inhibitors.
- Mitotic spindle inhibitors: little bit less toxic than other drugs
- Block mitosis through targeting entry/formation of spindles, how chromatids are aligned, preventing mitotic exit
- ex. vinblastine, vincristine, docetaxel, paclitaxel
- Topoisomerase allow DNA to unwind for DNA replication/ transcription
- TOPO inhibitors prevent action of TOPO-I (cuts single strand of DNA)/TOPO-II (cuts both strands of DNA): prevents re-ligation of DNA strand by binding to TOPO-DNA complex -> TOPO may be stuck on the DNA strands/adduction of DNA/interstrand crosslinks of DNA -> prevents DNA replication -> cell death
- ex. irinotecan, topotecan
What do targeted therapies focus on? Briefly explain the mechanisms of different targeted therapy.
- Targeted therapy: focuses on the hallmarks of cancer (mechanisms/genes only cancer cells require)
- Immunotherapy: increase anti-tumour immunity (ex. viruses that attack tumour cells, antibodies that produce antigens and increase immune response)
- Cell therapy (ex. CAR T): extract T cells from body -> modification (block suppression of T cells that occurs originally in body) -> multiply and put back in
Explain the reason of having side effects after receiving chemothereapy. Name the common GI side effects of chemotherapy. How about immunotherapy?
- Due to narrow therapeutic window/index (affects fast-dividing healthy cells like hair follicles, WBC, lining of gut)
- Causes unwanted induction of immune system
- GI tract side effects: sore mouth, changes in taste and smell, nausea and vomiting, changes in appetite, mucositis, diarrhoea, constipation
- Immunotherapy: can still cause lots of side effects, may require dose modifications
Explain the main and peripheral pathways of causing chemotherapy induced nausea and vomiting (CINV). What are the possible medications used to mitigate symptoms?
- Central pathway: chemotherapeutic agents directly activate chemoreceptors postrema (vomiting centre) of medulla -> substance P is released -> bind to NK-1 receptors -> induce CINV
- Peripheral pathway: chemotherapy drugs generate free radicals that can damage cells -> stimulate enterochromaffin cells of GI tract -> release serotonin (5-HT) -> bind to intestinal vagal afferent nerves via 5-HT3 receptors -> induce CINV
- ex. dopamine antagonists, 5HT3 antagonists, cannabinoids, substance P antagonists, antimuscarinic drugs, antihistamines
What are the causes of chemotherapy induced diarrhoea? What are the possible consequences?
- Caused by imbalance of water and electrolytes/movement in large intestine
- Increased intestinal inflammation (direct cell death/chronic inflammation) -> reduced α-diversity and increased intestinal permeability
Explain how chemotherapy causes mucositis. What would severe mucositis cause? What are the possible treatments to increase tolerability?
- Can cause diarrhoea and malabsorption
- Chemotherapy triggers immune response to produce materials that are toxic to tissues -> tissue/basal cell damage -> complete breakdown of barrier -> inflammation and possible sepsis -> healing of layer (after two weeks)
- Severe mucositis in mouth can disrupt eating, IV needed
- ex. antibiotics, probiotics, anti-oxidants, mucosal barrier regulators, anti-inflammatories, hormones, painkillers, nutrition replacement
Explain why cancer can still not be cured.
- Narrow therapeutic window of drugs
- High instability of tumour cells can bypass treatments after few cycles (mutations, evolution, microenvironment)
- Extrinsic factors: discovery and diagnosis, access to healthcare, health economics
