W5.2_Cancer Treatments Flashcards

1
Q

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?

A
  • 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
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2
Q

Explain the principle of chemotherapy. Explain the mechanism of alkylating agents and name some examples.

A
  • 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
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3
Q

Explain the mechanism of antimetabolites by using capecitabine as an exmaple. Why is folinic acid administered before 5-FU treatment?

A
  • 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
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4
Q

Explain the mechanism and give some examples of mitotic spindle inhibitors and topoisomerase inhibitors.

A
  • 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
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5
Q

What do targeted therapies focus on? Briefly explain the mechanisms of different targeted therapy.

A
  • 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
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6
Q

Explain the reason of having side effects after receiving chemothereapy. Name the common GI side effects of chemotherapy. How about immunotherapy?

A
  • 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
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7
Q

Explain the main and peripheral pathways of causing chemotherapy induced nausea and vomiting (CINV). What are the possible medications used to mitigate symptoms?

A
  • 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
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8
Q

What are the causes of chemotherapy induced diarrhoea? What are the possible consequences?

A
  • 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
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9
Q

Explain how chemotherapy causes mucositis. What would severe mucositis cause? What are the possible treatments to increase tolerability?

A
  • 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
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10
Q

Explain why cancer can still not be cured.

A
  • 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
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