Overview
The lecture covers why and how cytotoxic chemotherapy is used in cancer, then works through the mechanism of action, cell-cycle dependence, clinical uses and adverse effects of the four main classes of classical chemotherapy agents (alkylating/crosslinking agents, antimetabolites, microtubule inhibitors, topoisomerase inhibitors), before briefly contrasting these with other systemic therapy types (targeted, immunotherapy, hormonal).
Uses and clinical response to chemotherapy
- Chemotherapy is a systemic therapy, sometimes the only option for advanced metastatic disease.
- Tumour regression can be curative (e.g. some liquid/blood cell tumours), life-extending (e.g. advanced lung or ovarian cancers) or palliative.
- It is combined with surgery and/or radiation, given before, in parallel with, or after these. [slide poses the question “what do ‘adjuvant’ and ‘neoadjuvant’ mean in this context?” but does not define the terms]
- Response to chemotherapy is variable and is measured by survival or time to tumour progression (progression-free survival, PFS), summarised as median PFS: some patients progress before the median time, some later.
- Treatment is usually terminated because of lack of efficacy or intolerable toxicity.
- Example clinical evidence (Kaplan-Meier overall-survival data): KEYTRUDA + cisplatin/FU (n=373) maintained higher overall survival than cisplatin/FU alone (n=376) across the full ~36-month follow-up, with the curves converging only near the tail (around 33 months), illustrating the survival benefit combination therapy can add.
The cell cycle and how cytotoxic agents act
- Mechanism of action of cancer pharmacotherapies is focused on the Cell Cycle: interference with mitosis can induce Apoptosis.
- The cell cycle proceeds G1 phase to S phase (DNA replication) to G2 phase to M phase (mitosis: nuclear division, then cytokinesis: cytoplasmic division), then back to G1.
- Drugs act at various points in the cycle; combination therapy may use two or more drugs that target different parts of the cycle.
- This lecture covers 4 main classical chemotherapy classes: alkylating/crosslinking agents, antimetabolites, microtubule inhibitors (stabilising and destabilising), and topoisomerase inhibitors.
Alkylating and crosslinking agents
- Mechanism: addition of ethyl or methyl groups to various DNA base positions, causing intra- or inter-strand crosslinking, DNA damage and subsequent apoptosis.
- Cell cycle-independent: act at any point in the cycle, so the fraction of cells killed is directly proportional to dose.
- True alkylating agents (e.g. cyclophosphamide) transfer an alkyl group from one molecule to another. Platinum-based drugs do not have an alkyl group but do cause crosslinking, so are described as “alkylating-like”.
Cyclophosphamide
- A nitrogen mustard derivative, discovered from studying mustard gas.
- Attaches an alkyl group to the guanine base of DNA, causing crosslinking.
- Used for lymphomas, some brain cancers, leukaemia, some solid tumours, and as an immunosuppressant.
- Adverse effects (cumulative, dose-dependent): nausea, myelosuppression (bone marrow suppression), stomach-ache, darkening of skin/nails, alopecia, fatigue.
- Serious adverse effects, especially at higher doses: acute myeloid leukaemia, haemorrhagic cystitis, permanent infertility.
Platinum-based agents (cisplatin, carboplatin, oxaliplatin)
- Crosslink mainly at the N-7 position of guanine.
- Used across a wide variety of cancers; cisplatin is especially effective for testicular cancer, with a cure rate of up to 85%.
- Adverse effects: neurotoxic, nephrotoxic, myelosuppressive. Peripheral neurotoxicity/neuropathic pain accumulates with repeated dosing and is dose/treatment-limiting.
- Platinum and radiation: pre-treatment with platinum-based drugs can potentiate radiation therapy (systemic pre-treatment improving local tumour control). Radiation is less effective against hypoxic cells because oxygen increases generation of reactive oxygen species; a similar effect appears to occur with platinum.
Antimetabolites
- Inhibit enzymes needed for purine (G and A) and pyrimidine (T and C) synthesis, preventing mitosis; the resulting DNA damage can induce apoptosis.
- Subtypes:
- Antifolates, e.g. methotrexate.
- Nucleobase analogues: purine analogues (e.g. azathioprine) and pyrimidine analogues (e.g. fluorouracil/5-FU).
- Cell cycle-dependent: only act during S-phase (DNA synthesis). At a certain dose, cell death plateaus.
Methotrexate
- Inhibits dihydrofolate reductase, hence folate synthesis, needed to synthesise thymidine and therefore DNA.
- Used for breast, bladder, head and neck cancers, leukaemia, lymphoma, osteosarcoma, among others.
- Adverse effects: hepatotoxicity, stomatitis, myelosuppression, nausea, abdominal pain, fatigue, fever, dizziness, renal insufficiency; also a teratogen.
- Also used in rheumatoid arthritis and as an abortifacient.
Fluorouracil (5-FU)
- Inhibits thymidylate synthase, hence thymidine synthesis, required for DNA replication.
- Used for head and neck, skin, pancreatic, colorectal, oesophageal and stomach cancers.
- Adverse effects: myelosuppression, nausea, alopecia, cardiotoxicity, photosensitivity; more rarely central neurotoxicity.
- Very narrow therapeutic index: life-threatening toxicity can occur close to the therapeutic dose.
Microtubule polymerisation modifiers
- Microtubule remodelling is necessary for mitosis (spindle development). Two opposite mechanisms:
- Destabilising agents prevent chromosome division in mitosis, inducing apoptosis (vinca alkaloids prevent microtubule assembly/polymerisation).
- Stabilising agents block progression of mitosis, activating the mitotic checkpoint and causing apoptosis and/or cell cycle stasis (taxanes prevent microtubule disassembly/depolymerisation).
- Cell cycle-dependent: bind tubulin in S-phase and prevent the microtubule formation required for M-phase, i.e. act across the S-G2/M portion of the cycle.
Paclitaxel and docetaxel (taxanes, microtubule depolymerisation inhibitors)
- Inhibit mitotic spindle assembly.
- Used for metastatic breast, head and neck, prostate, gastric and lung cancers.
- Adverse effects: myelosuppression (neutropenia and anaemia; more rarely febrile neutropenia and thrombocytopenia), alopecia, fatigue.
- Hypersensitivity risk, managed with dexamethasone pre-treatment.
- Metabolised by CYP3A4, so interact with other CYP3A4 substrates or inducers.
Vinca alkaloids (microtubule polymerisation inhibitors) [flag: slide title reads “Vincra Alkaloids”, transcribed as printed; likely intended “Vinca Alkaloids” but not corrected in the transcript]
- E.g. vinblastine, used to treat Hodgkin’s lymphoma, bladder, lung, brain and testicular cancers, among others.
- Causes M-phase cell cycle arrest by blocking the microtubule assembly needed for chromosome separation during anaphase.
- Adverse effects: myelosuppression, gastrointestinal toxicity. Is a strong vesicant (blistering agent).
Topoisomerase inhibitors
- DNA replication requires unwinding of the strands, which produces supercoiling; to reduce the resulting tension and damage, targeted breaks are made by Topoisomerase.
- Cell cycle-dependent: inhibit DNA replication in S-phase, leading to cell death or G2-phase arrest.
Doxorubicin (an anthracycline)
- Interferes with topoisomerase II, preventing relaxation of DNA strand tension caused by supercoiling.
- Used for leukaemias, Hodgkin’s lymphoma, multiple myeloma, and a variety of solid tumours.
- Adverse effects: dose-dependent risk of cardiomyopathy (dexrazoxane, which traps free radicals, can reduce cardiotoxicity); a potentially fatal complication is typhlitis (an infection of the bowel); also skin problems.
Other systemic therapies, for comparison
- Receptor tyrosine kinase inhibitors: target specific mutated oncogenic RTKs, used for specific cancers with particular biomarkers (e.g. EGFR).
- Immunotherapies.
- Hormonal therapies.
- Despite advances in targeted and immunotherapies for some cancer subtypes, chemotherapy remains the mainstay of systemic cancer therapy.
- Targeted therapies are generally more effective, have fewer side effects and are easier to administer, but are often extremely expensive.
- “Targetable” tumours are currently a minority, so chemotherapy is often the only treatment option available.
Self-test
- What are the three possible outcomes of tumour regression with chemotherapy, and give an example cancer type for each.
- Define progression-free survival (PFS) and median PFS, and state the two main reasons chemotherapy treatment is usually terminated.
- Describe the mechanism by which alkylating agents kill cancer cells, and explain why cell kill is directly proportional to dose for this class.
- Distinguish true alkylating agents from platinum-based crosslinking agents in terms of chemical mechanism.
- Describe the adverse effect profile of cyclophosphamide, including its serious/rare adverse effects.
- Explain how pre-treatment with platinum-based drugs can potentiate radiation therapy, and why radiation is less effective against hypoxic cells.
- List the two main subtypes of antimetabolites, with one example drug for each, and state why this class is cell cycle-dependent.
- Describe the mechanism of action of methotrexate.
- Describe the mechanism of action of fluorouracil (5-FU), and explain why its narrow therapeutic index is clinically significant.
- Distinguish microtubule-destabilising agents from microtubule-stabilising agents, in terms of mechanism and give one example drug class for each.
- What cell cycle phases do microtubule polymerisation inhibitors act across, and why?
- A patient on a taxane develops a hypersensitivity reaction. What pre-treatment reduces this risk, and what class of drug interactions should be anticipated?
- Describe how vinca alkaloids cause cell cycle arrest, and name one serious local adverse effect associated with them.
- Describe the mechanism of action of topoisomerase inhibitors and the cell cycle phase in which they act.
- A patient receiving doxorubicin develops signs of cardiomyopathy. What is the underlying dose relationship, and what drug can be used to reduce this risk?
- List the three other types of systemic cancer therapy mentioned besides classical chemotherapy, and state one advantage and one disadvantage of targeted therapies compared with chemotherapy.
- Explain why combination chemotherapy regimens often use drugs from different classes that act at different points of the cell cycle.
Answers
Reveal answers
- Curative (e.g. some liquid/blood cell tumours), life extension (e.g. advanced lung or ovarian cancer), or palliation.
- PFS is survival time or time to tumour progression; median PFS is the midpoint of this across patients, some progressing before it and some after. Treatment is usually stopped due to lack of efficacy or intolerable toxicity.
- Alkylating agents add ethyl/methyl groups to DNA bases, causing intra- or inter-strand crosslinking, DNA damage and apoptosis; because they are cell cycle-independent and act at any point in the cycle, the fraction of cells killed rises directly with dose rather than being limited to a specific phase.
- True alkylating agents (e.g. cyclophosphamide) transfer an alkyl group from one molecule to another; platinum-based drugs (cisplatin, carboplatin, oxaliplatin) cause crosslinking without possessing an alkyl group themselves, so are “alkylating-like”.
- Cumulative, dose-dependent effects: nausea, myelosuppression, stomach-ache, darkening of skin/nails, alopecia, fatigue; serious/rare effects, especially at high dose: acute myeloid leukaemia, haemorrhagic cystitis, permanent infertility.
- Systemic platinum pre-treatment improves local tumour control by potentiating radiation. Radiation relies on oxygen to generate reactive oxygen species, so hypoxic cells (with less oxygen) are less affected; platinum appears to produce a similar oxygen-dependent effect.
- Antifolates (e.g. methotrexate) and nucleobase analogues, split into purine analogues (e.g. azathioprine) and pyrimidine analogues (e.g. fluorouracil). The class is cell cycle-dependent because it only acts in S-phase, when DNA synthesis occurs.
- Methotrexate inhibits dihydrofolate reductase, blocking folic acid metabolism and so preventing synthesis of thymidine, which is needed for DNA synthesis.
- 5-FU inhibits thymidylate synthase, blocking thymidine synthesis needed for DNA replication. Its very narrow therapeutic index means life-threatening toxicity can occur at doses close to the therapeutic dose, requiring careful dosing.
- Destabilising agents (vinca alkaloids) prevent microtubule assembly/polymerisation, blocking chromosome division and inducing apoptosis. Stabilising agents (taxanes) prevent microtubule disassembly/depolymerisation, blocking mitotic progression and triggering the mitotic checkpoint, apoptosis and/or cell cycle stasis.
- They act across S-G2/M, because they bind tubulin during S-phase, which then prevents the microtubule formation required for M-phase.
- Pre-treatment with dexamethasone reduces hypersensitivity risk; because taxanes are metabolised by CYP3A4, interactions with other CYP3A4 substrates or inducers should be anticipated.
- Vinca alkaloids block microtubule assembly needed for chromosome separation during anaphase, causing M-phase cell cycle arrest; they are also strong vesicants (blistering agents) if extravasated.
- They inhibit DNA replication in S-phase (by interfering with topoisomerase’s role in relieving supercoiling tension from strand unwinding), leading to cell death or G2-phase arrest.
- Cardiomyopathy risk from doxorubicin is dose-dependent; dexrazoxane, which traps free radicals, can be used to reduce this cardiotoxicity.
- Receptor tyrosine kinase inhibitors, immunotherapies, and hormonal therapies. Targeted therapies are generally more effective with fewer side effects and are easier to administer, but are often extremely expensive.
- Different classes act at different, specific points of the cell cycle (e.g. alkylating agents cell cycle-independently, antimetabolites and topoisomerase inhibitors in S-phase, microtubule inhibitors across S-G2/M), so combining drugs targeting different phases increases the fraction of cycling tumour cells that can be killed.