Anticancer drugs
Anticancer Drugs and Immunosuppressants: Mechanisms and Toxicity for FCPS Part 1
Cytotoxic classes, cell-cycle targets, targeted therapy, immunotherapy and transplant immunosuppressants for FCPS Part 1, with their signature toxicities. Covers paclitaxel, cisplatin hydration, bleomycin and oxygen, doxorubicin, G-CSF, R-CHOP, calcineurin inhibitors and anti-TNF TB risk.
Why cytotoxics harm normal tissue
Cytotoxic drugs damage DNA or block mitosis. They kill any rapidly dividing cell, so the marrow, gut mucosa, hair follicles and gonads suffer in common, and each drug adds its own organ damage. Tumours shrink because damaged cells undergo apoptosis.
| Cell cycle phase | Drugs acting there |
|---|---|
| S phase | Antimetabolites: methotrexate, 5-FU, cytarabine, 6-mercaptopurine, hydroxyurea |
| G2 | Bleomycin, etoposide (late S and G2) |
| M phase | Vinca alkaloids, taxanes |
| Cycle non-specific | Alkylating agents, platinum drugs, anthracyclines |
Cytotoxic classes
| Class | Examples | Mechanism | Signature toxicity |
|---|---|---|---|
| Alkylating agents | Cyclophosphamide, ifosfamide, chlorambucil, busulfan, nitrosoureas | Cross-link DNA | Cyclophosphamide is a prodrug activated by liver CYP450; its metabolite acrolein causes haemorrhagic cystitis (prevented by mesna), bladder cancer, infertility; busulfan: lung fibrosis |
| Platinum compounds | Cisplatin, carboplatin, oxaliplatin | DNA cross-links | Cisplatin: nephrotoxicity, high-frequency hearing loss, severe vomiting, hypomagnesaemia, neuropathy; carboplatin: marrow suppression; oxaliplatin: cold-induced neuropathy |
| Antimetabolites | Methotrexate (DHFR), 5-FU (thymidylate synthase), cytarabine, mercaptopurine, hydroxyurea | S phase | Methotrexate: mucositis, marrow, liver, pneumonitis (folinic acid rescue); 5-FU: hand–foot syndrome, coronary spasm; cytarabine: cerebellar toxicity |
| Anthracyclines | Doxorubicin, daunorubicin | Topoisomerase II, intercalation, free radicals | Dilated cardiomyopathy (cumulative dose; dexrazoxane; echo); red urine |
| Bleomycin | Free radical DNA breaks | Pulmonary fibrosis; skin pigmentation; little marrow suppression | |
| Vinca alkaloids | Vincristine, vinblastine | Inhibit microtubule assembly | Vincristine: peripheral and autonomic neuropathy (foot drop, constipation), fatal intrathecally; vinblastine: marrow |
| Taxanes | Paclitaxel, docetaxel | Stabilise microtubules, preventing disassembly, so the spindle cannot work and cells arrest in mitosis | Neuropathy, marrow suppression, hypersensitivity |
| Topoisomerase inhibitors | Etoposide (II), irinotecan (I) | DNA breaks | Secondary AML; irinotecan diarrhoea |
| Asparaginase | Depletes asparagine | ALL | Pancreatitis, thrombosis |
- Cisplatin nephrotoxicity is reduced most by IV saline hydration (with magnesium) before and after each dose, which dilutes the drug in the tubule; chloride also limits formation of the toxic aquated species. Carboplatin swaps kidney and ear toxicity for marrow suppression.
- Bleomycin lung injury is driven by free radicals, so high inspired oxygen can precipitate fibrosis even years later: at anaesthesia, keep FiO2 as low as safe and avoid fluid overload.
- Paclitaxel and vincristine both target tubulin but in opposite ways: taxanes freeze microtubules, vincas prevent them forming.
General chemotherapy problems
- Neutropenic sepsis (fever above 38 °C with neutrophils below 0.5 × 10^9/L): IV piperacillin–tazobactam within 1 hour.
- Filgrastim (recombinant G-CSF) stimulates neutrophil precursors to shorten chemotherapy-induced neutropenia and mobilise stem cells.
- Chemotherapy-induced vomiting (worst with cisplatin): 5-HT3 antagonist (ondansetron), NK1 antagonist (aprepitant) and dexamethasone.
- Tumour lysis syndrome (Burkitt lymphoma, ALL): hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, AKI; prevent with fluids and allopurinol or rasburicase (not in G6PD deficiency).
- Extravasation of vesicants (anthracyclines, vincas); infertility (sperm banking); secondary malignancy.
Common regimens
| Cancer | Regimen |
|---|---|
| Diffuse large B-cell lymphoma | R-CHOP: rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisolone |
| Hodgkin lymphoma | ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine |
| Testicular germ cell tumour | BEP: bleomycin, etoposide, cisplatin |
| Colorectal (adjuvant) | 5-FU or capecitabine with oxaliplatin |
Targeted and hormonal therapy
| Drug | Target | Use and notes |
|---|---|---|
| Imatinib | BCR-ABL tyrosine kinase, c-KIT | CML, GIST |
| Trastuzumab | HER2 | HER2-positive breast cancer; reversible cardiotoxicity |
| Rituximab | CD20 | B-cell lymphoma, RA; hepatitis B reactivation |
| Cetuximab | EGFR | RAS wild-type colorectal cancer |
| Osimertinib, erlotinib | EGFR kinase | EGFR-mutant lung adenocarcinoma |
| Bevacizumab | VEGF | Hypertension, poor wound healing, perforation |
| All-trans retinoic acid | Differentiation | Acute promyelocytic leukaemia t(15;17) |
| Bortezomib | Proteasome | Myeloma |
| Checkpoint inhibitors (pembrolizumab, nivolumab: PD-1; ipilimumab: CTLA-4) | Release T-cell brakes | Immune-related colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis; steroids |
| CAR-T cells | CD19 | Cytokine release syndrome (tocilizumab) |
- Hormonal: tamoxifen (endometrial agonist: endometrial cancer and VTE; bone protective), aromatase inhibitors, GnRH agonists, bicalutamide, abiraterone.
Immunosuppressants
| Drug | Mechanism | Key toxicity |
|---|---|---|
| Ciclosporin | Binds cyclophilin; inhibits calcineurin, so NFAT is not dephosphorylated and IL-2 transcription in T cells falls | Nephrotoxicity (afferent vasoconstriction), hypertension, gum hyperplasia, hirsutism, tremor, hyperkalaemia; no marrow suppression |
| Tacrolimus | Binds FKBP-12; calcineurin inhibitor | Nephrotoxicity, neurotoxicity, diabetes |
| Sirolimus, everolimus | mTOR inhibitors | Hyperlipidaemia, poor wound healing, mouth ulcers; not nephrotoxic |
| Azathioprine | Purine antimetabolite (to 6-MP) | Marrow suppression (TPMT deficiency), pancreatitis; allopurinol blocks breakdown: cut dose by 75% |
| Mycophenolate | Inhibits IMP dehydrogenase, depleting guanine in lymphocytes | GI upset, marrow, teratogenic |
| Basiliximab | Anti-CD25 (IL-2 receptor) | Induction |
| Corticosteroids | Broad cytokine suppression | Many; inhaled budesonide acts locally with little systemic suppression |
- Ciclosporin and tacrolimus prevent rejection by calcineurin inhibition; trough levels are monitored, and CYP3A4 inhibitors (macrolides, azoles) raise them.
- Long-term transplant risks: CMV, PCP, cryptococcal meningitis, BK virus, squamous cell skin cancer, EBV-driven post-transplant lymphoproliferative disorder.
- Acute cellular (T cell) rejection in the first months responds to increased immunosuppression; chronic rejection (vascular intimal fibrosis) does not. A graft from an identical twin is not rejected.
Anti-TNF therapy and tuberculosis
- TNF-α activates macrophages and maintains granulomas that wall off dormant *M. tuberculosis*. Blocking it (infliximab, adalimumab) lets granulomas break down and latent TB reactivate, often as extrapulmonary or disseminated disease. Screen for latent TB (IGRA, chest X-ray) and treat before starting.
Remember Mesna for cyclophosphamide, folinic acid for methotrexate, dexrazoxane for doxorubicin, hydration for cisplatin, low oxygen for bleomycin.
Exam trap Vincristine given intrathecally is fatal; it must only be given IV.
Related facts tested with this chapter
- After total gastrectomy, intrinsic factor is lost, so vitamin B12 must be replaced with IM hydroxocobalamin for life (every 3 months).
- Warfarin is guided and monitored by the prothrombin time expressed as INR (target usually 2–3).
How FCPS asks about this
- Paclitaxel mechanism: stabilises microtubules; vincristine prevents their assembly.
- Ciclosporin and tacrolimus: calcineurin inhibition reduces IL-2; ciclosporin gum hyperplasia and hirsutism.
- Reducing cisplatin kidney damage: IV saline hydration; high-tone hearing loss is its ear toxicity.
- Bleomycin patient needing anaesthesia: keep inspired oxygen low.
- First-line DLBCL treatment: R-CHOP.
- Filgrastim: G-CSF that shortens chemotherapy neutropenia.
- Why screen for TB before infliximab: TNF-α maintains granulomas.
Test yourself on this topic
5 of the 54 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
How does mycophenolate mofetil prevent transplant rejection?
Answer: Inhibits IMP dehydrogenase
Mycophenolate (converted to mycophenolic acid) inhibits IMP dehydrogenase, the rate-limiting enzyme of de novo guanine nucleotide synthesis. Lymphocytes lack an efficient salvage pathway, so their proliferation is selectively suppressed. It is used with a calcineurin inhibitor and steroids in transplantation, and in lupus nephritis and other autoimmune diseases. Adverse effects: GI upset, diarrhoea, leucopenia, infections (CMV) and teratogenicity. Azathioprine is a purine analogue; ciclosporin and tacrolimus inhibit calcineurin, blocking IL-2 transcription; sirolimus and everolimus inhibit mTOR; rituximab depletes CD20 B cells.
Immunosuppressant mechanisms
- Mycophenolate: IMP dehydrogenase (guanine synthesis)
- Azathioprine: purine analogue (6-MP)
- Ciclosporin/tacrolimus: calcineurin → IL-2↓
- Sirolimus: mTOR
- Mycophenolate: diarrhoea, teratogenic
Remember Lymphocytes need new guanine; mycophenolate cuts the supply.
Why the other options are wrong
- Inhibits calcineurin Ciclosporin and tacrolimus.
- Blocks mTOR Sirolimus.
- Depletes CD20 B cells Rituximab.
- Alkylates DNA Cyclophosphamide.
A man receiving cisplatin for testicular cancer has a rising creatinine and new difficulty hearing high-pitched sounds. Which measure is most important to reduce the kidney damage during further cycles?
Answer: IV saline hydration
Cisplatin is a platinum compound that cross-links DNA strands. It is concentrated in the proximal tubule, where it causes dose-related tubular injury: rising creatinine, magnesium and potassium wasting (hypomagnesaemia is very common). It also damages cochlear hair cells, causing high-frequency hearing loss and tinnitus, and causes peripheral neuropathy and severe nausea and vomiting (highly emetogenic). Nephrotoxicity is reduced by aggressive saline hydration before and after each dose (chloride also stabilises the drug), avoiding other nephrotoxins (aminoglycosides, NSAIDs, contrast) and replacing magnesium. Amifostine, a thiol, can protect the kidneys. Carboplatin is less nephrotoxic and neurotoxic but more myelosuppressive.
Cisplatin
- DNA cross-linking (platinum)
- Nephrotoxicity: proximal tubule; low Mg²⁺
- Ototoxicity: high-frequency loss
- Highly emetogenic → 5-HT3 + NK1 antagonists
- Protect: saline hydration, Mg replacement, amifostine
Remember Cisplatin: ears, kidneys, nerves, vomiting.
Exam trap Carboplatin swaps kidney and ear toxicity for bone marrow suppression.
Why the other options are wrong
- Furosemide alone Diuretics alone without hydration can worsen dehydration and injury.
- Add an aminoglycoside Aminoglycosides add nephro- and ototoxicity.
- Restrict fluids Fluid restriction increases tubular exposure and damage.
- Give allopurinol Allopurinol prevents urate nephropathy, not cisplatin tubular toxicity.
A man treated with bleomycin for testicular cancer two years ago needs general anaesthesia. What precaution is most important?
Answer: Keep inspired oxygen low
Bleomycin causes dose-related pulmonary toxicity (pneumonitis progressing to fibrosis), its main dose-limiting effect. Patients who have had it are at risk of acute lung injury from high inspired oxygen, even years later, so oxygen is kept to the lowest concentration that maintains adequate saturation, with careful fluid balance. Bleomycin causes little marrow suppression.
Bleomycin
- Toxicity: pulmonary fibrosis
- High oxygen worsens it, even years later
- Little marrow suppression
- Also: skin pigmentation
Remember After bleomycin, go easy on the oxygen.
Exam trap Most chemotherapy drugs suppress the marrow; bleomycin largely spares it.
Why the other options are wrong
- Avoid all opioid analgesics Not specifically needed.
- Avoid suxamethonium Not specifically needed.
- Give 100% oxygen throughout High oxygen can trigger lung injury.
- Avoid all local anaesthetics Not related.
Before starting warfarin, which baseline blood test is used to guide and monitor its effect?
Answer: Prothrombin time with INR
Warfarin blocks vitamin K epoxide reductase, lowering the functional levels of factors II, VII, IX and X (and proteins C and S). Factor VII has the shortest half-life, so the extrinsic pathway test (PT) changes first, and the PT standardised as the INR is used to adjust the dose. A baseline INR is checked before starting. APTT is used for unfractionated heparin.
Monitoring anticoagulants
- Warfarin: PT/INR
- Unfractionated heparin: APTT
- LMWH: anti-Xa if needed
- Factor VII falls first
Remember Warfarin watched by INR.
Exam trap Usual INR target is 2–3; mechanical mitral valves need a higher target.
Why the other options are wrong
- Activated partial thromboplastin time Monitors unfractionated heparin.
- Platelet count only Not a test of warfarin effect.
- Bleeding time Tests platelet function.
- Thrombin time Prolonged by heparin and fibrinogen problems.
Before starting infliximab for rheumatoid arthritis, a patient is screened for latent tuberculosis. Why?
Answer: TNF-α maintains granulomas
TNF-α from macrophages and T cells keeps granulomas organised and helps macrophages kill intracellular organisms. Anti-TNF drugs (infliximab, adalimumab, etanercept, certolizumab, golimumab) can make granulomas break down, reactivating latent TB—often extrapulmonary or disseminated. Patients are screened with interferon-gamma release assay or tuberculin test and chest X-ray, and latent infection is treated (e.g. isoniazid for 6 months or isoniazid plus rifampicin for 3 months) before therapy. Other opportunistic infections: histoplasmosis, listeriosis.
Anti-TNF and TB
- TNF maintains granulomas
- Anti-TNF → reactivation of latent TB
- Screen: IGRA/Mantoux + CXR
- Treat latent TB before starting
Remember Remove TNF, the wall around TB falls.
Why the other options are wrong
- Infliximab infects macrophages Not an infectious agent.
- Infliximab is made from mycobacteria It is a monoclonal antibody.
- TB speeds infliximab metabolism Not the reason.
- Infliximab makes Mantoux positive It does not.
Where this sits in the CPSP syllabus
- Paper 1: Chemotherapy, Anticancer drugs and immunosuppressants
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