Pharmacology chapters
Anticancer drugs and immunosuppressants
How anticancer drugs work on the cell cycle, the main classes (alkylating agents, antimetabolites, antitumour antibiotics, plant alkaloids, platinum drugs, hormones and targeted drugs) with their signature toxicities and rescue agents, and the immunosuppressants used in transplants and autoimmune disease.
In 30 seconds
- Most cytotoxics hit rapidly dividing cells, so shared toxicities are bone marrow suppression, mucositis, hair loss, nausea and vomiting, infertility and tumour lysis syndrome; some are cell cycle-specific (antimetabolites in S phase, vinca alkaloids and taxanes in M phase, bleomycin in G2).
- Signature toxicities and rescues: cyclophosphamide → haemorrhagic cystitis (acrolein; mesna); methotrexate → marrow and mucosal toxicity (folinic acid rescue), liver fibrosis, lung toxicity; doxorubicin → cardiotoxicity (dilated cardiomyopathy; dexrazoxane); bleomycin → pulmonary fibrosis; vincristine → peripheral neuropathy (spares marrow); cisplatin → nephrotoxicity, ototoxicity and severe vomiting; 6-mercaptopurine dose must be cut with allopurinol.
- Targeted and hormonal: imatinib (BCR-ABL, CML), trastuzumab (HER2, cardiotoxic), rituximab (CD20), tamoxifen (oestrogen receptor; endometrial cancer and clots); immunosuppressants ciclosporin/tacrolimus (calcineurin inhibitors → nephrotoxicity, hypertension, gum hyperplasia with ciclosporin).
On this page
Principles
- Cytotoxic drugs kill rapidly dividing cells, cancerous or normal.
- Cell cycle-specific drugs act in one phase (useful against fast-growing tumours); cell cycle-non-specific drugs (alkylating agents, platinum, anthracyclines) act in all phases.
- Drugs are combined (different mechanisms and toxicities) in cycles to allow normal tissues to recover.
| Phase | Drugs |
|---|---|
| S phase (DNA synthesis) | Antimetabolites: methotrexate, 5-fluorouracil, 6-mercaptopurine, cytarabine, hydroxyurea |
| G2 | Bleomycin, etoposide |
| M phase (mitosis) | Vinca alkaloids (vincristine, vinblastine), taxanes (paclitaxel) |
Common toxicities
- Bone marrow suppression (neutropenia → infection; thrombocytopenia → bleeding; anaemia). Neutropenic sepsis is an emergency: start IV broad-spectrum antibiotics within an hour.
- Gut: nausea and vomiting, mucositis, diarrhoea.
- Hair loss, infertility, teratogenicity, secondary cancers (leukaemia after alkylating agents).
- Tumour lysis syndrome: when bulky, sensitive tumours (leukaemia, high-grade lymphoma) are killed quickly → hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, acute kidney injury. Prevent with hydration, allopurinol or rasburicase.
- Nausea: ondansetron (5-HT3 antagonist), dexamethasone, aprepitant (NK1 antagonist), metoclopramide.
Main classes
| Class and drug | Mechanism | Signature toxicity | Rescue / prevention |
|---|---|---|---|
| Cyclophosphamide (alkylating agent) | Cross-links DNA (prodrug activated by liver) | Haemorrhagic cystitis (from acrolein), bladder cancer, marrow suppression, SIADH | Mesna, hydration |
| Busulfan | Alkylating | Pulmonary fibrosis, skin pigmentation | (none specific) |
| Nitrosoureas (carmustine, lomustine) | Alkylating; cross the blood-brain barrier | Brain tumours; delayed marrow suppression | (none specific) |
| Cisplatin, carboplatin, oxaliplatin | Platinum: cross-link DNA | Nephrotoxicity, ototoxicity, severe vomiting, neuropathy, low magnesium | Hydration, amifostine; carboplatin less nephrotoxic but more marrow-toxic |
| Methotrexate | Inhibits dihydrofolate reductase → no tetrahydrofolate → no DNA synthesis | Marrow suppression, mucositis, liver fibrosis, pneumonitis, teratogenic | Folinic acid (leucovorin) rescue (bypasses the block); weekly dosing in rheumatoid arthritis with folic acid; avoid with trimethoprim and NSAIDs |
| 5-Fluorouracil | Inhibits thymidylate synthase | Marrow suppression, mucositis, diarrhoea, hand-foot syndrome | (none specific) |
| 6-Mercaptopurine (and azathioprine) | Purine antagonist | Marrow suppression, liver toxicity | Reduce dose with allopurinol (xanthine oxidase breaks 6-MP down); check TPMT activity |
| Cytarabine | Pyrimidine antagonist | Marrow suppression, cerebellar toxicity | (none specific) |
| Doxorubicin (anthracycline) | Intercalates DNA, inhibits topoisomerase II, free radicals | Cardiotoxicity (dose-dependent dilated cardiomyopathy), red urine, marrow suppression | Limit cumulative dose; dexrazoxane; echocardiogram monitoring |
| Bleomycin | DNA strand breaks (free radicals) | Pulmonary fibrosis, skin pigmentation; little marrow suppression | Limit dose; avoid high oxygen |
| Actinomycin D (dactinomycin) | Intercalates DNA | Marrow suppression | Wilms tumour, rhabdomyosarcoma |
| Vincristine | Binds tubulin, blocks microtubule assembly (M phase) | Peripheral neuropathy, constipation (autonomic); marrow-sparing; fatal if given intrathecally | (none specific) |
| Vinblastine | Same | Marrow suppression | (none specific) |
| Paclitaxel (taxanes) | Stabilises microtubules (stops disassembly) | Neuropathy, hypersensitivity, marrow suppression | Premedication with steroids and antihistamines |
| Etoposide | Inhibits topoisomerase II | Marrow suppression, secondary leukaemia | (none specific) |
| Irinotecan | Inhibits topoisomerase I | Diarrhoea | (none specific) |
High-yield
Cyclophosphamide → mesna. Methotrexate → folinic acid. Doxorubicin → heart. Bleomycin → lungs. Vincristine → nerves. Cisplatin → kidneys and ears.
Hormonal therapy
| Drug | Mechanism | Use | Adverse effects |
|---|---|---|---|
| Tamoxifen | Selective oestrogen receptor modulator: blocks receptor in breast, stimulates in endometrium and bone | ER-positive breast cancer (premenopausal) | Hot flushes, endometrial cancer, venous thromboembolism |
| Aromatase inhibitors (letrozole, anastrozole) | Block conversion of androgens to oestrogen | ER-positive breast cancer (postmenopausal) | Osteoporosis, joint pain |
| GnRH agonists (goserelin, leuprolide) | Continuous use → suppress LH/FSH (after an initial flare) | Prostate cancer, breast cancer | Initial tumour flare (cover with anti-androgen) |
| Anti-androgens (bicalutamide, flutamide) | Block androgen receptor | Prostate cancer | Gynaecomastia, liver toxicity |
| Glucocorticoids (prednisolone) | Lymphocyte death | Leukaemia, lymphoma, myeloma | See steroids |
Targeted therapy
| Drug | Target | Use | Notes |
|---|---|---|---|
| Imatinib | BCR-ABL tyrosine kinase | CML, GIST (c-KIT) | Oedema, myelosuppression |
| Trastuzumab | HER2 receptor | HER2-positive breast cancer | Cardiotoxicity (reversible) |
| Rituximab | CD20 on B cells | B-cell lymphomas, CLL, rheumatoid arthritis | Infusion reactions, hepatitis B reactivation |
| Bevacizumab | VEGF | Colorectal and other cancers | Hypertension, bleeding, poor wound healing, gut perforation |
| Cetuximab | EGFR | Colorectal (RAS wild-type), head and neck | Acne-like rash |
| All-trans retinoic acid (ATRA) | PML-RARA | Acute promyelocytic leukaemia | Differentiation syndrome |
Immunosuppressants
| Drug | Mechanism | Main adverse effects |
|---|---|---|
| Ciclosporin | Calcineurin inhibitor → less IL-2 → less T-cell activation | Nephrotoxicity, hypertension, gum hyperplasia, hirsutism, tremor, hyperkalaemia; many CYP3A4 interactions |
| Tacrolimus | Calcineurin inhibitor (binds FKBP) | Nephrotoxicity, neurotoxicity, diabetes; no gum hyperplasia or hirsutism |
| Sirolimus (rapamycin) | mTOR inhibitor | Hyperlipidaemia, poor wound healing, marrow suppression; less nephrotoxic |
| Azathioprine | Purine antagonist (→ 6-MP) | Marrow suppression (check TPMT; reduce with allopurinol), liver toxicity, pancreatitis |
| Mycophenolate mofetil | Inhibits IMP dehydrogenase (purine synthesis in lymphocytes) | Gut upset, marrow suppression, teratogenic |
| Glucocorticoids | Broad anti-inflammatory and immunosuppressive effects | See steroid adverse effects |
| Basiliximab | Anti-CD25 (IL-2 receptor) antibody | Induction therapy in transplants |
All immunosuppressants increase the risk of infections (CMV, fungi, Pneumocystis) and cancers (skin cancer, EBV-related lymphoma).
Exam focus
Expect: cell cycle-specific drugs, common toxicities and neutropenic sepsis, tumour lysis syndrome, signature toxicities and their antidotes (mesna, folinic acid, dexrazoxane), methotrexate and 5-FU mechanisms, 6-MP with allopurinol, bleomycin lungs, vincristine neuropathy, cisplatin kidneys and ears, tamoxifen and aromatase inhibitors, imatinib, trastuzumab and rituximab targets, and ciclosporin vs tacrolimus adverse effects.
Quick revision
- Shared toxicity: marrow, mucosa, hair, nausea, infertility.
- Cyclophosphamide: haemorrhagic cystitis → mesna.
- Methotrexate: DHFR; folinic acid rescue; liver and lung.
- 5-FU: thymidylate synthase. 6-MP: reduce with allopurinol.
- Doxorubicin heart; bleomycin lungs; vincristine nerves; cisplatin kidneys and ears.
- Tamoxifen: endometrial cancer, clots. Imatinib: BCR-ABL. Trastuzumab: HER2. Rituximab: CD20.
- Ciclosporin: nephrotoxicity, hypertension, gum hyperplasia, hirsutism.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
Which drug prevents cyclophosphamide-induced haemorrhagic cystitis?
Mesna, which binds the toxic metabolite acrolein in the bladder, together with good hydration.
What is folinic acid rescue?
Giving folinic acid (leucovorin) after high-dose methotrexate to bypass the blocked dihydrofolate reductase and protect normal cells.
Which anticancer drug causes pulmonary fibrosis?
Bleomycin (busulfan can too).
Why must 6-mercaptopurine be reduced with allopurinol?
Allopurinol blocks xanthine oxidase, which breaks down 6-mercaptopurine, so levels rise and toxicity follows.