Chemotherapy Mechanisms of Action: A Complete FRCR Part 1 Pharmacology Guide
Master the mechanisms of action for all major chemotherapy drug classes including alkylating agents, antimetabolites, topoisomerase inhibitors, and mitotic inhibitors for FRCR Part 1.
Understanding chemotherapy mechanisms of action is essential for FRCR Part 1 Clinical Pharmacology. This guide covers the major drug classes, their cellular targets, and key toxicities you need to know.
Classification Overview
Chemotherapy agents are classified by mechanism of action:
- Alkylating agents - damage DNA directly
- Antimetabolites - interfere with DNA/RNA synthesis
- Topoisomerase inhibitors - disrupt DNA replication enzymes
- Anti-tumour antibiotics - multiple mechanisms including intercalation
- Mitotic inhibitors - disrupt microtubule function
- Platinum compounds - form DNA crosslinks
1. Alkylating Agents
Mechanism: Transfer alkyl groups (R-CH₂⁺) to nucleophilic sites on DNA bases, particularly the N7 position of guanine. This causes:
- DNA crosslinks (interstrand and intrastrand)
- DNA strand breaks
- Abnormal base pairing leading to miscoding
Cell Cycle: Non-phase specific (kill cells in all phases)
Subclasses and Examples:
- Nitrogen mustards: Cyclophosphamide, ifosfamide, chlorambucil, melphalan
- Nitrosoureas: Carmustine (BCNU), lomustine (CCNU) - cross blood-brain barrier
- Alkyl sulfonates: Busulfan
- Triazenes: Temozolomide, dacarbazine
Key Toxicities:
- Myelosuppression (dose-limiting)
- Haemorrhagic cystitis (cyclophosphamide/ifosfamide) - prevented by mesna
- Pulmonary fibrosis (busulfan, carmustine)
- Secondary malignancies (treatment-related MDS/AML)
- Infertility
2. Antimetabolites
Mechanism: Structurally similar to normal metabolites; interfere with DNA/RNA synthesis by:
- Inhibiting enzymes required for nucleotide synthesis
- Incorporating into DNA/RNA causing chain termination
Cell Cycle: S-phase specific
Subclasses and Examples:
Folate antagonists:
- Methotrexate - inhibits dihydrofolate reductase (DHFR)
- Pemetrexed - inhibits multiple folate-dependent enzymes
- Leucovorin (folinic acid) rescues normal cells from methotrexate toxicity
Pyrimidine analogues:
- 5-Fluorouracil (5-FU) - inhibits thymidylate synthase
- Capecitabine - oral prodrug of 5-FU
- Cytarabine (Ara-C) - inhibits DNA polymerase
- Gemcitabine - inhibits DNA polymerase, incorporated into DNA
Purine analogues:
- 6-Mercaptopurine (6-MP)
- Fludarabine
- Cladribine
Key Toxicities:
- Myelosuppression
- Mucositis (5-FU, methotrexate)
- Hand-foot syndrome (5-FU, capecitabine)
- Hepatotoxicity (methotrexate - chronic use)
- Neurotoxicity (high-dose cytarabine)
3. Topoisomerase Inhibitors
Mechanism: Inhibit topoisomerase enzymes required for DNA unwinding during replication:
Topoisomerase I inhibitors:
- Stabilise DNA-topoisomerase I complex
- Prevent DNA re-ligation after single-strand breaks
- Examples: Irinotecan, topotecan (camptothecin derivatives)
Topoisomerase II inhibitors:
- Stabilise DNA-topoisomerase II complex
- Prevent re-ligation of double-strand breaks
- Examples: Etoposide, teniposide (podophyllotoxins)
Cell Cycle: S and G2 phase specific
Key Toxicities:
- Myelosuppression
- Diarrhoea (irinotecan - can be severe)
- Secondary leukaemia (topoisomerase II inhibitors)
4. Anti-tumour Antibiotics (Anthracyclines)
Mechanism: Multiple mechanisms:
- DNA intercalation
- Topoisomerase II inhibition
- Free radical generation
- Inhibition of DNA and RNA synthesis
Examples: Doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin
Key Toxicities:
- Cardiotoxicity: Cumulative dose-dependent cardiomyopathy (lifetime limit ~450-550 mg/m² for doxorubicin)
- Myelosuppression
- Mucositis
- Alopecia
- Secondary malignancies
Non-anthracycline antibiotics:
- Bleomycin - causes single and double-strand DNA breaks; pulmonary fibrosis (dose-limiting)
- Mitomycin C - alkylating agent properties
5. Mitotic Inhibitors
Mechanism: Disrupt microtubule function, preventing mitotic spindle formation
Cell Cycle: M-phase specific
Vinca Alkaloids (inhibit microtubule polymerisation):
- Vincristine, vinblastine, vinorelbine
- Derived from periwinkle plant (Catharanthus roseus)
- Key toxicity: Peripheral neuropathy (vincristine)
Taxanes (stabilise microtubules, prevent depolymerisation):
- Paclitaxel, docetaxel, cabazitaxel
- Derived from Pacific yew tree (Taxus brevifolia)
- Key toxicities: Peripheral neuropathy, myelosuppression, hypersensitivity reactions
6. Platinum Compounds
Mechanism: Form platinum-DNA adducts causing intrastrand and interstrand crosslinks
Examples: Cisplatin, carboplatin, oxaliplatin
Key Toxicities:
- Nephrotoxicity (cisplatin) - requires vigorous hydration
- Ototoxicity (cisplatin)
- Peripheral neuropathy (cisplatin, oxaliplatin)
- Myelosuppression (carboplatin dose-limiting)
- Severe nausea/vomiting (highly emetogenic)
Drug Resistance Mechanisms
Cancer cells develop resistance via:
- Drug efflux: P-glycoprotein (MDR1) pumps drugs out of cells
- Target alteration: Increased expression or mutation of drug targets
- DNA repair upregulation: Enhanced repair of drug-induced damage
- Drug inactivation: Increased glutathione/antioxidant levels
- Apoptosis evasion: Altered Bcl-2 family expression
Key Exam Points
- Alkylating agents: non-phase specific, DNA crosslinks, secondary leukaemia risk
- Antimetabolites: S-phase specific, inhibit nucleotide synthesis
- Methotrexate inhibits DHFR; leucovorin provides rescue
- 5-FU inhibits thymidylate synthase
- Anthracyclines: cumulative cardiotoxicity (450-550 mg/m² limit)
- Vincristine: neurotoxicity; bleomycin: pulmonary fibrosis
- Cisplatin: nephrotoxicity requiring hydration
- P-glycoprotein mediates multidrug resistance
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