PharmacologyTier 1Medical Sciences concept

Cell cycle phases and drug-induced cell cycle arrest (tamoxifen and other agents)

Core concept

G1 -> S -> G2 -> M, with G0 as the quiescent exit
- G1 growth, checkpoint at the restriction point (Rb)
- S DNA replication
- G2 checkpoint for replication fidelity
- M mitosis
The Rb-E2F switch is the gate
- Growth signal -> cyclin D -> CDK4/6 -> phosphorylates Rb -> E2F released -> S-phase genes
- p53 senses DNA damage -> p21 -> CDK inhibition -> G1 arrest or apoptosis
Cell-cycle-specific drugs kill only cycling cells in a given phase; non-specific agents kill in any phase including G0
- Specific -> schedule-dependent (infusion), non-specific -> dose-dependent (bolus)

Phase	Agents
G0/G1 arrest	Tamoxifen and aromatase inhibitors, CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib), corticosteroids, asparaginase
S	Antimetabolites - methotrexate, 5-FU, capecitabine, cytarabine, gemcitabine, hydroxyurea; topoisomerase I inhibitors (irinotecan, topotecan)
G2	Bleomycin, etoposide (topo II)
M	Vinca alkaloids (depolymerise microtubules), taxanes (stabilise microtubules), colchicine
Non-specific	Alkylating agents, platinums, anthracyclines, nitrosoureas

Tamoxifen - blocks ER-driven transcription of cyclin D1 and c-myc -> Rb stays hypophosphorylated -> G0/G1 arrest, cytostatic rather than cytotoxic
CDK4/6 inhibitors - prevent Rb phosphorylation directly -> G1 arrest
- Require an intact Rb - Rb-null tumours are resistant
- Neutropenia is the dose-limiting toxicity, and is reversible marrow G1 arrest, not cytotoxicity - shorter and less infection-prone than chemotherapy neutropenia
Vincristine vs vinblastine - both M phase; vincristine = neuropathy, vinblastine = myelosuppression
Vinca alkaloids are fatal if given intrathecally - IV bag, never a syringe
Slowly proliferating tumours have a low growth fraction -> relatively resistant to cycle-specific agents

ER+/HER2- metastatic breast cancer: aromatase inhibitor or fulvestrant + CDK4/6 inhibitor is standard first-line - the two arrest mechanisms are synergistic
- On progression: everolimus (mTOR) + endocrine, or alpelisib if PIK3CA-mutant
Cell-cycle specificity explains the toxicity pattern - marrow, gut mucosa and hair follicles have the highest growth fraction
Cytostatic G1 arrest with tamoxifen explains why response is slow and measured in disease control, not shrinkage
Tumour lysis syndrome follows rapid kill of high-growth-fraction tumours (Burkitt, ALL, high-grade NHL)
Ribociclib prolongs QT - baseline and on-treatment ECG

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