Traditional cytotoxic chemotherapy delivers DNA-damaging insults that proliferating cells (cancer cells, plus bone marrow + GI + hair follicle) cannot repair in time. Mechanisms: (1) DNA cross-linking — cisplatin/carboplatin form Pt-DNA adducts, cyclophosphamide forges interstrand alkyl bridges; (2) Topoisomerase poisoning — doxorubicin traps Top2-DNA complexes; (3) Microtubule disruption — paclitaxel stabilizes microtubules → arrests mitosis at metaphase; (4) Antimetabolites — 5-FU is a thymidylate synthase inhibitor (block dTMP synthesis), methotrexate is DHFR inhibitor (broader folate-cycle block — purine + pyrimidine + amino-acid synthesis). Immune-modulating offshoots: mycophenolate (IMPDH inhibitor → de novo purine synthesis block, T/B cell selective); azathioprine (6-MP prodrug, thiopurine → DNA incorporation + de novo purine block).
Organ Systems
immune-hematologic
Pathway Steps
cellular-dna → dna-damage — via cross-links, strand breaks, antimetabolite incorporation. Cellular DNA is continuously damaged by endogenous (ROS, replication errors) and exogenous (radiation, chemotherapy) insults. Many cytotoxic cancer therapies work precisely by inflicting unrepairable DNA damage — exploiting tumor cells’ high proliferation and often-defective repair.
dna-damage → apoptosis-mitotic-catastrophe — via unrepairable damage → p53-dependent or independent cell death. When damage exceeds repair capacity, the DNA-damage response (ATM/ATR-p53) triggers death by apoptosis or mitotic catastrophe. This is the intended endpoint of genotoxic chemo/radiotherapy — and defective checkpoints (e.g. p53 loss) underlie both resistance and the therapeutic window.
Known Modulators
doxorubicin (inhibitor) — topoisomerase II (DNA-Top2 covalent complex). anthracycline; cardiomyopathy cumulative-dose-limited (~450 mg/m²); dexrazoxane cardioprotection in late therapy