Table 1

Mechanisms of action and resistance to therapies

1. 5-FU: An antimetabolite (interferes with DNA/RNA synthesis) that is cell-cycle specific (synthetic periods) because its metabolite, FdUMP,a binds/inhibits TS. It can be blocked by:
Enzyme deregulation/poor activation
Alternative thymidine synthetic pathways
 Alterations in the binding site of TS
Enzyme gene amplification (increased levels of TS)
Increased pool of competing base-precursors (dUMP)
Increased degradation of FdUMP (dihydropyrimidine de-hydrogenase)
2. Platinum-containing drugs: An alkylating agent that is non-cell-cycle specific (G1-M ≫ G0). Cisplatin and carboplatin irreversibly cross-links DNA strands with platinum and blocks DNA repair after damage, signaling apoptosis. Cisplatin resistance:
Improved DNA repair
 Mismatch repair proteins that recognize DNA damage and attempt repairs; if unable to repair, they signal the apoptosis cascade.
   hMSH-2 (human MutS homolog-2)
   hMLH-1 (human MutL homolog-1)
   ERCC-1 (excision repair −1)
Increased intracellular levels of heavy metal chelators:
Increased intracellular glutathione levels
  GST-π binds to platinum and allows exportation from cytosol using a MDR (P-gp) energy-dependent efflux pump mechanism.
3. Irradiation: Irradiation photons release excited electrons: H2O + O2 to form O3-OH-free radicals. These cause DNA double-strand breaks “reproductive death” and activate the apoptotic pathway. Radiation is blocked by:
Oxygen free radical scavengers (i.e., glutathione, reactivated by GST-π)
Lack of available substrates (hypoxia)
  • a FdUMP, 5-fluoro-dUMP.