General concepts / Resistance / Mechanisms
RESISTANCE MECHANISMS
- can be broadly divided into two types:
-
alterations that affect the mechanism of action of the drugs:
- increased DNA repair: crosslinking agents, bleomycin
- formation of trapping agents: crosslinking agents
- changes in target proteins (esp. enzymes): drugs that prevent DNA synthesis, some natural products, signal transduction inhibitors, antibodies
- alterations that affect drug concentrations INSIDE THE TUMOUR CELL:
- decreased activation of prodrugs: 5-FLUOROURACIL, CYCLOPHOSPHAMIDE, IRINOTECAN/TOPOTECAN
- increased inactivation: antimetabolites (esp. purine analogues)
- decreased accumulation:
- decreased transport into the cell: folate analogues, MECHLORETHAMINE, platins
- increased export from the cell due upregulation of efflux transporters (esp. increased P-glycoprotein):
natural products (esp. anthracyclines, vinca alkaloids, taxanes, epipodophyllotoxins)
- this is an important cause of multidrug resistance