A 65-year-old man with relapsed multiple myeloma is started on bortezomib. The molecular basis of its cytotoxicity is:
- A Cross-linking of immunoglobulin heavy chain genes at the switch region
- B Irreversible inhibition of thymidylate synthase in rapidly dividing plasma cells
- C Reversible inhibition of the 26S proteasome, causing accumulation of misfolded proteins and apoptosis ✓
- D Antagonism of IL-6 signalling at the gp130 receptor
Correct answer: C. Reversible inhibition of the 26S proteasome, causing accumulation of misfolded proteins and apoptosis
Explanation
Bortezomib is a boronic acid dipeptide that reversibly inhibits the chymotrypsin-like site of the 26S proteasome. Myeloma cells produce large amounts of misfolded immunoglobulin, so proteasome blockade triggers overwhelming ER stress and caspase-dependent apoptosis, giving selective toxicity to plasma cells. Its characteristic limiting toxicity is painful peripheral neuropathy. Thymidylate synthase and IL-6 pathways are unrelated to its mechanism.
Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.