title: Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma.
abstract: OBJECTIVE
  To examine the effects the proteasome inhibitor bortezomib (VELCADE) on transcription factor nuclear factor-kappaB (NF-kappaB) and target genes and the feasibility of combination therapy with reirradiation in patients with recurrent head-and-neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  The tolerability and response to bortezomib 0.6 mg/m2 and 0.9 mg/m2 given twice weekly concurrent with daily reirradiation to 50-70 Gy was explored. Blood proteasome inhibition and NF-kappaB-modulated cytokines and factors were measured. Proteasome inhibition, nuclear localization of NF-kappaB phospho-p65, apoptosis, and expression of NF-kappaB-modulated mRNAs were compared in serial biopsies from accessible tumors.
  
  
  RESULTS
  The maximally tolerated dose was exceeded, and study was limited to 7 and 2 patients, respectively, given bortezomib 0.6 mg/m2 and 0.9 mg/m2/dose with reirradiation. Grade 3 hypotension and hyponatremia were dose limiting. Mucositis was Grade 3 or less and was delayed. The mean blood proteasome inhibition at 1, 24, and 48 h after 0.6 mg/m2 was 32%, 16%, and 7% and after 0.9 mg/m2 was 56%, 26%, and 14%, respectively. Differences in proteasome and NF-kappaB activity, apoptosis, and expression of NF-kappaB-modulated cell cycle, apoptosis, and angiogenesis factor mRNAs were detected in 2 patients with minor tumor reductions and in serum NF-kappaB-modulated cytokines in 1 patient with a major tumor reduction.
  
  
  CONCLUSIONS
  In combination with reirradiation, the maximally tolerated dose of bortezomib was exceeded at a dose of 0.6 mg/m2 and the threshold of proteasome inhibition. Although this regimen with reirradiation is not feasible, bortezomib induced detectable differences in NF-kappaB localization, apoptosis, and NF-kappaB-modulated genes and cytokines in tumor and serum in association with tumor reduction, indicating that other schedules of bortezomib combined with primary radiotherapy or reirradiation may merit future investigation.
authors: Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA. vanwaesc@nidcd.nih.gov
authors: Carter
authors: C
authors: Van Waes
authors: Angela A
authors: AA
authors: Chang
authors: Peter F
authors: PF
authors: Lebowitz
authors: Colleen H
authors: CH
authors: Druzgal
authors: Zhong
authors: Z
authors: Chen
authors: Yusri A
authors: YA
authors: Elsayed
authors: John B
authors: JB
authors: Sunwoo
authors: Susan F
authors: SF
authors: Rudy
authors: John C
authors: JC
authors: Morris
authors: James B
authors: JB
authors: Mitchell
authors: Kevin
authors: K
authors: Camphausen
authors: David
authors: D
authors: Gius
authors: Julian
authors: J
authors: Adams
authors: Edward A
authors: EA
authors: Sausville
authors: Barbara A
authors: BA
authors: Conley
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D016207:Cytokines / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000628:therapy*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D013280:Stomatitis / Q000209:etiology; D051996:Transcription Factor RelA / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016207:Cytokines; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D051996:Transcription Factor RelA; D000069286:Bortezomib