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.
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.
Van Waes
Carter
C
Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892, USA. vanwaesc@nidcd.nih.gov
Chang
Angela A
AA
Lebowitz
Peter F
PF
Druzgal
Colleen H
CH
Chen
Zhong
Z
Elsayed
Yusri A
YA
Sunwoo
John B
JB
Rudy
Susan F
SF
Morris
John C
JC
Mitchell
James B
JB
Camphausen
Kevin
K
Gius
David
D
Adams
Julian
J
Sausville
Edward A
EA
Conley
Barbara A
BA
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
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016207:Cytokines; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D051996:Transcription Factor RelA; D000069286:Bortezomib