Inhibition of nuclear factor-{kappa}B and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma

Journal Article · Thu Dec 01 00:00:00 EST 2005 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2005.0· OSTI ID:20788232

Van Waes, Carter ^[1]; Chang, Angela A ^[1]; Lebowitz, Peter F ^[2]; Druzgal, Colleen H ^[1]; Chen, Zhong ^[1]; Elsayed, Yusri A ^[2]; Sunwoo, John B ^[1]; Rudy, Susan ^[1]; Morris, John C ^[3]; Mitchell, James B ^[4]; Camphausen, Kevin ^[4]; Gius, David ^[4]; Adams, Julian ^[5]; Sausville, Edward A ^[2]; Conley, Barbara A ^[2]

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1. Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD (United States)
2. Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD (United States)
3. Metabolism Branch, National Cancer Institute, Bethesda, MD (United States)
4. Radiation Oncology Sciences Program, National Cancer Institute, Bethesda, MD (United States)
5. Millennium Pharmaceuticals, Cambridge, MA (United States)

Purpose: To examine the effects the proteasome inhibitor bortezomib (VELCADE) on transcription factor nuclear factor-{kappa}B (NF-{kappa}B) and target genes and the feasibility of combination therapy with reirradiation in patients with recurrent head-and-neck squamous cell carcinoma (HNSCC). Methods and Materials: The tolerability and response to bortezomib 0.6 mg/m{sup 2} and 0.9 mg/m{sup 2} given twice weekly concurrent with daily reirradiation to 50-70 Gy was explored. Blood proteasome inhibition and NF-{kappa}B-modulated cytokines and factors were measured. Proteasome inhibition, nuclear localization of NF-{kappa}B phospho-p65, apoptosis, and expression of NF-{kappa}B-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/m{sup 2} and 0.9 mg/m{sup 2}/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/m{sup 2} was 32%, 16%, and 7% and after 0.9 mg/m{sup 2} was 56%, 26%, and 14%, respectively. Differences in proteasome and NF-{kappa}B activity, apoptosis, and expression of NF-{kappa}B-modulated cell cycle, apoptosis, and angiogenesis factor mRNAs were detected in 2 patients with minor tumor reductions and in serum NF-{kappa}B-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/m{sup 2} and the threshold of proteasome inhibition. Although this regimen with reirradiation is not feasible, bortezomib induced detectable differences in NF-{kappa}B localization, apoptosis, and NF-{kappa}B-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.

• OSTI ID: 20788232
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 63, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2005.05.007; PII: S0360-3016(05)00820-5; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
APOPTOSIS
BIOPSY
BLOOD
CARCINOMAS
CELL CYCLE
COMBINED THERAPY
GENES
HEAD
HYPOTENSION
INHIBITION
LYMPHOKINES
NECK
PATIENTS
RADIATION DOSES
RADIOTHERAPY
TRANSCRIPTION FACTORS