title: Correlation of the expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1 (TNFR 1) and c-Myc with the clinical course in the treatment of malignant astrocytomas with recombinant mutant human tumor necrosis factor-alpha (TNF-SAM2).
abstract: We present our experience with a combination chemotherapy regimen consisting of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor-alpha (TNF-SAM2) for malignant astrocytomas. We also investigated the expression of nuclear factor-kappa B (NF-kappa B), tumor necrosis factor receptor type 1 (TNFR1), and c-Myc in human astrocytoma tissues in vivo in patients treated with TNF-SAM2 by RT-PCR and immunohistochemical analysis to examine whether there is any correlation between the prognosis of these patients after TNF-SAM2 treatment and the expression of these factors. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. Newly diagnosed patients were treated with up to four cycles of this regimen (TNF-SAM2, MCNU, and radiotherapy: TMR group). Four patients with anaplastic astrocytomas and 13 patients with glioblastomas (11 men and 6 women) aged 24 to 68 years (median 55.7 years) were eligible and evaluated for response and toxicity. The estimated median survival time was 354 weeks with anaplastic astrocytomas, and 79 +/- 10.8 weeks with glioblastomas. One- and 2-year survival rates were 100% and 100% with anaplastic astrocytomas, and 69.2% and 30.8% with glioblastomas. Grade 3 and 4 hematological toxicities were not experienced. None of the patients experienced a treatment delay due to toxicity. All other acute toxicities were anticipated and manageable. Two of the 4 patients with anaplastic astrocytomas were positive for the expression of NF-kappa B, TNFRl and c-Myc. The expression of NF-kappa B, TNFR1 and c-Myc was investigated in 10 of the 13 patients with glioblastoma, and c-Myc, TNFRl and NF-kappa B were detected in 9, 7, and 8 of these 10 patients' surgical specimens, respectively. Despite the small number of patients, these clinical results suggest that combined chemotherapy with mutant TNF-alpha (TNF-SAM2) was safe and well tolerated, and may confer a survival benefit for patients with malignant astrocytomas in comparison to our historical controls. Its effectiveness as an adjuvant therapy deserves a properly stratified randomized trial. Although there was no significant correlation between the efficacy of TNF-SAM2 treatment and the expression of NF-kappa B, our results suggest that the constitutive activation of NF-kappa B subunits in malignant astrocytomas, especially in glioblastoma, could be associated with resistance to TNF-alpha immunotherapy. These results could offer new insight to help establish a new chemotherapeutic strategy for malignant astrocytomas.
authors.affiliation: Department of Neurosurgery, Fukuoka University School of Medicine, Japan. masaaki@msat.fukuoka-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Fukushima
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: H
authors.initials: H
authors.lastname: Tsugu
authors.forename: H
authors.initials: H
authors.lastname: Kimura
authors.forename: G
authors.initials: G
authors.lastname: Soma
authors.forename: M
authors.initials: M
authors.lastname: Tomonaga
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D015703:Antigens, CD; D017931:DNA Primers; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha