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)

We present our experience with a combination chemotherapy regimen consistin g of ranimustine (MCNU) and recombinant human mutant tumor necrosis factor- alpha (TNF-SAM2) for malignant astrocytomas. We also investigated the expre ssion of nuclear factor-kappa B (NF-kappa B), tumor necrosis factor recepto r type I (TNFR1), and c-Myc in human astrocytoma tissues in vivo in patient s a eared with TNF-SAM2 by RT-PCR and immunohistochemical analysis to exami ne whether there is an)? correlation between the prognosis of these patient s after TNF-SAM2 treatment and the expression of these factors. The initial regimens were prescribed as adjuvant therapy in conjunction with radiother apy following standard surgical treatment. Newly diagnosed patients were tr eated with lip to four cycles of this regimen (TNF-SAM2, MCNU, and radiothe rapy: TMR group). Four patients with anaplastic astrocytomas and 13 patient s with glioblastomas (II men and 6 women) aged 24 to 68 years (median 55.7 years) Mere 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% a nd 100% with anaplastic astrocytomas, and 69.2% and 30.8% with glioblastoma s. Grade 3 and 4 hematological toxicities were not experienced None of the patients experienced a treatment delay due to toxicity All other acute toxi cities were anticipated and manageable. Two of the 4 patients with anaplast ic 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 la of the 13 patients with glioblastoma, and c-Myc, TNFRl and NF-kappa B were detected in 9, 7, and 8 of these la patients' surgical specimens, respectiv ely. Despite the small number of patients, these clinical results suggest t hat combined chemotherapy with mutant TNF-alpha (TNF-SAM2) was safe and wel l 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. Altho ugh there was no significant correlation between thc efficacy of TNF-SAM2 t reatment and the expression of NF-kappa B, our results suggest that the con stitutive activation of NF-kappa B subunits in malignant astrocytomas, espe cially in glioblastoma, could be associated with resistance to TNF-alpha im munotherapy. These results could offer new insight to help establish a new chemotherapeutic strategy for malignant astrocytomas.