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.