Antitumor Effect of Exogenous/Endogenous TNF (EET) Therapy with Cyclophosphamide on C6 Glioma in Rat

Abstract

We earlier reported that endogenous TNF could be induced in mice as well as in patients by successive administration of exogenous TNF as a primer and OK-432 as a trigger, and we termed this exogenous/endogenous TNF (EET) therapy. We studied the effect of EET therapy with cyclophosphamide (CY) on tumor-transplanted rats. In order to induce endogenous TNF, 5 x 10(5) U/kg of recombinant human TNF-S(AM2) (rTNF; 5.6x10(6) U/mg protein) was injected intravenously (iv) as a primer followed by injection of 25 KE/kg of OK-432 as a trigger. TNF activity induced in serum was about 500 U/ml. Only 1 U/g of TNF was detected in the brain. To evaluate the antitumor effect, C6 glioma cells (1.6 x 10(4) cell/5 microliters) was transplanted into the brain. On day 7 of the transplantation, the rats were administered iv with CY (75 mg/kg), treated with EET therapy 7 days thereafter, and survival days were checked. No clear difference in survival days was observed between the rats treated with the EET and the control group. Three rats out of 6 treated with CY survived for more than 40 days, and all the rats treated with the combination of CY and EET continued to survive. The histological examination on day 44 revealed necrotic changes at the tumor lesions in all of the surviving rats, and the animals were evaluated as completely cured. These results suggest that applied treatment based on the EET therapy will be also effective against malignant brain tumors.

Expression of Nuclear Factor-κB, Tumor Necrosis Factor Receptor Type 1, and c-Myc in Human Astrocytomas

“…To determine whether TNF-SAM 2 is useful for the treatment of malignant gliomas, we previously studied the effect of TNF-SAM 2 with an alkylating agent on rat C6 experimental glioma, and observed a dramatic antitumor effect in vivo. 24) We also reported early results in patients treated with TNF-SAM 2 as part of initial therapy for glioblastoma, but the preliminary results of TNF-SAM 2 treatment for malignant astrocytomas, especially for glioblastoma, achieved only a modest level of significance. 7) TNF-a triggers a biochemical pathway that leads to programmed cell death, i.e., apoptosis, but also activates a key molecule that can block this apoptotic pathway, which reflects the dual nature of TNF-a.…”