ANTITUMOR EFFECT OF EXOGENOUS ENDOGENOUS TNF (EET) THERAPY WITH CYCLOPHOSPHAMIDE ON C6 GLIOMA IN RAT

We earlier reported that endogenous TNF could be induced in mice as we ll as in patients by successive administration of exogenous TNF as a p rimer and OK-432 as a trigger, and we termed this exogenous/endogenous TNF (EET) therapy. We studied the effect of EET therapy with cyclopho sphamide (CY) on tumor-transplanted rats. In order to induce endogenou s TNF, 5x10(5) U/kg of recombinant human TNF-S(AM2) (rTNF; 5x10(6) U/m g protein) was injected intravenously (iv) as a primer followed by inj ection of 25 KE/kg of OK-432 as a trigger. TNF activity induced in ser um was about 500 U/ml. Only 1 U/g of TNF was detected in the brain. To evaluate the antitumor effect, C6 glioma cells (1.6x10(4) cells/5 mul ) was transplanted into the brain. On day 7 of the transplantation, th e rats were administered iv with CY (75 mg/kg), treated with EET thera py 7 days thereafter, and survival days were checked. No clear differe nce in survival days was observed between the rats treated with the EE T 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 o f CY and EET continued to survive. The histological examination on day 44 revealed necrotic changes at the tumor lesions in all of the survi ving rats, and the animals were evaluated as completely cured. These r esults suggest that applied treatment based on the EET therapy will be also effective against malignant brain tumors.