LACK OF CELL-CYCLE-SPECIFIC EFFECTS OF RECOMBINANT TUMOR-NECROSIS-FACTOR IN-VIVO

Several in vitro studies have demonstrated that tumor cells arrested i n the G2 and M phases of the cell cycle expressed an increased sensiti vity to the tumor necrosis factor (TNF). The scope of the present stud y was to investigate whether this cycle dependence of TNF effects also exists in vivo. The experiments were performed by using the Lewis lun g carcinoma (LLC), which had been allotransplanted to nude mice. In or der to induce delays of the tumor cell cycle in G2, the animals were t reated with etoposide (40 mg/kg body weight i.p.) or with local radiat ion (15 Gy), each increasing the G2 fraction of the LLC from 10% to 35 % and 50% respectively. For combination therapy with recombinant (r)TN F, the tumor was transplanted to four groups of six mice each, one of them serving as a control group the others being treated either with a G2 inductor alone, with rTNF alone, or with rTNF and a G2 inductor co mbined. Administration of rTNF (125 or 250 mu g/kg body weight i.v.) w as always carried out 24 h after therapy with etoposide or radiation w hen the maximum of G2 accumulation had developed. The growth behavior of the treated tumors revealed that the response of the LLC to rTNF in vivo was not improved by pretreatment with a G2 inductor and, thus, o bviously lacked cell-cycle specificity. It is supposed that direct int eractions of TNF with the tumor cells, which are a basic requirement f or cell-cycle-linked phenomena, play a minor role in the therapeutic o utcome of the LLC under in vivo conditions.