Potential limitation of growth-inhibitory action of recombinant human tumor necrosis factor (PAC-4D) due to easy induction of resistance: evidence in vitro.

The growth-inhibitory activity of recombinant human tumor necrosis factor (rH-TNF: PAC-4D) against 32 human cultured cell lines derived from leukemias and lymphomas (7 T cell, 11 B cell, 5 non-T,non-B cell and 9 myeloid cell lines) was measured quantitatively by in vitro regrowth assay. The growth of two non-T,non-B-cell lines (Reh, P30/OHK) and six myeloid cell lines (ML-1, U937, THP-1-0, P31/FUJ, P39/TSU, HEL) was found to be significantly inhibited by a 72 hr treatment with PAC-4D. Although the levels of sensitivity of these cell lines to PAC-4D were different, it was common to all these cell lines that increasing the dose of PAC-4D did not augment the growth-inhibitory action above a certain level. Neither dose-dependent nor time-dependent growth-inhibitory action was observed, namely, exposure to 100 U/ml of PAC-4D for 48 hr was sufficient to exhibit maximum growth-inhibitory action. Furthermore U937 cells were found to become completely resistant to PAC-4D during a continuous 12-day exposure to it. This resistance, however, was lost on culture of the cells with PAC-4D-free growth medium for 15 days. These results suggested that some non-T,non-B acute lymphoblastic leukemias and acute myelogenous leukemias might show an initial response to PAC-4D therapy, but prolonged administration might induce resistance to PAC-4D rather than increase the anti-tumor effect.