TUMOR-NECROSIS-FACTOR ADMINISTRATION IS ASSOCIATED WITH INCREASED ENDOGENOUS PRODUCTION OF M-CSF AND G-CSF HUT NOT GM-CSF IN HUMAN CANCER-PATIENTS

In humans, tumor necrosis factor (TNF) treatment has been associated w ith characteristic changes in circulating white blood cell populations (leukopenia followed by leukocytosis) and increased cell-surface expr ession of integrins. A similar pattern of effects on leukocytes occurs with granulocyte-macrophage colony-stimulating factor (GM-CSF) and G- CSF treatment. To determine whether these effects were caused directly by TNF or as a result of secondary CSF release, G-, GM-, and M-CSF le vels were measured after TNF infusion (9.6x10(6) U/mg protein; <5.0 en dotoxin U/mg protein) in cancer patients during two phase I trials of TNF. One patient with aggressive fibromatosis was treated with TNF alo ne (200 mu g/m(2), days: 1-5 every third week) and 10 patients (four c olon cancer, four head and neck canter; one melanoma; one sarcoma) rec eived mitomycin C (15 mg/m(2), day I) followed by TNF (60-180 mu g/m(2 ), days 1-3) every sixth week. All treatments were given IV, mitomycin C over 5 minutes and TNF over 2 hours. Serum samples were collected a t times 0 (before mitomycin C and TNF) and 1, 2, 4, 6, 12, and 24 hour s after TNF initiation on day 1 and at similar times on subsequent tre atment days. M-CSF samples were analyzed by radioimmunoassay (RW) and G-CSF and GM-CSF by ELISA. The mean baseline M-CSF levels in normal co ntrol subjects (n=12) was 158.4 +/- 36.2 (SD) U/mL, and in pretreatmen t cancer patients (n=10) 235.7 +/- 60.9 U/mL (p = 0.004, Wilcoxon test ). M-CSF levels increased 4 hours after TNF initiation (mean 354.7 +/- 96.3 U/mL; p = 0.020), remained elevated at 6 hours (305.6 +/- 45.4 U /mL; p = 0.004, Wilcoxon signed-rank test), and subsequent ly declined . This pattern was seen in all patients treated with TNF; whether trea tment was TNF alone or TNF with mitomycin C. In patients treated with mitomycin C and TNF, G-CSF levels increased at 4 hours after TNF initi ation (mean 3886 +/- 2009 pg/mL; p = 0.004), remained elevated at 6 ho urs (mean 2140 +/- 1131 pg/mL; p = 0.004), and subsequently declined. GM-CSF levels were not measurable before or after treatment with TNF. The changes in all three endogenous cytokines were not temporally rela ted to the previously described leukopenia and integrin upregulation o n circulating leukocytes and, therefore, appear to be unrelated to thi s event. However, release of endogenous G-CSF and M-CSF under the infl uence of TNF does temporally coincide with the previously described le ukocytosis, suggesting a possible role for these endogenous cytokines in the release of bone marrow cellular stores.