Modulation of growth supportive and oncogenic properties of murine leukemia cells

A leukemoid reaction occurs after inoculation of L1210 leukemic cells into recipient mice and the degree of granulocytosis is correlated with tumor progression. It was found that the sera of leukemic mice contained elevated levels of colony stimulating activity (CSA) when compared with normal mouse sera. Media conditioned by L1210 cells in vitro (L1210-CM) contained CSA which stimulated normal bone marrow myeloid colony growth and an auto-stimulatory activity (ASA) which stimulated L1210 cell proliferation. We studied the effects of trans-retinoic acid (RA) and 1,25 dihydroxyvitamin D3 (VD3) on the production of growth substances by L1210 cells. When L1210-CM was prepared in the presence of RA and VD3, the CSA and ASA were markedly inhibited. A combination of the two agents was more effective than either agent. Mice inoculated with 1 x 10(5) L1210 suspension culture cells treated with either agent or both combined survived significantly longer than controls. Mice inoculated with L1210 cells treated with the two agents combined survived longest. By using antibodies, preliminary analysis of growth substances generated in L1210-CM showed that it contains primarily GM-CSF and M-CSF-like activities which were distinct from ASA. Combination antibody titer assays revealed that ASA was not significantly inhibited with anti-GM-CSF and anti-M-CSF antibodies, while CSA was inhibited by between 61 and 84%. We conclude that RA and VD3 synergistically inhibit the release of growth-enhancing substances by L1210 cells which may reduce the growth advantage of leukemic cells and the resulting leukocytosis in lymphocytic leukemia.