Antiproliferative and Antitumor Activity of the 2-Cyanoaziridine Compound Imexon on Tumor Cell Lines and Fresh Tumor Cells In Vitro

Abstract

Background : Imexon, a 2-cyanoaziridine, is therapeutic and reverses lymphadenopathy and splenomegaly in the LP-BM5 murine retrovirus-induced immunodeficiency disease (murine AIDS). It can restore chemotherapy-induced immunosuppression. Imexon reduced the incidence of lym-phoma in severe combined immune deficient mice inoculated with human lymphocytes. Purpose : To determine its antitumor activity, we screened imexon against fresh human tumor cells and tumor cell lines. To determine the time-concentration relationships of its cytotoxicity, we studied the effects of imexon on macromolecular synthesis and on the cell cycle. Methods : Imexon was incubated at 1–200 xg/mL with various tumor cell lines, mitogen-stimulated peripheral blood lymphocytes, and fresh tumor cells. Cell survival, macromolecular synthesis, and cell cycle progression were studied. Results: The concentration of imexon that caused 50% inhibition of growth was under 10 (jLg/mL for lymphocytes stimulated with mitogens. It was about 3–10 xg/mL for B-cell lymphomas and both multi-drug-resistant and -sensitive myeloma cell lines. Imexon inhibited four of seven fresh lymphoma and 11 of 16 fresh myeloma biopsy specimens to less than 40% of the control. A 1-hour exposure of lymphoma cells to 50–100 (xg/mL followed by removal of drug by washing the cells and continuing culture resulted in greater than 95% inhibition during the next 48–72 hours. Imexon selectively inhibited protein synthesis during the first 24–48 hours of exposure of lymphoma and myeloma cells. Cells exposed to inhibitory concentrations of imexon were blocked in cell cycle progression. Conclusion: Imexon may be a potentially useful agent in the treatment of malignant disease, particularly lymphoid malignancies, and should be explored further. [J Natl Cancer Inst 84: 1238–1244, 1992]