Antiproliferative and antitumor activity of the 2-cyanoaziridine compound imexon on tumor cell lines and fresh tumor cells in vitro

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]