Time-dependent resistance or susceptibility of tumor cells to cytotoxic antibody after exposure to a chemotherapeutic agent

Abstract

A chemotherapeutic agent (melphalan) affected the sensitivity of tumor cells [in vitro] to cytotoxic antibody. Depending on the time interval between drug treatment and subsequent exposure to antibody and complement, the tumor cells can be more resistant or more susceptible to antibody when compared to control cells. The number of tumor cells surviving the combined treatment was determined by a colony inhibition assay. The 2 antisera used in this study were directed against [Kristen murine leukemia-sarcoma] virus-specific or myeloma protein-specific antigens on the surface S107 murine myeloma cells; identical results were obtained with both sera. At 24 h after exposure to the drug, the number of tumor cells surviving the antibody treatment increased. During this period of increased resistance, the tumor cells were temporarily arrested in the G2 phase of the cell cycle. After this period of maximal resistance, the effect of cytotoxic antibody on the cells changed such that 4 days after melphalan treatment the cells were significantly more susceptible to the antibody than were the sham-treated control cells. The period of increased susceptibility correlated with an increased density of S107 myeloma protein and viral antigens on the surface of the tumor cells. By 8 days after drug treatment, the susceptibility of the tumor cells and the density of surface antigens returned to normal levels. The correct time interval between exposure to a drug and subsequent treatment with antibody is critical for maximal killing of the tumor cells. The basis for the differential sensitivity of the tumor cells to antibody may be related to the drug-induced changes in the cell cycle and in antigen expression on the cell surface.