INFLUENCE OF AN AUTOCRINE DIFFUSIBLE RESISTANCE FACTOR ON CELL-SURVIVAL AFTER EXPOSURE TO THERAPEUTIC AGENTS

A subclone of Cloudman mouse melanoma cells (S91/I3) produces a resist ance factor (RF) that increases the survival of a different but relate d subclone, S91/Amel, after exposure to either ultraviolet C (UVC) rad iation or to mitomycin C (MMC). The presence of RF was deduced from ex periments in which heavily irradiated S91/I3 cells were plated with th e target S91/Amel cells. The effect of RF was also present in cell-fre e conditioned tissue culture medium (CM) from S91/I3 cultures. These r esults extend previous findings that both subclones produce an autocri ne resistance factor (RF) that alters the radiation response of target S91/Amel cells making them less sensitive to death by low linear ener gy transfer (LET) ionizing radiation. S91/I3 cells are radioresistant relative to S91/Amel and produce the RF more effectively than S91/Amel . S91/I3 cells do not respond to the RF, being themselves, presumably, maximally stimulated. The significant findings are (1) the RF is effe ctive at decreasing the killing of the target cells using cytotoxic ag ents that operate by different mechanisms; (2) The relative sensitivie s of S91/Amel and S91/I3 to the toxic agents is not a factor in the re sponses of these cells to the RF: S91/Amel survivals are increased by the RF, those of S91/I3 are not; (3) the RF is elaborated by the melan oma cells whether or not they have been irradiated; it is, apparently, a normal cell product; (4) the RF is effective when added after the c ytotoxic insult; its presence is not required during irradiation or dr ug treatment. The RF appears to act by novel mechanisms. it may repres ent a new function for a previously described cytokine or it may be a new phenomenon.