Myeloma cells in cultures established from transplantable murine myelomas (plasmacytomas) have been observed to lose oncogenicity for unknown reasons after prolonged periods in vitro. Cultured cells at various levels of oncogenic potential have been characterized by in vivo and in vitro techniques. We propose to evaluate a variety of in vitro procedures for causing loss of oncogenicity in highly oncogenic lines from these tumors. Methods for alteration and/or selection within a population will be studied by systematic analysis of growth conditions and by use of specific selective agents for saturation density and drug resistance. Mutagens will be used in vitro to alter cells genetically to produce variants which differ in oncogenicity. Manipulation of known viral (C-type) content of the cells will be attempted. Direct attack on the cell membrane will be made with enzyme digestion and addition of substances which bind with or coat the cell surface. These experiments will be evaluated primarily by tumor production in mice. Other cellular characteristics will be examined to determine any which can be correlated with the loss of oncogenicity. Such observations should contribute to an understanding of the mechanism of this alteration.