Specific nuclear and nucleolar ultrastructural lesions induced by proflavin and similarly acting antimetabolites in tissue culture.

Abstract

Proflavin induces a series of ultrastructural alterations in cultures of rat embryonic cells. Nonspecific cytoplasmic lesions include disorganization of endoplasmic reticulum and large cytoplasmic inclusions with osmiophilic material and myelin figures, similar to those described in HeLa cells treated with acridine orange and in liver and pancreatic acinar cells of rats fed with ethionine and azaserine. However, characteristic nuclear and nucleolar lesions such as clumping of the chromatin with unsticking from the nuclear membrane, disappearance of the nucleoplasmic matrix, and segregation of nucleolar components occur as treatment progresses in time and concentration. Two other antimetabolites, daunomycin and ethidium bromide, chemically unrelated to proflavin, produce identical nuclear and nucleolar lesions at adequate concentrations. Since proflavin, daunomycin, and ethidium bromide form complexes with DNA by intercalation between base pairs, the nuclear and nucleolar lesions may represent the morphologic expression for a specific molecular action. Possible explanations are proposed, taking into account the physicochemical properties of the drug-DNA complex and their effect on nucleic acid and protein synthesis.