Actinomycin D: drug concentrations and actions in mouse tissues and tumors.

Concentrations of actinomycin D-3H in tissues and organs of mice were measured at 30 min and other times up to 48 hr after injection (600 ~g/kg). Although this dose is sublethal for mice, it is known to damage cells of the intestinal epithelium, spleen, thymus, and the sensitive Ridgway osteogenic sarcoma (ROS). I t has little or no cytotoxic effects on mouse liver or the solid, transplantable 7,12-dimethylbenz(a)anthracene (DMBA)-induced tumor. By 30 min, the average concentrations of labeled antibiotic in liver, salivary gland, and spleen (1.5-1.7 #g/gm) were already considerably higher than blood concentrations (0.1 ~g/ml). Concentrations in other tissues were less: small intestine (0.8 ~g/gm), ROS tumor (0.4 ~g/ gm), and DMBA tumor and thymus (0.2 ~g/gm). Thereafter, concentrations decreased in liver, salivary gland, small intestine, and DMBA tumor while ROS and thymus continued to cumulate the antibiotic. By 48 hr, high concentrations were localized in spleen, thymus, and ROS, all of which are considered to be highly sensitive to the agent. Shorter retention times may be associated with moderate damage in salivary gland and small intestine and with little or no damage in liver and DMBA tumors. Uridine-3H incorporation into RNA was estimated at 3 hr after actinomycin, when most tissues had maximal drug concentrations, and at 24 hr, when most were depleted of drug. The inhibitory effects of actinomycin on incorporation rates were correlated with tissue levels of the drug but not with the susceptibility of the tissue to cytotoxicity.