Anthracycline-induced histamine release from rat mast cells

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminaryin vitro experiments indicated that doxorubicin (10^–6 to 2.5×10^–4M), in contrast to compound 48/80 and the calcium inophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. Inin vivo experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10^–5 to 3.3×10^–3M revealed that all caused histamine release, with 10^–3M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5×10^–6M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent.The results indicate thatin vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat skin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparationsin vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.