The general pharmacology of aclacinomycin A, a new antitumor antibiotic, was studied in mice, rats, guinea-pigs, frogs, rabbits and dogs. The LD50 values of aclacinomycin A were 32.5 mg/kg (i.v.), 30.1 mg/kg (i.p.), 33.9 mg/kg (s.c.) and 69.7 mg/kg (p.o.), respectively in male mice, and 28.8 mg/kg (i.v.), 21.1 mg/kg (i.p.), 26.4 mg/kg (s.c.) and 58.6 mg/kg (p.o.), respectively in male rats. Aclacinomycin A had no effect on the central nervous system except potenciation of the pentobarbital sodium-induced anesthesia in mice. The contraction of isolated heart was stimulated in frogs while slightly inhibited in rabbits at higher concentration. Transient increases in the heart rate and the blood flow of peripheral vasculature were observed but the blood pressure was slightly lowered with respiratory excitation in anesthetized rabbits and dogs. The ECG (II-lead) demonstrated slight depression of R wave amplitude and slight sinus arrhythmia in dogs. Aclacinomycin A inhibited the contraction of isolated smooth muscle and antagonized some spasmogens. It inhibited the spontaneous movement of isolated rabbit ileum and rat uterus at higher concentration, and antagonized acetylcholine, histamine, serotonin and barium chloride in the contraction of isolated guinea-pig ileum. The antagonism was competitive to oxytocin and noncompetitive to acetylcholine in rat uterus, and noncompetitive to noradrenaline in rat deferent duct. The drug showed no apparent effect on the gastrointestinal propulsion in mice and on mucous membrane of the stomach in rats. However, it depressed gastric acid secretion in rats while slightly increased bile secretion in guinea-pigs. Urine volume and urinary excretion of electrolytes (Na+, K+) decreased in rats. Vascular permeability was slightly inhibited by the drug in rabbits and mice. No hemolytic effect was shown. Aclacinomycin A showed no antigenicity in anaphylactic reaction and SCHULTZ-DALE reaction in guinea-pigs.

Walker 256 carcinosarcomas were transplanted under the skin and in the bone marrow of the femur of Wistar rats to investigate the tumor angiogenesis and effect of anticancerous agents on it. Microangiography was performed on tumors in different stages after transplantation and on treated tumors in different stages after a single shot of Adriacin or Endoxan into the intraperitoneum. The tumors were histologically examined. The results were as follows: 1. Angiogenesis was found at the host side near the tumor in the beginning of the subcutaneous transplantation and formation of vascaular network was seen at the peripheral area in the tumor after 5-7 days. No blood vessel was found at the central region of the tumor, and so-called "sinusoidal lake" was seen at the border zone of central and peripheral regions, suggesting the impending central necrosis. The vascular network became loose and blood vessels became of larger diameters and sinusoidal blood vessels were found afater about 14 days. In the case of intramedullary transplantation, blood flow stopped in the marrow already after about 10 days and rich network of blood vessels was observed in the spicula. 2. In the Adriacin group, only a weak inhibitory effect on tumor growh was found. There was no degeneration of tumor cells, but a little disorder of tumor cell cords. The effects of the drug on the capillaries were remarkable. The diameter of the capillary was narrowed, with fragmented vascularity and disappearance of capillary network. It was estimated that effective amount of the drug might not reach tumor cells because of circulatory disturbance due to obstruction of the capillaries caused by Adriacin. 3. In the Endoxan group, inhibitory effect of the drug was remarkable, and degeneration and transformation into giant cells of tumor cells, with a decrease of tumor cells and proliferation of interstitial connective tissues. The microvascular system maintained its network structure for rather a long period and the network was reduced with an increase of the connective tissue, but no fragmentation was found. It was suggested that sufficient Endoxan might have reached the tumor cells and cause their degeneration and destruction, followed by decrease of tumor angiogenesis factor (TAF) and by secondary reduction and disappearance of the microvascular system.