STUDIES ON ANTITUMOUR DRUGS——ⅩⅧ.EXPERIMENTAL THERAPY AND TOXICITY OF 5-BIS-(2-CHLOROETI-IYL)-AMINO-INDOLE-2-CARBOXYLIC ACID (AT-346)

In anabolic metabolism the precursor of melanin is an indolic compound. It is of interest to study some compound containing both nitrogen mustard and indole group in order to find effective agents against melanoma. A seies of these compounds were synthesized in this Institute. After pharmacological studies two drugs (designated as AT-267 and AT-346,Fig,1)were found to be more powerful than others. (1)Intragastric administrations of AT-267, AT-346, and sarcolysin (PAM) at the 1/6 acute LD₅₀ produced a marked inhibitory effect on sarcoma 180, spindle cell sarcoma, reticulum cell sarcoma (L-Ⅱ), sarcoma AK, Ehrlich carcinoma (solid form), and mammary carcinoma (ascitic form) in mice, but no effect on Ehrlich ascites carcinoma. The former two drugs exhibited also a definite inhibition on melanoma and brain tumour (B-22)in mice, and Jensen sarcoma in rats. (2)In mice, the acute LD₅₀ after intragastric administration of AT-267, AT-346, and PAM were found to be 120, 16, and 33 mg/kg, and the subacute LD₅₀ to be 33, 6.8, and 10 mg/kg respectively. The chemotherapeutic indices (MTD/MED) of AT-267 and AT-346 for sarcoma 180 were about 6 and 13 respectively. (3)In dogs, oral administration of 0.9 and 2.7 mg/kg/day of AT-346 for 10 days caused a definite depression on the heamopoietic organs. At autopsy and microscopic examinations heamorrhage points in intestinal mucosa and a slight degree of fatty degeneration in liver were found. In the group of 0.3 mg/kg, white cell counts slightly decreased but other examinations did not show any alterations. Three monkeys were given AT-346 at the total dosages of 5, 56, and 122 mg respectively, and the heamopoietic depression was noticed in two animals (receiving 56 and 122 mg).