抗癌新药-乙双吗啉(AT-1727)的药理研究

乙双吗啉(AT-1727)是我国合成的一种抗癌新药。它是一种双内酰亚胺化合物,实验证明,乙双吗啉对小鼠肉瘤S₃₇、S₁₈₀有显著抗肿瘤作用,对ECS,HCS,脑瘤B₂₂及L₆₁₅等移植性肿瘤亦有明显抗肿瘤作用。它对S₃₇的50%抑制剂量(ID₅₀)为1.88 mg/kg(ip)及6.61 mg/kg(po)。其抗肿瘤作用与给药方案有一定关系。乙双吗啉对小白鼠毒性LD₅₀为372.8±27.mg/kg(ip)及243.8±26.1 mg/kg(po)。因此,乙双吗啉腹腔注射及口服时,对S₃₇的化疗指数分别为47.5及36.9。给健康犬肌肉注射乙双吗啉25及50 mg/kg/天,连用10天,除出现食量减少,白细胞轻度下降外,对红细胞,血小板、肝、肾功能均无明显影响。乙双吗啉对以溶血素反应为指标的体液免疫有抑制作用;对以移植物抗宿主反应为指标的细胞免疫则无抑制作用。

PHARMACOLOGICAL STUDIES ON BIMOLANE(AT-1727), A NEW ANTINEOPLASTIC AGENT

Bimolane (AT-1727), bis N-morpholinomethyl-piperazinedine 1,2-bis (3,5-dioxopiperazinyl)-ethane], is a derivative of ICRF-154. Experiments Showed that this compound was an effective antineoplastic agent with a wide antitumor spectrum and low toxicity. The main results were as follows:1. AT-1727 showed marked inhibitory effect on mouse tumors of S 180 and S37. At the dose of 25 mg/kg ip or 50 mg/kg po, the growth, of these tumors was almost completely inhibited. Its antitumor action decreased with the decrease in dosage. The 50% inhibitory doses (ID₅₀) of AT-1727 against S37 were 1.88 mg/kg ip and 6.61 mg/kg po. It was also effective against solid mouse tumors of Ehrlish carcinoma, hepatoma and brain tumor B 22 and against L 615 leukemia. The antitumor effect was Schedule-dependent.2. The single intraperitoneal LD₅₀ on mice was 372.8±27.4 mg/kg. The acute toxicity of AT-1727 by oral administration was so low that it can't be determined. The subacute lethal doses(LD₅₀) were 89.3±7.6 mg/kg ip and 243.8±261/mg/kg po. Therefore, the chemotherapeutic indices (LD₅₀/ID₅₀) of AT-1727 by intraperitoneal and oral administration were 47.5 and 36.9 respectively.3. When AT-1727 was injected into dogs intra-muscularly (at doses of 25 and 50 mg/kg/day for 10 days), a slight decrease in leukocyte counts was observed. No significant changes were noted in liver, and kidney function tests and blood platelet count.4. The hemolysin test and graft versus host reaction test were used to monitor the humoral-mediated and cell-mediated immunities respectively. At the dose of 25 mg/kg ip, it depressed the humoral-mediated immunity, but the depressant effect was less than that of ICRF-154 and ICRF-159. The cell mediated-immunity was not depressed by AT-1727.