Ouchi M, Toriyama K, Matsumoto T, Baba T
Department of Experimental Cell Research, Medical Institute of Bioregulation, Kyushu University.
Jpn J Antibiot. 1988 Jan;41(1):105-15.
In clinical chemotherapy with neocarzinostatin (NCS) against cancers, side effects such as leukopenia, anorexia, vomiting and nausea were mainly observed when parenteral administration was used. To prevent these adverse side effects without changing the anticancer activity of the drug, we attempted to apply the two-route-infusion chemotherapy using NCS and antidotes for the NCS treatment devised by Baba. This report presents the results of our study on effects of some antidotes on the acute toxicity of NCS in mice and also on the antitumor activity of NCS against Sarcoma-180 in mice (ICR-JCL strain) when used with tiopronin. The results are summarized as follows. 1. LD50 values of NCS administered via intravenous route increased 2.3- to 3.2-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered subcutaneously together with NCS, 1.3- to 1.4-fold when 50 or 100 mg/kg of sodium thioglycolate was used. When antidotes were given prior to the administration of NCS, 1.8- to 5.4-fold increase in LD50 values of NCS resulted with 300, 500 or 1,000 mg/kg of tiopronin administered 1 hour prior to NCS, 2.3-fold increase resulted with 2,000 mg/kg reduced glutathione, 1.2-fold increase with 100 mg/kg of sodium thioglycolate and 1.9-fold increase with 1,000 mg/kg of L-cysteine monohydrochloride monohydrate. Furthermore, 4.8- to 13.1-fold increase in LD50 of NCS occurred when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered 15 minutes prior to NCS. When these antidotes were administered 1 hour after the administration of NCS, however, no changes in the LD50 value occurred. 2. The LD50 value of NCS given intraperitoneally increased 1.6- to 5.8-fold when 150, 300, 500 or 1,000 mg/kg of tiopronin was administered intravenously at the same time as NCS, 1.4- to 1.6-fold when tiopronin was given 1 hour prior to NCS, intraperitoneally and 1.3- to 1.7-fold when it was given 1 hour after NCS. 3. It was recognized that the acute toxicity of NCS was the most effectively reduced by tiopronin, but only slightly by glutathione, sodium thioglycolate or L-cysteine monohydrochloride monohydrate. The action of tiopronin was the most effective when it was given subcutaneously 15 minutes prior to NCS administered intravenously. 4. The combination chemotherapy on Sarcoma-180 in mice using NCS intraperitoneally and tiopronin intravenously was markedly effective when these agents were given simultaneously.
在使用新制癌菌素（NCS）进行临床癌症化疗时，采用肠胃外给药时，主要会出现白细胞减少、厌食、呕吐和恶心等副作用。为了在不改变药物抗癌活性的情况下预防这些不良副作用，我们尝试应用两路输注化疗，使用NCS以及由 Baba 设计的用于 NCS 治疗的解毒剂。本报告展示了我们关于某些解毒剂对 NCS 在小鼠体内急性毒性的影响以及与硫普罗宁一起使用时 NCS 对小鼠（ICR-JCL 品系）肉瘤-180 的抗肿瘤活性的研究结果。结果总结如下。1. 当与 NCS 同时皮下注射 150、300、500 或 1000 mg/kg 的硫普罗宁时，经静脉途径给药的 NCS 的半数致死量（LD50）值增加 2.3 至 3.2 倍；当使用 50 或 100 mg/kg 的巯基乙酸钠时，增加 1.3 至 1.4 倍。当在给予 NCS 之前给予解毒剂时，在 NCS 前 1 小时给予 300、500 或 1000 mg/kg 的硫普罗宁，NCS 的 LD50 值增加 1.8 至 5.4 倍；给予 2000 mg/kg 的还原型谷胱甘肽时增加 2.3 倍；给予 100 mg/kg 的巯基乙酸钠时增加 1.2 倍；给予 1000 mg/kg 的一水合盐酸半胱氨酸时增加 1.9 倍。此外，当在 NCS 前 15 分钟给予 150、300、500 或 1000 mg/kg 的硫普罗宁时，NCS 的 LD50 增加 4.8 至 13.1 倍。然而，当在给予 NCS 1 小时后给予这些解毒剂时，LD50 值没有变化。2. 当与 NCS 同时静脉注射 150、300、500 或 1000 mg/kg 的硫普罗宁时，腹腔内给予的 NCS 的 LD50 值增加 1.6 至 5.8 倍；当硫普罗宁在 NCS 前 1 小时经腹腔内给予时增加 1.4 至 1.6 倍；当在 NCS 后 1 小时给予时增加 1.3 至 1.7 倍。3. 已认识到硫普罗宁最有效地降低了 NCS 的急性毒性，但谷胱甘肽、巯基乙酸钠或一水合盐酸半胱氨酸的作用较小。当在静脉注射 NCS 前 15 分钟皮下给予硫普罗宁时，其作用最有效。4. 当同时给予腹腔内注射 NCS 和静脉注射硫普罗宁时，对小鼠肉瘤-180 的联合化疗效果显著。
