Differential Neutralizing Effect of Tiopronin on the Toxicity of Neocarzinostatin and SMANCS: a New Rescue Cancer Chemotherapy

The toxic effect and antitumor activity of neocarzinostatin (NCS) and SMANCS [copoly(styrenemaleic acid)-conjugated NCS] were greatly affected by N-(2-mercaptopropionyl)-glycine [tiopronin] both in vitro and in vivo, in cultured HeLa cells and RL male 1 tumor-bearing mice. The cytotoxicity of NCS and SMANCS against HeLa cells was remarkably reduced by the addition of tiopronin during drug treatment. Interestingly, the neutralizing effect of tiopronin on the toxicity of SMANCS was greater than that in the case of NCS. In the continuous presence of 10 mM tiopronin during a 1 h drug treatment, the 50% cell-killing doses of NCS and SMANCS were increased 72 and 208 times as compared to those without tiopronin, respectively, whereas tiopronin itself has no cytotoxicity to HeLa cells up to 100 mM. Furthermore, more effective reduction of the lethal toxicity of SMANCS was observed by the intraperitoneal (ip) administration of tiopronin after ip injection of a lethal dose of SMANCS as compared to the same protocol in the case of NCS in mice. Therapeutic studies on RL male 1 tumor-bearing mice revealed that delayed (time lag) ip administration of tiopronin after high-dose SMANCS administration ip was much superior to the combination of NCS with tiopronin, or SMANCS alone. In this time-lag combination chemotherapy of SMANCS with tiopronin, 60% of treated mice survived more than 60 days after tumor inoculation, while all the untreated control mice died within 20 days.