[Screening for antagonistic agents to the lethal toxicity of neocarzinostatin. II. Effects of various drugs in inhibiting the toxicity of neocarzinostatin in vivo].
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.
Ouchi
M
M
Department of Experimental Cell Research, Medical Institute of Bioregulation, Kyushu University.
Toriyama
K
K
Matsumoto
T
T
Baba
T
T
D000603:Amino Acids, Sulfur / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D003545:Cysteine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000627:therapeutic use; D008297:Male; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy; D013864:Thioglycolates / Q000627:therapeutic use; D008625:Tiopronin / Q000627:therapeutic use*; D009353:Zinostatin / Q000037:antagonists & inhibitors / Q000627:therapeutic use / Q000633:toxicity*
D000603:Amino Acids, Sulfur; D000903:Antibiotics, Antineoplastic; D013864:Thioglycolates; C017487:2-mercaptoacetate; D009353:Zinostatin; D008625:Tiopronin; D005978:Glutathione; D003545:Cysteine