zinostatin and Sarcoma-180

Zinostatin stimalamer (ZSS) is a new anticancer agent derived from neocarzinostatin (NCS), which is synthesized by conjugation of one molecule of NCS and two molecules of poly(styrene-co-maleic acid). ZSS exhibited potent in vitro and in vivo antitumor activity in preclinical experiments, and a clinical trial of the intra-arterial administration of ZSS with iodized oil on hepatocellular carcinoma showed potent antitumor activity. We investigated the effect of ZSS and NCS on antitumor resistance and found that pretreatment with either drug suppressed the growth of MethA tumors in Balb/c mice and induced tumor eradication when given separately by single administration at therapeutic doses between 1 day and 4 weeks before tumor transplantation. The findings that the cytocidal activity of these drugs was not detected in vivo at the time of tumor transplantation and that tumor regression was preceded by a period of transient growth suggested that tumor regression was due to host-mediated antitumor activity induced by these drugs. Pretreatment with ZSS or NCS also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. The finding that NCS showed the same effect as ZSS suggests that poly(styrene-comaleic acid) is not essential for the induction of host-mediated antitumor activity. Furthermore, apo-ZSS, which lacks cytocidal activity, did not induce antitumor activity. From this, it is suggested that the cytocidal effect of ZSS involves the induction of host-mediated antitumor resistance. In athymic Balb/c nu/nu mice, pretreatment with ZSS or NCS did not induce tumor eradication, suggesting that mature T lymphocytes play an important role in tumor eradication. Challenging MethA was rejected without transient growth in mice that had been cured of MethA, but challenging Colon 26 was not, showing that anti-MethA resistance was augmented selectively in the MethA-eradicated mice. Splenocytes from MethA-bearing mice pretreated with the drug showed tumor-neutralizing activity beginning 14 days after tumor transplantation. Tumor-neutralizing activity was only induced after MethA transplantation. The effector cells of this tumor-neutralizing activity were Thy1.2+ T lymphocytes that had been passed through a nylon-wool column, but no significant augmentation of cell-mediated cytotoxic activity of splenocytes from MethA-eradicated mice was observed in vitro.

Topics: Animals; Carcinoma; Colonic Neoplasms; Cytotoxicity, Immunologic; Drug Screening Assays, Antitumor; Female; Graft Survival; Male; Maleic Anhydrides; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred ICR; Mice, Nude; Neoplasm Transplantation; Polystyrenes; Sarcoma 180; Sarcoma, Experimental; T-Lymphocytes, Cytotoxic; Zinostatin

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.

Topics: Amino Acids, Sulfur; Animals; Antibiotics, Antineoplastic; Cysteine; Drug Therapy, Combination; Glutathione; Male; Mice; Sarcoma 180; Thioglycolates; Tiopronin; Zinostatin

Topics: Animals; Antibiotics, Antineoplastic; Bacterial Proteins; Biological Assay; Chemical Phenomena; Chemistry; DNA, Neoplasm; Electrophoresis, Disc; Fermentation; HeLa Cells; Hydrogen-Ion Concentration; Isoelectric Focusing; Lethal Dose 50; Mice; Microbial Sensitivity Tests; Nephelometry and Turbidimetry; Sarcina; Sarcoma 180; Streptomyces; Time Factors; Transplantation, Homologous; Zinostatin

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Ascites; Leukemia; Leukemia, Experimental; Mice; Molecular Weight; Pharmacology; Research; Sarcina; Sarcoma 180; Staphylococcus; Streptomyces; Tissue Culture Techniques; Zinostatin