zinostatin and Carcinoma

Techniques which can increase the expression level of tumor-associated antigens may improve immunotargeting therapy. We studied the reactivity of MAb A7 toward an antigen expressed on the surface of the human pancreatic cancer cell line HPC-YS after treatment with various antitumoral agents. When we applied 1 microg/ml mitomycin C (MMC) or 0.1 microg/ml neocarzinostatin (NCS) for 1 h, A7 recognizing antigen expression was enhanced until 24 h after the treatments. At a dose that completely suppressed cell growth, increased antigen expression was maintained for 96 h. Therefore, this study suggests that the combined application of an anticancer drug and MAb A7 may be useful for immunotargeting chemotherapy.

Topics: Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigens, Neoplasm; Carcinoma; Cell Count; Cell Cycle; Humans; Mitomycin; Pancreatic Neoplasms; Tumor Cells, Cultured; Zinostatin

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

We studied a prophylactic chemotherapy against hepatic metastases arising from the shedding of tumor cells into the portal circulation. The therapy was done with a lymphographic oily contrast medium, Lipiodol, and a high molecular weight anticancer agent named poly(styrene-maleic acid) copolymer conjugated neocarzinostatin (SMANCS), developed in our laboratory. SMANCS was dissolved in Lipiodol by sonication (SMANCS/Lipiodol, 1 mg of SMANCS in 1 ml of Lipiodol). Twelve rabbits were simply inoculated with the highly malignant carcinoma VX-2. Fifteen rabbits were given injections of SMANCS in glucose and Lipiodol into the portal vein and were subsequently inoculated with the tumor cells. Eighteen were given injections of SMANCS/Lipiodol and then the tumor cells. These rabbits were killed 12 days later. Thirteen were given injections of the tumor cells alone and were allowed to survive. Sixteen were given injections of SMANCS/Lipiodol and then with the tumor cells; they were allowed to survive. Rabbits given injections of SMANCS/Lipiodol before tumor inoculation had significantly fewer (P less than 0.001) metastases than those not treated or those given SMANCS in glucose and Lipiodol. Survival was significantly longer [P less than 0.005; 36.0 +/- 7.7 (SD) days] with SMANCS/Lipiodol before tumor inoculation than without treatment [23.5 +/- 3.0 days]. SMANCS/Lipiodol has a prolonged anticancer effect because it remains in the portal vein and allows sustained drug release from the oil (Lipiodol) to aqueous spaces. Hepatic metastases might be prevented by portal administration of the appropriate oily anticancer agent.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma; Furans; Injections, Intravenous; Iodized Oil; Liver Neoplasms; Maleic Anhydrides; Polystyrenes; Portal Vein; Rabbits; Radiography; Zinostatin