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.