Host-Mediated Antitumor Activity Induced by Neocarzinostatin and Its Polymer-Conjugated Derivative SMANCS in Tumor-Bearing Mice

Abstract

Pretreatment with neocarzinostatin (NCS) or its polymer-conjugated derivative, zinostatin stimalamer (usually called SMANCS), induced Meth A tumor eradication in Balb/c mice. Tumor eradication was induced by a single administration of NCS or SMANCS between 4 weeks and 1 day before tumor transplantation. Meth A was always eradicated after transient growth. These results suggested that Meth A was eradicated by host-mediated antitumor activity induced by NCS or SMANCS. Pretreatment with these drugs also suppressed the growth of Colon 26 carcinoma and Sarcoma 180. Apo-SMANCS, which lacks cytocidal activity, did not induce antitumor activity, suggesting that cytocidal activity was required for induction of host-mediated antitumor activity. Spleen cells from Meth A-bearing mice pretreated with NCS or SMANCS showed tumor-neutralizing activity, and the effector cells were T cells, but the spleen cells did not exhibit cytotoxic activity or cytotoxic T-lymphocyte (CTL) activity. Flow cytometric analysis indicated that a decrease of B cells was prominent in spleen cells and lymph node cells after NCS or SMANCS treatment. In vivo depletion experiments using antibodies and carrageenan suggested that the effector cells for tumor eradication were asialo-GM1+/Lyt2+/Thy1.2+ and possibly asialo GM1−/Lyt2+/Thy1.2+, and that asialo GM1−/Lyt2+/Thy1.2+ cells were essential for the generation of antitumor activity. It was also suggested that host-mediated antitumor activity was augmented not only by pretreatment but also by posttreatment. These studies suggest that NCS or SMANCS exhibits antitumor activity through both direct cytotoxicity and indirect host-mediated antitumor activity.