MECHANISTIC ANALYSIS OF HIGH ANTITUMOR EFFECT OF INTRADERMAL ADMINISTRATION OF LIPOPOLYSACCHARIDE FROM PANTOEA-AGGLOMERANS

Lipopolysaccharide from Pantoea Agglomerans (LPSp) has a remarkably hi gh antitumor activity even against poorly immunogeneic tumors when giv en by intradermal injection combined with cyclophosphamide (CY). We ha ve extended this study to gain an insight into the mechanism of this a ntitumor effect, and especially into the induction of cell mediated im munity. In immunohistological studies, extensive necrosis and marked i nfiltration of the inflammatory cells at the tumor were observed after intradermal injection of LPSp combined with CY, but not after CY alon e or after no treatment. The cells around the tumors were mostly neutr ophils and macrophages (Mac 1+); T cells (CD4+, CD8+) were also presen t. The serum levels of cytokines, induced after intradermal injection of LPSp, were determined and compared with intravenous administration of LPSp or recombinant TNF-SAM2. TNF-alpha, IL-1, IL-6 and GM-CSF were measured by ELISA as a marker of cytokine induction. The peak level o f TNF-alpha induced by intradermal injection of LPSp was about 5000 pg ml(-1), which was considered relatively small since this level was ob served even in clinical trial. There seems to be a longer period of re lease of TNF-alpha after an intradermal injection than after an intrav enous injection. This may produce the remarkably high antitumor effect of the intradermal injection. The antitumor effect of intradermal adm inistration combined with CY was evaluated in nude mice to clarify the role of T cells in high antitumor activity. In this experiment, antit umor activity was found to be much less in BALB/c nu/nu mice without r egression, while complete regression was frequently observed in syngen eic mice, showing the crucial role of T cells in this treatment. These observations suggest that intradermal administration of LPSp in combi nation with CY continuously releases and induces not only extensive ne crosis of the tumor but also cell mediated antitumor immunity, which m ay be indispensable for complete regression of the tumor. Clinical app lication of this treatment for advanced cancer patients is in progress .