The Dendrogenine A: A New Aminosteroid for the Immunotherapy of Cancers.

5551 The existence of a new metabolism in the aminosteroid series in fish was suggested, after the isolation of squalamine from the shark. Squalamine is a product of condensation of 24-sulfo-7,24 cholestane diol and spermidine in the C-3 position of the sterol. The squalamine and its analogues are currently evaluated for the treatment of small cell lung cancer, breast and ovaries cancers. We discovered the existence of such a metabolism in the mammals by identifying a new aminosteroid that we named “dendrogenine A (DA)” (World Patent 2003/089449). The aim of the present study was to characterize the biological properties of DA and to determine whether DA displays anti-tumor activity. We showed that in vitro nanomolar concentrations of DA stimulate the differentiation of monocytes into dendritic-like cells that activate the T Lymphocyte response. We have tested the antitumor activity of DA on syngenic mammary tumors (TS/A) injected subcutaneous on the flanc of normal mice and observed that DA (2.5 μg DA/ kg) can control 60% of the growth of tumors after 30 days, while such effect was not observed when similar experiment was performed on athymic mice, confirming that T Lymphocytes are important actors of the antitumor activity of DA. Because no tumor antigenes were injected, we investigated whether DA could also affect tumor cells. TS/A cells treated with DA were shown to produce multivesicular bodies in their cytoplasm and to express major histocompatibility complexes (MHC) of class II, suggesting that DA-treated cells produce tumor antigenes that are presented by MHC to T lymphocytes. Similar results were obtained on B16F10 melanoma cells treated by DA in vivo and in vitro. In conclusion, we have identified a new aminosteroid metabolite that displays a dual anti-tumor mechanism of action by activating the T lymphocyte response through its action on dendritic cells and by inducing the recognition of the tumor cells by T lymphocytes.