The biological activity of new tuftsin derivatives--induction of phagocytosis.

Phagocytosis plays a crucial role in a host defense against invading microorganisms. This process can be induced by many phagocytosis stimulating factors. One of them is an endogenous tetrapeptide - tuftsin that occurs in the blood of mammals including human beings. Tuftsin is capable of potentiating granulocyte and macrophage functions such as: phagocytosis, motility, and chemotaxis as well as bactericidal and tumoricidal activity. The other particle able to induce phagocytosis is muramyl dipeptide (MDP), the smallest synthetic glycopeptide of bacterial origin that possesses an immunogenic activity. MDP is known to affect most functions of macrophages. Phagocytosis stimulating properties of a new group of tuftsin and MDP analogues (one tuftsin analogue and four conjugates of tuftsin/retro tuftsin and muramyl dipeptide or nor-muramyl dipeptide) were tested. The results of the study show that all of the examined conjugates are able to generate oxidative burst. The most promising analogues proved to be kd6 and kd7.

A novel mechanism of action of the fumagillin analog, TNP-470, in the B16F10 murine melanoma cell line.

TNP-470, a semisynthetic derivative of fumagillin, is an acknowledged angiogenesis inhibitor, presently undergoing clinical trials. It exerts an anti-proliferative effect directed against endothelial cells. This effect is known to be based on cell cycle inhibition effected by the p53/p21 pathway. We observed short-term toxicity of TNP-470 in the B16F10 murine melanoma cell line in vitro and investigated the mechanism of action. Cell death occurred as soon as 2 h after the addition of TNP-470, without typical apoptotic features. The toxic effect could be modulated and it depended on the type of culture medium or supplementation with anti-oxidants. Addition of N-acetylcysteine protected B16F10 cells from TNP-470-induced death and inhibited an increase in the generation of reactive oxygen species (ROS), which are detected by the 2',7'-dichlorodihydrofluorescein diacetate probe. We conclude that TNP-470 can induce intracellular generation of ROS, which act toxically inside B16F10 cells. One may suggest that this novel activity of TNP-470 might be beneficial in some cases, but it could also be responsible for some undesirable side-effects. The possibility of its modulation gives a prospect for controlling the action of this potential drug and probably its derivatives.