Claus Fittschen

In vivo therapy of malignant melanoma by means of antagonists of αv integrins

Integrin αvβ3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of αvβ3. In this report, we characterize the activities of 2 antagonists of αvβ3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate‐attached cells in vitro. In vivo, αvβ3 antagonists behaved as anti‐tumor drugs in a dose‐ and time‐dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing αvβ3 as xenografts but did not affect the αvβ3‐negative (although αv integrin‐positive) tumors. This demonstrated that αvβ3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine αvβ3, the effect is due only to the direct anti‐tumor activity and not to the well‐known anti‐angiogenic activity of αv‐integrin antagonists. Taken together, our results confirm the essential role of αvβ3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of αv‐integrin antagonists for the treatment of such tumors. Int. J. Cancer 87:716–723, 2000.

EMD273316 & EMD95833, type 4 phosphodiesterase inhibitors, stimulate fibroblastic-colony formation by bone marrow cells via direct inhibition of PDE4 and the induction of endogenous prostaglandin synthesis

BackgroundType 4 phosphodiesterase (PDE4) inhibitors have been shown to stimulate bone formation in vivo and to stimulate osteoblastic differentiation in vitro. As one possible mechanism for the stimulation of bone formation is the recruitment of osteoprogenitor cells from the bone marrow, we have investigated the effect of the PDE4 inhibitors EMD273316, EMD95833, EMD249615 and EMD 219906 on fibroblastic colony formation by whole bone marrow cells and on the ability of these colonies to adopt an osteoblastic phenotype.ResultsAll four agents stimulated colony formation in a concentration dependent manner, however, in the case of EMD273316 & EMD95833, the effect was evident at lower concentrations and the addition of prostaglandin E2 (PGE2) was not necessary for maximal stimulation. It was subsequently found that co-incubation with indomethacin reduced the stimulatory effects of EMD273316 & EMD95833 but had no effect on the actions of EMD249615 and EMD 219906 and that EMD273316 & EMD95833 stimulated the synthesis of endogenous PGE2 by whole bone marrow cells whereas EMD249615 and EMD 219906 had no significant effect.ConclusionsThese data suggest that EMD249615, EMD 219906, EMD273316 & EMD95833 can promote the recruitment of bone marrow osteoprogenitor cells leading to a stimulation of bone formation via their direct inhibitory effects on PDE4. The actions of EMD273316 & EMD95833 however, are augmented by their ability to stimulate endogenous prostanoids synthesis which acts synergistically with their direct effects on PDE4.