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Bleomycin A, which is a complex of water‐soluble peptides produced by a Streptomyces, inhibits DNA synthesis in intact cells of E. coli and HeLa cells and also inhibits Ehrlich carcinoma and Sarcoma 180. When it is injected, it distributes in lung and skin at higher concentration than in blood and kidney. In dogs a large dose caused liver damage which was reversible but, when a lower dose was injected twice weekly, toxic signs appeared; the signs—inflammation of the foot pad and loss of hair—disappeared after cessation of the injection. It gave curative effect on a skin cancer in a dog. The authors conclude that the effect on skin cancer was due to the high concentration in skin.

Recent studies have shown that integrin ␣v␤3, a receptor for vitronectin, plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of ␣v␤3 inhibit angiogenic processes including endothelial cell adhesion and migration. On the other hand, most inhibitors of integrin ␣v␤3 are peptide antagonists that include the ArgGly-Asp (RGD) motif. We therefore reasoned that non-peptide inhibitors of endothelial cell adhesion to vitronectin might be useful for inhibition of tumor angiogenesis in vivo. We screened for low-molecular-weight natural products able to inhibit adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin, and pyrrothine group compounds including aureothricin, thioaurin and thiolutin were isolated from microbial culture broths. Of these compounds, thiolutin inhibited adhesion of HUVECs to vitronectin the most effectively (IC 50 , 0.83 M). In vivo experiments showed that thiolutin significantly suppressed angiogenesis induced by tumor cells (S-180), a pathological form of neovascularization, in a mouse dorsal air sac assay system. To explore the mechanism of inhibition of HUVEC adhesion to vitronectin by thiolutin, we examined the effect of this agent on intracellular cell adhesion signaling. We found that the amount of paxillin in Key words: thiolutin; paxillin; HUVEC; vitronectin; tumor angiogenesisThe growth of solid tumors has been shown to be dependent on the development of new blood vessels. 1 Growing solid tumors produce diffusible angiogenic factors that induce host capillary endothelial cells to proliferate, migrate and form new vessels in a process termed tumor-induced angiogenesis. 2-4 Once vascularized, tumors increase in size almost exponentially. 1 The dependence of solid tumor growth upon neovascularization provides a therapeutic opportunity to inhibit neoplastic growth by blocking tumor-induced angiogenesis. Angiogenesis is characterized by invasion, migration and proliferation of endothelial cells, processes that depend on cell interactions with extracellular matrix (ECM) components. In this context, integrin ␣v␤3, the endothelial adhesion receptor for vitronectin, was shown to be a key player, 5-7 by providing a vasculature-specific target for antiangiogenic treatment strategies. The requirement for vascular integrin ␣v␤3 in angiogenesis was demonstrated by several in vivo models in which the generation of new blood vessels by transplanted human tumors was completely inhibited by systemic administration of peptide antagonists of integrin ␣v␤3 or anti-␣v␤3 antibody. 5,6,8 Integrins are ␣/␤ heterodimeric cell-surface receptors that link the ECM with the cell cytoskeleton and generate intracellular signals to regulate cell survival and growth, cell differentiation and cell motility. Integrins themselves have no instrinsic enzymatic activity and appear to function by interacting with a number of other proteins. Integrin aggregation upon their binding to the substratum, which accompanies an assembly of several proteins at or near the cytopla...