The autocrine͞paracrine peptide signaling molecules such as growth factors have many promising biologic activities for clinical applications. However, one cannot expect specific therapeutic effects of the factors administered by ordinary drug delivery systems as they have limited target specificity and short half-lives in vivo. To overcome the difficulties in using growth factors as therapeutic agents, we have produced fusion proteins consisting of growth factor moieties and a collagen-binding domain (CBD) derived from Clostridium histolyticum collagenase. The fusion proteins carrying the epidermal growth factor (EGF) or basic fibroblast growth factor (bFGF) at the N terminal of CBD (CBEGF͞ CBFGF) tightly bound to insoluble collagen and stimulated the growth of BALB͞c 3T3 fibroblasts as much as the unfused counterparts. CBEGF, when injected subcutaneously into nude mice, remained at the sites of injection for up to 10 days, whereas EGF was not detectable 24 h after injection. Although CBEGF did not exert a growth-promoting effect in vivo, CBFGF, but not bFGF, strongly stimulated the DNA synthesis in stromal cells at 5 days and 7 days after injection. These results indicate that CBD may be used as an anchoring unit to produce fusion proteins nondiffusible and long-lasting in vivo.Currently, more than 100 soluble peptide signaling molecules, including peptide hormones, growth factors, and lymphokines, are known. These molecules can be classified into two types: one, like classic hormones, is produced in a specific organ͞cell and exerts a characteristic effect on relatively limited target cells via blood flow (endocrine), and the other is produced in a wide variety of tissues and acts in an autocrine or a paracrine manner with low target specificity. In the latter case, the specificity of the action depends for the most part on spatiotemporarily controlled production of the signaling molecule and the local tissue architecture. The former type of molecules (endocrine factors) are suitable as therapeutic agents as they can be delivered systemically without loss of target specificity. In contrast, autocrine͞paracrine factors may induce diverse responses in various tissues when present in the blood at concentrations higher than a threshold value. Thus, one cannot expect specific therapeutic effects of the factors administered by ordinary methods, though they have many promising biologic activities for clinical applications.

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ABSTRACT:To find candidates for the mediator of the growth-promoting action of androgen in rat prostates, the changes in the steady-state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration-induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200-300% of the normal level 3-5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor-a (TGF-a), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF-P1, TGF-P type I1 receptor, hepatocyte growth factor (HGF), and c-MET/ HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3-5 days after androgen replacement. The second increase was evident in TGF-a, EGF receptor, KGF, and c-MET mRNAs. These results indicate the possibility that multiple growth factor-receptor systems participate in the androgen-dependent regrowth of castrated rat prostates. 0 1996 Wiley-Liss, Inc.

Rhodium complexes (RhClL3, RhCl(CO)L2, [RhCl(COD)]2; L=PPh3) catalyze hydrostannation of terminal acetylenes (RC≡CH; R=Ph, Me3Si, R1OC(R2)(R3), and R1OCH2CH2; R1=THP, OAc; R1, R2=H, Me) with Bu3SnH to produce R(Bu3Sn)C=CH2 selectively. Other transition metal complexes [MCl2L2(M=Ni, Pd, Pt, Co)] are also active for the hydrostannation, but with less selectivity.

To find candidates for the mediator of the growth‐promoting action of androgen in rat prostates, the changes in the steady‐state levels of mRNAs coding for several growth factors and their receptors were examined by Northern blot analysis during castration‐induced involution, and subsequent regrowth induced by androgen in the ventral and dorsolateral lobes. The changes in the growth factor systems and a typical secretory protein in the ventral lobe were similar to, but more prominent than, those in the dorsolateral lobe, showing the higher androgen dependency of the ventral lobe. Among the growth factors and their receptors investigated, only epidermal growth factor (EGF) showed apparent positive androgen dependency: EGF mRNA content in the ventral lobe decreased to about 30% of the normal level within 24 hr after castration, and increased, attaining about 200–300% of the normal level 3–5 days after androgen administration to castrated rats. mRNAs coding for all other factors examined, i.e., transforming growth factor‐α (TGF‐α), EGF receptor, basic fibroblast growth factor (bFGF), keratinocyte growth factor (KGF), FGF receptor 1, TGF‐β1, TGF‐β type II receptor, hepatocyte growth factor (HGF), and c‐MET/HGF receptor, increased after castration in greater or lesser degree, and after a brief pause or a decrease some of them increased again attaining a second peak 3–5 days after androgen replacement. The second increase was evident in TGF‐α, EGF receptor, KGF, and c‐MET mRNAs. These results indicate the possibility that multiple growth factor‐receptor systems participate in the androgen‐dependent regrowth of castrated rat prostates. © 1996 Wiley‐Liss, Inc.