Rosenblatt M, Caulfield M P, Fisher J E, Horiuchi N, Mckee R L, Rodan S B, Thiede M A, Thompson D D, Seedor J G, Nutt R E
Department of Biological Research and Molecular Biology, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Ann N Y Acad Sci. 1988;548:137-45. doi: 10.1111/j.1749-6632.1988.tb18800.x.
This investigation addresses a theoretical concept of tumor pathogenesis proposed over 40 years ago, namely that malignancy-associated hypercalcemia can result from endocrine secretion by tumors of a PTH-like factor. These studies demonstrate that a fragment of hHCF alone, without added or tumor-secreted cofactors or hormones, can produce hypercalcemia and other biochemical abnormalities associated with HHM. The hypercalcemia can be generated by hHCF-(1-34)NH2 action on bone, although kidney and gut could contribute to the HHM syndrome when it occurs naturally. No other tumor-secreted peptide displays this biological profile. These studies establish one (PTH-like) mechanism by which human tumors could produce hypercalcemia. Furthermore, the finding that hHCF-(1-34)NH2 is more potent than PTH in some systems is of considerable interest for the future design of hormone analogs. A broad spectrum of biological properties of hHCF-(1-34)NH2, including production of components of the HHM syndrome, can be inhibited by a PTH antagonist. Because [Tyr-34]bPTH-(7-34)NH2 selectively and competitively occupies PTH receptors, our studies demonstrate formally that hHCF-(1-34)NH2 mediates some (and perhaps all) of its actions via receptors conventionally regarded as intended for interaction with PTH, but which actually may be present to allow for expression of bioactivity of both secreted proteins. Although some structural homology is shared by the two hormones and many contribute to interaction with receptors, the disparity in structure, especially within the 1-34 domains responsible for bioactivity in both hormones, is more pronounced. The similarity in biological profiles despite structural differences between hHCF and PTH is emphasized by the inhibitory action of [Tyr-34]bPTH-(7-34)NH2 against the tumor peptide even in the absence of much of the homologous region in the PTH antagonist. This investigation provides impetus for designing more potent antagonists, which must now be regarded more appropriately as inhibitors of both PTH and hHCF. Such antagonists may best be generated from hybrid structures of the two hormones. In any case, these studies establish a promising new approach to therapy of tumor-associated hypercalcemia.
本研究探讨了40多年前提出的肿瘤发病机制的一个理论概念，即恶性肿瘤相关的高钙血症可能源于肿瘤分泌的一种类甲状旁腺激素因子的内分泌作用。这些研究表明，单独的人甲状旁腺激素相关肽片段（hHCF），在没有添加或肿瘤分泌的辅助因子或激素的情况下，就能导致高钙血症以及与恶性肿瘤高钙血症综合征（HHM）相关的其他生化异常。hHCF-(1-34)NH2对骨骼的作用可引发高钙血症，不过在HHM综合征自然发生时，肾脏和肠道也可能起作用。没有其他肿瘤分泌的肽具有这种生物学特性。这些研究确立了人类肿瘤产生高钙血症的一种（类甲状旁腺激素）机制。此外，hHCF-(1-34)NH2在某些系统中比甲状旁腺激素（PTH）更具活性这一发现，对未来激素类似物的设计具有重要意义。hHCF-(1-34)NH2的一系列生物学特性，包括引发HHM综合征的各种成分，都可被一种PTH拮抗剂抑制。由于[Tyr-34]bPTH-(7-34)NH2能选择性且竞争性地占据PTH受体，我们的研究正式证明hHCF-(1-34)NH2通过传统上认为用于与PTH相互作用的受体介导其部分（或许全部）作用，而这些受体实际上可能是为使两种分泌蛋白都能表达生物活性而存在的。尽管这两种激素存在一些结构同源性，且许多同源性有助于与受体相互作用，但结构差异更为明显，尤其是在两种激素中负责生物活性的1-34区域内。即使PTH拮抗剂中大部分同源区域缺失，[Tyr-34]bPTH-(7-34)NH2对肿瘤肽仍有抑制作用，这突出了hHCF和PTH尽管结构不同但生物学特性相似。这项研究为设计更有效的拮抗剂提供了动力，现在必须更恰当地将其视为PTH和hHCF的抑制剂。这种拮抗剂最好由两种激素的杂交结构产生。无论如何，这些研究为治疗肿瘤相关高钙血症建立了一种有前景的新方法。
