VITAMIN D & PRELEUKIA/LEUKEMIA--CANCER CHEMOPREVENTION

肿瘤是一种典型的分化异常。这些细胞 不成熟为有功能的末端细胞，但仍处于增殖期 与普通克隆相比具有增长优势的池。诱导 分化可能提供了一种从生物学上改变恶性肿瘤的方法。 通过诱导肿瘤细胞分化为功能成熟， 有丝分裂后细胞。白血病和白血病前期是很好的研究模型 生物响应性调节剂，以及被称为 1，25-二羟基维生素D3(1，25(OH)2D3是表征最好的， 生理分化诱导剂。这种第二种类固醇已知是 通过与特定基因的相互作用产生不同的生物反应 靶器官的受体。然而，1，25(OH)2D3本身已被发现 有严重的、剂量限制的高钙血症毒性。一项基本原则 这一应用的前提是1，25(OH)2D3受体存在于 不同的靶组织会有一些不同的结构 最佳配基相互作用的要求。因此，NCCP的这个提案， 它由四个相关的程序组成，提出了化学合成 1，25(OH)2D3的新类似物(包括侧链，三烯基改性，A环， 和CD环类似物)，并对它们的 生物学特性。这些类比将被测试它们的能力 诱导分化和抑制白血病细胞系增殖 以及从患者身上获取的肿瘤细胞。白血病细胞将是 使用多种克隆形成和分化试验进行体外研究 并利用裸鼠和同基因小鼠进行了体内研究。一种决心 会产生体内毒性(慢性毒性的后果 高钙血症)以及维生素D类似物的能力 促进大鼠肠道钙离子吸收和骨钙重吸收 体内(高钙血症的潜在贡献者)和影响内源性 1，25(OH)2D3的生产。我们还建议分离出1，25(OH)2D3 来自反应灵敏的白血病细胞系的受体来比较和对比 与肠道受体的配基特异性。从这些 研究表明，我们应该能够识别出一种维生素D类似物 白血病及白血病前期细胞的分化和抑制增殖 而不会引起高钙血症。我们的方法将为 肿瘤生长生物改良剂的选择 其中几种化合物可能对多种肿瘤具有活性。 和癌前病变。

Neoplasia is phenotypically an abnormality of differentiation. The cells do not mature into functional end cells but remain in the proliferative pool with a growth advantage over the normal clone. Induction of differentiation might afford a method to biologically modify the malignancy by inducing the neoplastic cells to differentiate to functionally mature, post-mitotic cells. Leukemia and preleukemia are excellent models to study biological respone modifiers, and the active vitamin D metabolite known as 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 is one of the best characterized, physological inducers of differentiation. This seco-steroid is known to produce its diverse biological responses via interaction with specific receptors of a target organ. However, 1,25(OH)2D3 itself has been found to have a serious, dose-limiting toxicity of hypercalcemia. A fundamental premise of this application is that the 1,25(OH)2D3 receptors present in differing target tissues will have somewhat different structural requirements for optimal ligand interaction. Thus this NCCP proposal, which consists of four related programs, proposes to chemically synthesize new analogs of 1,25(OH)2D3 (including side chain, triene-modified, A-ring, and CD-ring analogs) and to carry out a compehensive evaluation of their biological properties. These analogs will be tested for their ability to induce differentiation and to inhibit proliferation of leukemia cell lines and neoplastic cells harvested from patients. The leukemic cells will be studied in vitro using a variety of clonogenic and differentiation assays and studied in vivo using nude mice and syngenic mice. A determination will be made of the in vivo toxicity (the consequence of chronic hypercalcemia) of the vitamin D analogs along with their ability to stimulate intestinal Ca2+ absorption and Ca2+ reabsorption from bone in vivo (potential contributors to hypercalcemia) and to affect the endogenous production of 1,25(OH)2D3. Also we propose to isolate the 1,25(OH)2D3 receptor from a responsive leukemic cell line to compare and contrast the ligand specificities with that of the intestinal receptor. From these studies we should be able to identify a vitamin D analog that will induce differentiation and inhibit proliferation of leukemia and preleukemia cells without causing hypercalcemia. Our approach will provide a model for selection of biological modifiers to neoplastic growth in general and several of the compounds may have activity on a wide spectrum of neoplastic and preneoplastic lesions.