VITAMIN D & PRELEUKIA/LEUKEMIA--CANCER CHEMOPREVENTION

维生素D

• 批准号: 3548877
• 负责人: Harold Phillip Koeffler
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1991-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3548877
• 关键词: 1,25 dihydroxycholecalciferol; athymic mouse; biological response modifiers; calcium metabolism; cell differentiation; chemical structure function; chickens; drug design /synthesis /production; gastrointestinal absorption /transport; hematopoietic stem cells; hormone receptor; human tissue; laboratory mouse; laboratory rat; leukemia; neoplasm /cancer pharmacology; neoplastic cell; preneoplastic state; vitamin analog

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.

瘤形成是一种表型分化异常。 细胞 未成熟为功能性终末细胞，但仍处于增殖状态。 与正常克隆相比具有生长优势的池。 诱导 分化可能提供一种方法，生物学修改恶性肿瘤 通过诱导肿瘤细胞分化为功能成熟， 有丝分裂后的细胞 白血病和白血病前期是很好的研究模型 生物反应调节剂和活性维生素D代谢物， 1，25-二羟基维生素D3（1，25（OH）2D3）是最好的表征之一， 分化的生理诱导物。 已知这种开环类固醇 通过与特定的细胞相互作用， 靶器官的受体。 然而，1，25（OH）2D3本身已被发现 有严重的高钙血症的剂量限制性毒性。 一项基本 本申请的前提是，存在于细胞中的1，25（OH）2D3受体 不同的靶组织将具有稍微不同的结构 最佳配体相互作用的要求。 因此，NCCP的这一提议， 包括四个相关的项目，建议化学合成 1，25（OH）2D3的新类似物（包括侧链，三烯修饰的，A环， 和CD-环类似物），并对其进行综合评价， 生物学特性 将测试这些类似物的能力， 白血病细胞系诱导分化和抑制增殖 以及从患者身上收集的肿瘤细胞。 白血病细胞会 使用多种克隆形成和分化测定进行体外研究 并使用裸鼠和同基因小鼠进行体内研究。 的确定 将由体内毒性（慢性毒性的后果）组成。 高钙血症）的维生素D类似物沿着与他们的能力， 刺激小肠Ca~（2+）吸收和骨Ca~（2+）重吸收 体内（高钙血症的潜在贡献者），并影响内源性 产生1，25（OH）2D3。 我们还建议分离1，25（OH）2D3 受体从响应白血病细胞系比较和对比， 配体特异性与肠受体的特异性。 从这些 我们应该能够确定一种维生素D类似物， 抑制白血病和白血病前期细胞的增殖 而不会引起高钙血症 我们的方法将提供一个模型， 选择一般肿瘤生长的生物修饰剂， 几种化合物可能对广谱肿瘤具有活性 和癌前病变。