INHIBITION OF HUMAN PROSTATE-CANCER METASTASIS BY MODIFIED CITRUS PECTIN

改性柑橘果胶对人类前列腺癌转移的抑制作用

• 批准号: 6237683
• 负责人: KENNETH J. PIENTA
• 金额: $ 19.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237683
• 关键词: SCID mouse; SDS polyacrylamide gel electrophoresis; affinity chromatography; angiosperms; antineoplastics; athymic mouse; bioassay; carbohydrates; carcinogenesis inhibitor; cell adhesion; disease /disorder model; gel filtration chromatography; lectin; male; metastasis; molecular cloning; monoclonal antibody; pectins; plant extracts; prostate neoplasms; prostate surgery; stereochemistry; synthetic peptide; western blottings

Prostate cancer is the most common cancer diagnosed in American men and remains incurable once it has metastasized. Many stages of the metastatic cascade involve cellular interactions mediated by cell surface components such as carbohydrate-binding proteins, which include galactoside binding lectins (galectins). Specifically, tumor cell-endothelial cell adhesion and tumor cell-tumor cell emboli are known to be mediated in part by lectin-carbohydrate interactions. We have demonstrated that oral intake of a pH-modified citrus pectin (modified citrus pectin), a non-cytotoxic natural complex carbohydrate fiber found in citrus fruits and rich in galactose residues, acted as a potent inhibitor of spontaneous prostate carcinoma metastasis in the rat and believe that modified citrus pectin could potentially be developed for clinical antimetastasis therapy as well as metastasis prevention (JNCI, In Press, 1995). Modified citrus pectin inhibits the adhesion of both rat and human prostate cancer cells to endothelial cells and also inhibits tumor cell - tumor cell interactions in vitro but does not affect the growth of cancer cells in vitro or in vivo. We hypothesize, therefore, that modified citrus pectin acts as an "anti-adhesive" agent. Anti-adhesive agents, i.e., agents which disrupt cell-cell adhesion or cell-extracellular matrix interactions, have been proposed as potential anti-cancer drugs but have received little study. We propose to define the mechanism of action of modified citrus pectin. Specifically, we will (1): Define the active, stereospecific, carbohydrate moiety of modified citrus pectin which confers anti-adhesive activity. (2) Identify the cell surface components which bind to modified citrus pectin. (3) Test the ability of modified citrus pectin to inhibit metastasis of human prostate cancer cells utilizing in vivo models. The results of these studies will further define the ability of the stereospecific carbohydrate moiety of modified citrus pectin to inhibit human prostate cancer metastasis. We believe that an inhibitor of metastasis such as modified citrus pectin could have great clinical impact. Patients at high risk for continued tumor growth and subsequent metastasis, e.g., patients with positive margins at radical prostatectomy but no clinical evidence of disease, may benefit from a nontoxic agent which prevented further spread of tumor.

前列腺癌是美国男性最常见的癌症， 一旦转移，它仍然无法治愈。 转移的许多阶段 级联反应涉及细胞表面成分介导的细胞相互作用 例如碳水化合物结合蛋白，其中包括半乳糖苷结合 凝集素（甘叶蛋白）。 具体而言，肿瘤细胞内皮细胞粘附 已知肿瘤细胞肿瘤细胞栓塞部分由 凝集素 - 碳水化合物相互作用。 我们已经证明了口腔摄入量 pH修饰果胶（改性柑橘果胶）的pH修饰，一种非胞毒性的 柑橘类水果中发现的天然复合碳水化合物纤维，富含 半乳糖残留物，充当自发前列腺的有效抑制剂 大鼠的癌转移，并认为修饰的柑橘果胶 也可能开发用于临床抗替代治疗 作为预防转移（JNCI，印刷中，1995年）。 改性柑橘果胶 抑制大鼠和人前列腺癌细胞的粘附 内皮细胞并抑制肿瘤细胞 - 肿瘤细胞相互作用 体外，但不会影响癌细胞在体外或IN的生长 体内。 因此，我们假设修饰的柑橘果蛋白充当 “抗粘合剂”代理。 抗粘附剂，即破坏的代理 细胞 - 细胞粘附或细胞 - 细胞基质基质相互作用已是 提议作为潜在的抗癌药物，但很少接受研究。 我们建议定义改性柑橘果胶的作用机理。 具体来说，我们将（1）：定义活性，立体特异性，碳水化合物 赋予抗粘附活性的修饰柑橘果胶的部分。 （2） 识别与改性柑橘果胶结合的细胞表面成分。 （3）测试改性柑橘果胶抑制转移的能力 人类前列腺癌细胞利用体内模型。 这些研究的结果将进一步定义 改性柑橘果胶的立体特异性碳水化合物部分抑制 人前列腺癌转移。 我们相信 诸如改性柑橘果胶之类的转移可能具有很好的临床 影响。 肿瘤持续生长的高风险患者及其随后的患者 转移，例如，前列腺切除术阳性缘的患者 但是没有疾病的临床证据，可以从无毒剂中受益 这阻止了肿瘤的进一步扩散。