RANDOM PEPTIDE DRUG DEVELOPMENT

项目29的中心焦点是开发生长抑制多肽。 使用随机合成多肽文库治疗癌症 合成和测试技术(“选择性过程”) 由这个项目的领导构思的。这项新技术(它可以 使用天然和/或非天然氨基酸)将用于识别新的 与3种特异性多肽中的1种具有高亲和力的多肽配体 分子靶点：(1)B细胞性非霍奇金淋巴瘤细胞表面Ig (2)基质溶酶(MMP7)，与肿瘤细胞有关 侵袭，以及(3)磷脂酰肌醇磷脂酶 C(PtdInsPLc，PLC)，参与生长后的细胞内信号转导 因子与肿瘤细胞的相互作用。结合高亲和力的多肽 人类B细胞淋巴瘤的细胞表面Ig将被检测 免疫治疗生长抑制特性在临床前人类中首次出现 未标记或联合应用的体外和SCID小鼠淋巴瘤模型 放射性碘化技术。这些模式的成功将导致 通过项目实现患者癌症中心的后续临床发展 19.与基质金属蛋白酶-7高度结合的特异性随机多肽的合成 而这也抑制了这种肿瘤分泌的功能 酶将被放大以用于体外和动物的临床前试验 肿瘤细胞侵袭和癌症辅助治疗的模型。 抑制PLC酶的特异性随机多肽的鉴定 活动之后将在蜂窝系统中进行测试，以确定 多肽先导是否能抑制细胞内信号传导 生长因子对肿瘤细胞的刺激。先导肽抑制剂，用于 PLC还将在SCID小鼠的相关人类肿瘤模型中进行测试。 这些酶抑制模型的成功将导致选择 通过工业途径进行正式药物开发的候选多肽 合作者。成功的酶抑制剂的I/II期研究 动物模型中的抗肿瘤活性将通过项目19进行 在FDA批准IND之后。

The central focus of project 29 is to develop growth-inhibitory peptides for the treatment of cancer using the random synthetic peptide library synthesis and testing technology ("Selective process") originally conceived of by this project's leaders. This new technology (which can use natural and/or unnatural amino acids) will be used to identify novel peptide ligands which bind with high affinity to 1 of 3 specific molecular targets: (1) cell-surface Ig in B-cell non-Hodgkin's lymphoma (NHL), (2) the enzyme matrilysin (MMP-7), implicated in tumor cell invasion, and (3) the enzyme phosphatidylinositol phospholipase C(PtdInsPLc, PLC), implicated in intracellular signalling after growth factor interaction with tumor cells. High affinity peptides binding to cell-surface Ig from human B-cell lymphomas will be tested for immunotherapeutic growth-inhibitory properties first in preclinical human lymphoma models in vitro and in SCID mice using either unlabeled or radioiodinated techniques. Success in these models will be lead to the subsequent clinical development of patient Cancer Center through project 19. Synthesis of specific random peptides which bind MMP-7 with high affinity and which also inhibit the function of this tumor-secreted enzyme will be scaled up for preclinical testing in vitro and in animal models for tumor cell invasion and for adjuvant therapy of cancer. Identification of specific random peptides which inhibit PLC enzyme activity will be followed with testing in cellular systems to determine whether the peptide leads can inhibit intracellular signalling after growth factor stimulation of tumor cells. Lead peptide inhibitors for PLC will also be tested in relevant human tumor models in SCID mice. Success in these enzyme-inhibition models will lead to selection of candidate peptides for formal pharmaceutical development via industrial collaborators. Phase I/II studies of successful enzyme inhibitors with antitumor activity in animal models would be conducted via project 19 after approval of IND's by the FDA.