TREATMENT OF OSTEOSARCOMA WITH INTEGRIN-PERTURBING DRUGS

用干扰整合素的药物治疗骨肉瘤

• 批准号: 2099211
• 负责人: VIRGIL L WOODS
• 金额: $ 12.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1996-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2099211
• 关键词: antineoplastics; athymic mouse; cytotoxicity; human tissue; integrins; monoclonal antibody; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic growth; osteosarcoma; peptides; tissue /cell culture

There is a pressing need for more efficacious treatment and palliative modalities for osteosarcoma as well as other solid tumors. Substantial in vitro and in vivo evidence, derived primarily from the study of cultured osteosarcoma and melanoma cell lines, indicates that integrin- type cell surface receptors for extracellular matrices present on malignant cells play critical roles in mediating the invasive and metastatic properties of solid tumors. Peptides containing the Arg-Gly- Asp (RGD) tripeptide sequence and certain integrin-specific monoclonal antibodies can block the ligand binding site of many of the integrins. These agents have found diverse applications ranging from wound healing to treatment of heart attacks and some of these applications are currently in clinical trials. One promising use of these agents is to prevent tumor invasion and metastasis. Model systems employing animal tumors have shown that these agents can inhibit tumor invasion and lung implantation of intravenously administered murine tumor cells. While many anti-human integrin monoclonal antibodies had been produced by ourselves and others, few monoclonals reactive with murine integrins are available and therefore the ability of anti-integrin monoclonals to modulate human tumor invasion and metastasis in vivo is untested. Further exploration of the potential clinical utility of integrin-reactive peptides as anti-tumor drugs has been hindered by the fact that the peptides utilized to date have relatively low affinities for the critical integrins, and their blood half-lives are short. The purpose of this project is to test our improved forms of anti-integrin peptides and monoclonal antibodies for their ability to modulate the in vivo invasiveness and metastatic ability of human primary osteosarcoma. These agents as well as our next generation of anti-integrin reagents will be produced and tested for their ability to modulate in vivo growth and metastasis of human osteosarcoma transplanted to athymic nude mice employing a novel osteosarcoma orthotopic transplantation model we have developed. Peptide and monoclonal antibody design will follow the same approaches that have been extremely successful in the development of RGD peptides for the inhibition of platelet aggregation. We anticipate that a new class of anti-metastatic drugs will result from these studies and that these agents will prove to be clinically useful as adjuncts to the treatment of human osteosarcoma and other solid tumors.

迫切需要更有效的治疗和姑息治疗 骨肉瘤以及其他实体瘤的治疗方法。 重大的 体外和体内证据，主要来自以下研究 培养的骨肉瘤和黑色素瘤细胞系，表明整合素 细胞外基质的细胞表面受体类型 恶性细胞在介导侵袭性和侵袭性方面发挥着关键作用 实体瘤的转移特性。 含有Arg-Gly-的肽 Asp (RGD) 三肽序列和某些整合素特异性单克隆抗体 抗体可以阻断许多整合素的配体结合位点。 这些药物已发现多种应用，包括伤口愈合 治疗心脏病，其中一些应用是 目前正在进行临床试验。 这些药物的一种有前途的用途是预防肿瘤侵袭和 转移。 采用动物肿瘤的模型系统表明，这些 静脉注射制剂可抑制肿瘤侵袭和肺植入 施用小鼠肿瘤细胞。 虽然许多抗人类整合素 单克隆抗体已经由我们自己和其他人生产，很少 与鼠整合素反应的单克隆抗体是可用的，因此 抗整合素单克隆抗体调节人类肿瘤侵袭的能力 且体内转移未经测试。 进一步探索潜力 整合素反应肽作为抗肿瘤药物的临床应用 迄今为止使用的肽已受到阻碍 对关键整合素及其血液的亲和力相对较低 半衰期很短。 这个项目的目的是测试我们的 抗整合素肽和单克隆抗体的改进形式 它们调节体内侵袭性和转移能力的能力 人类原发性骨肉瘤。 这些代理商以及我们的下一个 将生产并测试抗整合素试剂的产生 它们调节人类体内生长和转移的能力 采用新型方法将骨肉瘤移植到无胸腺裸鼠中 我们开发了骨肉瘤原位移植模型。 肽 单克隆抗体设计将遵循与 在 RGD 肽的开发中取得了巨大成功 抑制血小板聚集。 我们预计会出现一类新的 这些研究将产生抗转移药物，并且这些 药物将被证明作为治疗的辅助手段在临床上是有用的 人类骨肉瘤和其他实体瘤。