TREATMENT OF OSTEOSARCOMA WITH INTEGRIN-PERTURBING DRUGS

迫切需要更有效的治疗和姑息治疗 骨肉瘤以及其他实体肿瘤的治疗方法。相当可观 体外和体内证据，主要来自于对 培养的骨肉瘤和黑色素瘤细胞株表明整合素- 细胞外基质的类型细胞表面受体 恶性细胞在介导肿瘤侵袭和转移过程中发挥重要作用 实体瘤的转移特性。含有Arg-Gly-的多肽- 天冬氨酸(RGD)三肽序列与某些整合素特异性单抗 抗体可以阻断许多整合素的配体结合部位。 这些药物已经发现了从伤口愈合到治疗的各种应用 用于治疗心脏病发作，其中一些应用是 目前正在进行临床试验。 这些药物的一个有希望的用途是防止肿瘤侵袭和 转移。使用动物肿瘤的模型系统表明，这些 静脉注射药物可抑制肿瘤侵袭和肺种植 注射小鼠肿瘤细胞。虽然许多抗人类整合素 我们自己和其他人都产生了单抗，很少 与小鼠整合素反应的单克隆是可用的，因此 抗整合素单克隆体对人肿瘤侵袭的调控作用 体内的转移也是未经测试的。进一步挖掘潜力 整合素反应肽作为抗肿瘤药物的临床应用 因为到目前为止使用的多肽 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 抗整合素多肽和抗整合素单抗的改良形式 它们调节体内侵袭和转移能力的能力 人类原发骨肉瘤。这些特工以及我们的下一个 将生产和检测新一代抗整合素试剂 它们对人体内生长和转移的调控能力 一种新型的骨肉瘤移植到裸鼠体内的研究 我们建立了骨肉瘤原位移植模型。多肽 和单抗设计将遵循相同的方法， 在开发RGD多肽方面非常成功 抑制血小板聚集。我们预计会有一批新的 这些研究将产生抗转移药物，这些药物 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肿瘤。

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.