TREATMENT OF OSTEOSARCOMA WITH INTEGRIN-PERTURBING DRUGS

目前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式。 实质性 体外和体内证据，主要来自于 培养的骨肉瘤和黑色素瘤细胞系，表明整合素- 型细胞表面受体的细胞外基质存在于 恶性细胞在介导肿瘤的侵袭性和 实体瘤的转移特性。 含有Arg-Gly- 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联蛋白的配体结合位点。 这些试剂已经发现了多种应用， 心脏病发作的治疗，其中一些应用是 目前在临床试验中。 这些药剂的一个有希望的用途是防止肿瘤侵袭， 转移 采用动物肿瘤的模型系统已经表明，这些 药物可以抑制肿瘤的侵袭和肺植入， 给予小鼠肿瘤细胞。 虽然许多抗人整合素 单克隆抗体已经被我们和其他人生产出来， 可获得与鼠整联蛋白反应的单克隆抗体， 抗整合素单克隆抗体调节人肿瘤侵袭能力 并且体内转移是未经测试的。 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已 由于迄今为止使用的肽 对关键整合素的亲和力相对较低， 半衰期很短。 这个项目的目的是测试我们的 抗整联蛋白肽和单克隆抗体的改进形式 它们调节体内侵袭和转移能力的能力 人类原发性骨肉瘤 这些探员以及我们的下一个 将生产抗整联蛋白试剂，并检测 它们调节人肿瘤细胞的体内生长和转移的能力 骨肉瘤移植到无胸腺裸鼠， 骨肉瘤原位移植模型。 肽 单克隆抗体的设计将遵循相同的方法 在开发用于治疗糖尿病的RGD肽方面取得了极大的成功。 抑制血小板聚集。 我们预计，一类新的 抗转移药物将从这些研究中产生， 药物将被证明是临床上有用的治疗药物 人类骨肉瘤和其他实体瘤的研究。

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.