TREATMENT OF OSTEOSARCOMA WITH INTEGRIN-PERTURBING DRUGS

迫切需要更有效的治疗和缓和手段

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.