ANTIFOLATE RESISTANCE OSTEOSARCOMA

描述：（改编自研究者的摘要）骨肉瘤患者有效的化疗和适当的手术治疗的确定导致了结果的显著改善。骨肉瘤的预后仍以临床分期系统为基础。确定其他预后因素将允许分层治疗，这可能提高“高风险”患者的持久性，并最大限度地减少对“良好风险”患者的毒性。研究与化疗反应相关的生物学特征可以确定预后因素。对甲氨蝶呤耐药性的分子基础的认识取得了进展，甲氨蝶呤是一种常规高剂量治疗这种疾病的药物，这使人们能够开展体外试验，预测对这种药物的反应。对这些生物学因素的研究可能会发现新的抗叶酸二氢叶酸还原酶抑制剂，这些抑制剂克服了相关的耐药机制，可能对骨肉瘤的治疗更有效。本研究的目的是探讨与甲氨蝶呤耐药性相关的生物学因素作为骨肉瘤患者术前化疗组织学反应和预后的预测因子。从儿童癌症组和儿童肿瘤组治疗的患者中获得的骨肉瘤肿瘤样本将被检测甲氨蝶呤摄取、甲氨蝶呤聚谷氨酰化以及叶酸载体减少、二氢叶酸还原酶、叶酸聚谷氨酸合成酶和γ -谷氨酰水解酶表达的变化。这些检测的结果将与肿瘤对术前化疗的组织学反应和患者生存率相关联，以潜在地确定这些检测作为预后因素。这些研究可能确定肿瘤样本中固有和获得性甲氨蝶呤耐药的发生率，并建议在骨肉瘤的治疗中使用新的抗叶酸药物和治疗策略。

DESCRIPTION: (adapted from the investigator's abstract) The identification of effective chemotherapy and appropriate surgical treatment for patients with osteosarcoma has led to significant improvements in outcome. The determination of prognosis in osteosarcoma continues to be based on clinical staging systems. The identification of additional prognostic factors would allow stratification of therapy, which may improve the durability of "high risk" patients and minimize toxicity to the "good risk" patients. Investigation of biological features related to chemotherapy response may identify prognostic factors. Advances in the understanding of the molecular basis of resistance to methotrexate, an agent routinely used in high doses for the treatment of this disease has emerged, allowing the development of in vitro assays which may predict response to this drug. Studies of these biological factors may identify new antifolate inhibitors of dihydrofolate reductase which overcome the relevant mechanisms of resistance as being potentially more effective for the treatment of osteosarcoma. The purpose of this study is to investigate biological factors related to methotrexate resistance as predictors of histologic response to preoperative chemotherapy and outcome in patients with osteosarcoma. Osteosarcoma tumor samples obtained from patients treated by the Childrens' Cancer Group and the Pediatric Oncology Group will be assayed for alterations in methotrexate uptake, methotrexate polyglutamylation as well as reduced folate carrier, dihydrofolate reductase, folylpolyglutamate synthestase and gamma- glutamyl hydrolase expression. The results of these assays will be correlated with the histologic response of the tumors to preoperative chemotherapy and patient survival to potentially identify these assays as prognostic factors. These studies may define the incidence of intrinsic and acquired methotrexate resistance in tumor samples and suggest the use of new antifolates and therapeutic strategies in the treatment of osteosarcoma.