FACTORS IN COMBINED RADIOIMMUNOTHERAPY AND CHEMOTHERAPY IN CANCER MANAGEMENT

本项目拟议研究的总体目标是确定 放射免疫疗法（赖特）如何与化疗一起使用， 改善结肠癌和胰腺癌抗肿瘤反应， 建立指导最佳组合使用的生物学原则 这两种治疗方法的区别 研究将主要针对 三种结肠癌细胞系（GW-39、LS 174 T、HT-29）和一种胰腺癌细胞系（PNS-174）。 细胞系（CaPan-1），其对赖特和化疗的敏感性不同。 将对皮下生长的肿瘤进行研究，以及在 微转移和原位模型。 将使用GW-39异种移植物 作为皮下（SC）模型和作为肺内模型 微转移模型LS 174 T和HT-29生产线将同时用作 sc和肝转移模型。 对赖特或 所有3种结肠SC模型的单独化疗已经被证实是有效的。 测定 GW-39对赖特有良好的反应， 到化疗。 LS 174 T对赖特的反应良好， HT-29对化疗有反应，HT-29对每种化疗都有中度反应。 治疗 良好表征的sc异种移植和原位模型 将使用CaPan-1。 这四条线都已经被用来 评价抗原（Ag）表达、抗体（MAb）靶向和生长 在裸鼠中的动力学。 放射性标记MN-14抗癌胚抗原 (CEA)和PAM 4（抗MUC-1表位）将用于这些研究。 化疗将单独使用5-氟尿嘧啶（5-FU）进行， 胰腺癌和5-FU+甲酰四氢叶酸（LV）用于结肠肿瘤。 四个主要目标将被审查：[1]使用的最佳方法 化疗和赖特一起将被检查，[2]的重要性， (a)体外化疗和放射敏感性，和（B）体内化疗和 放射敏感性（肿瘤内pH和pO 2）对肿瘤对 将检查化疗和赖特，[3]抗原的表达， 肿瘤内pH和pO 2，以及整体的靶向性和反应性 在赖特、化疗或联合治疗中存活的肿瘤 将被确定，以及[4]抗体或细胞毒性药物的沉积 作为血管化的功能。肿瘤的大小和生存能力 使用结肠和胰腺异种移植物的视频图像分析评估 切片，接受单周期或多周期化疗或 放射性抗体疗法

The overall goal of the proposed studies in this project is to determine how radioimmunotherapy (RAIT) can be used together with chemotherapy to improve anti-tumor responses of colonic and pancreatic cancer and to establish biological principles that will guide the optimal combined use of these two therapeutic modalities. Studies will be done primarily on three colonic cancer lines (GW-39, LS174T, HT-29) and on one pancreatic line (CaPan-1) that vary in their sensitivity to RAIT and chemotherapy. Studies will be performed on tumors grown s.c., as well as in micrometastatic and orthotopic models. The GW-39 xenograft will be used as both a subcutaneous (sc) model and as an intrapulmonary micrometastatic model. The LS174T and HT-29 lines will be used as both sc and liver metastasis models. The responsiveness to RAIT or to chemotherapy alone of all 3 colonic sc models has already been determined. GW-39 is a good responder to RAIT and a moderate responder to chemotherapy. LS174T is a good responder to RAIT and a poor responder to chemotherapy and HT-29 exhibits a moderate response to each treatment. The well characterized sc xenograft and orthotopic models of CaPan-1 will be used. All four lines have already been used to evaluate antigen (Ag) expression, antibody (MAb) targeting, and growth kinetics in nude mice. Radiolabeled MN-14 anti-carcinoembryonic antigen (CEA) and PAM4 (anti-MUC-1 epitope) will be used for these studies. Chemotherapy will be done with 5-fluorouracil (5-FU) alone for pancreatic cancer and with 5-FU+leucovorin (LV) for colonic tumors. Four major aims will be examined: [1] the optimal approach for using chemotherapy and RAIT together will be examined, [2] the importance of (a) in vitro chemo- and radiosensitivity, and (b) in vivo chemo- and radiosensitivity (intratumor pH and pO2) on tumor responsiveness to chemotherapy and RAIT will be examined, [3] the expression of antigen, intratumor pH and pO2, and targetability and responsiveness of whole tumor that survive either RAIT, chemotherapy or the combination therapy will be determined, and [4] the deposition of antibody or cytotoxic drug as function of vascularization. tumor size and viability will be assessed using video image analysis of colonic and pancreatic xenograft sections, treated with a single cycle or multiple cycles of chemo- or radioantibody therapy.