PRE TARGETED THERAPY USING THE NOVEL TACHYKININ (NK) REC

描述：（申请人的描述） 这些研究的长期目标是开发肽靶向的用途 新的神经内分泌神经激肽（NK）受体系统， 在乳腺癌中组成型过表达。未标记的P物质（SP），或 将在体外评价选择性结合NK-1或NK-2的类似物 和体内。俄歇发射放射性核素（例如，IN-111）将被螯合， NK-受体靶向剂。在载体的细胞内化后，In-111 预期具有显著的放射性毒性作用， 转化为体内肿瘤生长控制效果。这些研究已经 细分为四个假设驱动的目标。为了实现既定目标，我们 将：（1）利用培养的乳腺癌细胞系建立合适的载体 治疗剂的NK受体系统。的体外细胞毒性 未缀合的SP激动剂和拮抗剂（氨基末端片段6-11， CP-96，345）进行评价。结果将与运营商进行比较 含有放射性铟。结合亲和力、内化率和细胞 将确定放射性核素的保留。(2)确定是否 NK-1和NK-2结合位点的数量受暴露于细胞因子的影响 (e.g., IFN α、IL-1、IL-6）或化疗（例如，紫杉醇、阿霉素）。（三） 建立NK导向载体在乳腺肿瘤中的体内生物分布 异种移植摄取将使用全组织计数、全 动物成像和组织切片的显微放射自显影。(4)评价 基于SP的载体在皮下乳腺肿瘤模型中的治疗功效 和微转移（心内MDA-231）乳腺模型。潜在GI和 将通过监测体重变化和白色 血细胞和血小板计数。还将监测小鼠是否可能 神经毒性

DESCRIPTION: (Applicant's Description) The long-term goal of these studies is to develop the use of peptide taraeting for the novel neuroendocrine neurokinin (NK) receptor system, which is constitutively overexpressed in breast cancer. Unlabeled substance P (SP), or analogues that selectively bind either NK-1 or NK-2 will be evaluated in vitro and in vivo. Auger-emitting radionuclides (e.g., IN-111) will be chelates to NK-Receptor targeting agents. Upon cell internalization of the carrier, In-111 is expected to have substantial radiotoxic effects, which are expected to translate into tumor growth controt effects in vivo. The studies have been subdivided into four hypothesis-driven aims. To achieve our stated goal, we will: (1) Use cultured breast cancer lines to establish an appropriate carrier of therapeutic agents to the NK-receptor system. The in vitro cytotoxicity of unconjugated SP agonist and antagonists (amino terminal fragment 6-11, CP-96,345) will be evaluated. Results will be compared with carriers containing radioindium. Binding affinity, internalization rate, and cell retention of the radionuclide will be established. (2) Determine whether the number of NK-1 and NK-2 binding sites is affected by exposure to cytokines (e.g., IFNa, IL-1, IL-6) or chemotherapy (e.g., taxol, doxorubicin). (3) Establish the biodistribution of NK-directed carriers in vivo in breast tumor xenografts. Uptake will be determined using whole tissue counting, whole animal imaging and microautoradiography of tissue sections. (4) Evaluate the therapeutic efficacy of SP-based carriers in a subcutaneous breast tumor model and a micrometastatic (intracardiac MDA-231) breast model. Potential GI and marrow toxicity will be assessed by monitoring body weight changes and white blood cell and platelet counts. Mice will also be monitored for possible neurotoxicity.