PRE TARGETED THERAPY USING THE NOVEL TACHYKININ (NK) REC

描述：(申请人描述) 这些研究的长期目标是开发多肽靶标的用途。 对于新的神经内分泌神经激肽(NK)受体系统， 在乳腺癌中呈结构性过度表达。未标记的P物质(SP)，或 选择性结合NK-1或NK-2的类似物将在体外进行评估 在活体内。发射俄歇的放射性核素(例如，In-111)将被螯合到 NK受体靶向剂。在载体In-111的细胞内化时 预计会有很大的辐射毒性作用，预计会 在体内转化为肿瘤生长控制效应。这些研究一直在进行 细分为四个假设驱动的目标。为了实现我们的既定目标，我们 将：(1)利用培养的乳腺癌株建立合适的载体 NK受体系统的治疗药物。人血清白蛋白的体外细胞毒性 未结合的SP激动剂和拮抗剂(氨基端片段6-11， 将对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量。(2)确定是否 NK-1和NK-2结合位点数受细胞因子影响 (如IFNA、IL-1、IL-6)或化疗(如紫杉醇、阿霉素)。(3) NK导向载体在乳腺肿瘤体内的生物分布研究 异种移植物。摄取将使用全组织计数、全组织计数 组织切片的动物成像和显微放射自显影。(4)评估 SP载体在皮下乳腺肿瘤模型中的治疗作用 和微转移(心内MDA-231)乳腺模型。潜在的GI和 骨髓毒性将通过监测体重变化和白蛋白来评估 血细胞和血小板计数。老鼠也将被监测是否有可能 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.