RADIOIMMUNOTHERAPY AND TUMOR VASCULAR PHYSIOLOGY

据报道，有几种人类肿瘤可以控制肿瘤生长。 异种移植模型和使用放射性核素的几项临床试验 与肿瘤相关抗体结合。这些放射免疫结合物 并在肿瘤组织中滞留许多天，从而 提供持续的低剂量辐射。细胞杀伤力和 与短持续时间相关的靶组织的生理变化- 高剂量的电离辐射是众所周知的。然而，其影响 低剂量率照射，如放射免疫疗法(RAIT)， 仍然不为人所知。 放射自显影分析表明，放射性抗体 分布在血管周围空间，初步结果表明 这种局部的辐射剂量改变了肿瘤血管的生理和 用额外剂量的RAIT重定向这些肿瘤的能力。 这些辐射引起的血管功能变化可能反过来 影响瘤内pH值和氧分压。细胞密度的破坏可能 也影响肿瘤间质内的压力。这些措施的净效果是 变化可能不仅影响额外剂量的增加 多周期方案中的放射抗体，但也可能影响聚集 分次剂量方案中的放射抗体，并可能影响 吸收其他较小的抗肿瘤药物(如药物、BRM)。 该提案有三个广泛的目标：(A)确定低收入和低收入的影响； 剂量率辐射对肿瘤血管结构和功能的影响 在肿瘤和微观层面，(B)确定RAIT如何影响 肿瘤间质内压力、pH和pO2，以及(C)评估 这些变化影响了多发性骨髓瘤的生长和治疗潜力。 剂量的放射抗体或低分子治疗药物。我们会 使用抗结肠特异性抗原-p(CSAP)抗体(Mu-9) I-131，一种在1毫米范围内储存能量的放射性核素，或 Re-186，一个中程贝塔发射器，或两个高能贝塔发射器- 具有较长路径长度的Re-188和Y-90发射器，以解决这些问题 问题。具体来说，我们将：(1)建立剂量-反应关系 在辐射剂量和血管变化之间，(2)决定辐射是否与 其他核素标记抗体改变肿瘤血管功能，(3) 确定肿瘤中是否发生血管变化如果放射抗体 分布于血管周围间隙，(4)确定是否 如果RAIT的总剂量被分次，就会发生血管变化 肿瘤。(5)评估RAIT对pH、PO2和间质的影响 压力(6)评估存活的细胞群体是否可访问和 在肿瘤血管形成后对第二剂RAIT有反应 中断，以及(7)确定肿瘤中的中断是否 血管系统阻碍小分子药物的摄取和治疗效果 重量物质。 总体而言，低剂量率辐射源于 放射抗体在血管周围的分布也会损害肿瘤血管 通过直接和/或间接破坏对辐射敏感的内皮细胞 通过影响内源性血管刺激剂的产生 如血管内皮生长因子/血管内皮细胞生长因子。该提案还提出了另外两个假设：[a] 一旦血管受损，靶向肿瘤的能力就会增加 治疗(免疫结合物、BRMS或细胞毒性药物)可能是有限的， 受损的血管会影响肿瘤的内环境， 从而影响病毒的分布和细胞毒作用。 依赖于肠道等因素的其他疗法 压力、氧分压和pH值。

Control of tumor growth has been reported for several human tumor xenograft models and for a few clinical trials using radionuclides coupled to tumor-associated antibodies. These radioimmunoconjugates accrete and are retained in tumor tissue for many days, thereby delivering a continuous low dose of radiation. The cytocidal and physiological changes in target tissue associated with short duration- high dose ionizing radiation are well understood. However, the effects of low dose rate irradiation, such as from radioimmunotherapy (RAIT), remain unknown. Autoradiographic analysis has demonstrated that radioantibodies distribute in the perivascular space, and preliminary results indicate that this localized radiation dose alters tumor vascular physiology and the ability to retarget these tumors with additional doses of RAIT. These radiation-induced changes in vascular function may in turn influence intratumoral pH and pO2. The disruption in cell density may also affect intratumoral interstitial pressure. The net effect of these changes may not only impact on the accretion of additional doses of radioantibody in a multiple cycle scheme, but may also affect accretion of radioantibody in a fractionated dose scheme and may influence the uptake of other smaller anti-tumor agents (e.g. drugs, BRMs). This proposal has three broad goals: (a) To determine the effects of low- dose rate radiation on tumor vascular structure and function on the whole tumor and on the microscopic level, (b) To determine how RAIT affects intratumoral interstitial pressure, pH, and pO2, and (c) To assess how these changes influence accretion and therapeutic potential of multiple doses of radioantibody or lower molecular weight therapeutics. We will use an anti-colon-specific antigen-p (CSAp) antibody (Mu-9) labeled with I-131, a radionuclide that deposits its energy within a 1-mm range, or Re-186, an intermediate range beta-emitter, or two high-energy beta- emitters, Re-188 and Y-90, with longer path lengths, to address these issues. Specifically we will: (1) establish a dose-response relationship between rad dose and vascular change, (2) determine whether RAIT with other nuclide-labeled antibodies alters vascular function of tumors, (3) determine whether vascular changes occur in tumors if the radioantibody distributes away from the perivascular space, (4) determine whether vascular changes occur if the total dose of RAIT is fractionated, ed tumors. (5) assess the effect of RAIT on pH, and pO2, and interstitial pressure (6) assess whether surviving cell populations are accessible and responsive to a 2nd dose of RAIT after the tumor vasculature is disrupted, and (7) determine whether the disruption in the tumor vasculature impedes uptake and therapeutic efficacy of small molecular weight substances. Overall, the hypothesis that low dose rate radiation derived from the perivascular distribution of radioantibodies damages tumor vessels either directly by disrupting radiosensitive endothelial cells and/or indirectly by influencing the production of endogenous vascular stimulating agents like VEGF/VPF. The proposal also addresses two other hypotheses: [a] once vessels are damaged, the ability to target tumor with additional therapeutics (immunoconjugates, BRMS, or cytotoxic drugs) may be limited, and [b] damaged vessels will effect the internal milieu of the tumor and thereby influence the distribution and the cytotoxic potential of additional therapeutics that are dependent on factors like intestinal pressure, pO2, and pH.