Buchsbaum Donald J
Department of Radiation Oncology, University of Alabama at Birmingham, 35294-6832, USA.
Semin Nucl Med. 2004 Jan;34(1):32-46. doi: 10.1053/j.semnuclmed.2003.09.005.
The fields of radioimmunodetection and radioimmunotherapy began with an initial paradigm that a targeting molecule (eg, antibody) carrying a radioisotope had the potential of selectively imaging and delivering a therapeutic dose of radiation to tumor sites. A second paradigm was developed in which injection of the targeting molecule was separated from injection of a short-lived radioisotope-labeled ligand (so-called "pretargeting strategy"). This strategy has improved radioisotope delivery to tumors in animal models, enhanced radioimmune imaging in man, and therapeutic trials are in an early phase. We proposed a third paradigm to achieve radioisotopic localization at tumor sites by inducing tumor cells to synthesize a membrane expressed receptor with a high affinity for infused radiolabeled ligands. The use of gene transfer technology to induce expression of high affinity membrane receptors can enhance the specificity of radioligand localization, while the use of radioisotopes with the ability to deliver radiation damage across several cell diameters will compensate for less than perfect transduction efficiency. This approach was termed "Genetic Radioisotope Targeting Strategy." Using this strategy, induction of high levels of gastrin releasing peptide receptor or human somatostatin receptor subtype 2 expression and selective tumor uptake of radiolabeled peptides was achieved. The advantages of the genetic transduction approach are (1) constitutive expression of a tumor-associated antigen/receptor is not required; (2) tumor cells are altered to express a new target receptor or increased quantities of an existing receptor at levels that may significantly improve tumor targeting of radiolabeled ligands compared with normal tissues; (3) gene transfer can be achieved by intratumoral or regional injection of gene vectors; (4) it is feasible to target adenovirus vectors to receptors overexpressed on tumor cells by modifying adenoviral tropism (binding) so that the virus will be targeted specifically to the desired tumor; and (5) it is possible to coexpress the receptor gene and a therapeutic gene, such as cytosine deaminase, for molecular prodrug therapy to produce an enhanced therapeutic effect.
放射免疫检测和放射免疫治疗领域始于一个最初的模式，即携带放射性同位素的靶向分子（如抗体）有潜力选择性地对肿瘤部位进行成像并输送治疗剂量的辐射。随后发展出了第二种模式，其中靶向分子的注射与短寿命放射性同位素标记配体的注射分开（所谓的“预靶向策略”）。这种策略在动物模型中改善了放射性同位素向肿瘤的递送，增强了人体的放射免疫成像，并且治疗试验正处于早期阶段。我们提出了第三种模式，即通过诱导肿瘤细胞合成对注入的放射性标记配体具有高亲和力的膜表达受体，来实现放射性同位素在肿瘤部位的定位。利用基因转移技术诱导高亲和力膜受体的表达可以提高放射性配体定位的特异性，而使用具有跨几个细胞直径传递辐射损伤能力的放射性同位素将弥补转导效率不够理想的问题。这种方法被称为“基因放射性同位素靶向策略”。使用这种策略，实现了胃泌素释放肽受体或人生长抑素受体亚型2的高水平表达诱导以及放射性标记肽的选择性肿瘤摄取。基因转导方法的优点包括：（1）不需要组成性表达肿瘤相关抗原/受体；（2）改变肿瘤细胞以表达新的靶受体或增加现有受体的数量，与正常组织相比，其水平可能显著改善放射性标记配体对肿瘤的靶向性；（3）可以通过瘤内或区域注射基因载体来实现基因转移；（4）通过修饰腺病毒嗜性（结合）使腺病毒载体靶向肿瘤细胞上过表达的受体是可行的，这样病毒将特异性地靶向所需的肿瘤；（5）有可能共表达受体基因和治疗基因，如胞嘧啶脱氨酶，用于分子前药治疗以产生增强的治疗效果。
