Reubi Jean Claude, Maecke Helmut R
Institute of Pathology, University of Berne, Berne, Switzerland; and.
Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany
J Nucl Med. 2017 Sep;58(Suppl 2):10S-16S. doi: 10.2967/jnumed.116.186882.
Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quantitative receptor autoradiography, we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high density. In addition, nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high density. We propose 3 strategies for exploiting these findings for multireceptor targeting in vivo: use of heterobivalent or heteromultivalent ligands, which may bind simultaneously or monovalently to their different molecular targets; coinjection of a cocktail of radioligands; and sequential injection of different radioligands. Any of these strategies may help to remedy some of the major problems in cancer targeting: heterogeneity, change in phenotype during disease progression, and resistance.
现代药物发现高度依赖于药物靶点的识别与验证。通过体外定量受体放射自显影法，我们证明，例如在神经内分泌肿瘤中，多达3种受体可以以相对较高的密度共表达。此外，诸如乳腺癌、前列腺癌和脑肿瘤等非内分泌肿瘤也会同时高密度表达多种G蛋白偶联受体。我们提出了3种在体内利用这些发现进行多受体靶向的策略：使用异双价或异多价配体，其可以同时或以单价形式结合到不同的分子靶点；共同注射放射性配体混合物；以及顺序注射不同的放射性配体。这些策略中的任何一种都可能有助于解决癌症靶向中的一些主要问题：异质性、疾病进展过程中表型的变化以及耐药性。
