CC-1065 ANALOGS--IDEAL DRUGS FOR ANTICANCER CONJUGATES

目前使用的抗癌剂对肿瘤的选择性有限。 从这些药物制备的免疫缀合物不是有效的 足以达到治疗效果。 因此，我们建议使用100 1000倍的细胞毒性药物，并赋予它们肿瘤选择性 将它们与抗体连接起来。 因此，毒性太大而不能使用的药物 单独使用也可以在治疗上有用。 有效的免疫缀合物将通过以下方式产生：a）将免疫缀合物置换成免疫缀合物。 目前在抗体中使用的中等细胞毒性抗肿瘤剂- 具有CC-1065类似物的药物缀合物， B）通过二硫化物将这些CC-1065类似物与抗体连接 在流通中应该是稳定的，但有效地分裂的债券 在细胞内释放完全活性的药物。 为了实现这个 目标是合成新的含二硫化物的CC-1065类似物 不影响母体药物的高细胞毒性。 初步 实验表明二硫化物官能团的存在 保持药物的效力。 这些药物中最具细胞毒性的 将通过二硫键与抗体连接， 将测定这些缀合物的细胞毒性和特异性。 的 我们建议在这项研究中使用的抗体已经被用于 人体临床试验

Currently used anti-cancer agents have limited selectivity for the tumor. Immunoconjugates that have been prepared from these drugs are not potent enough to be therapeutically effective. We therefore propose using 100 to 1000-fold more cytotoxic drugs and endow them with tumor-selectivity by linking them to antibodies. Thus, drugs that are too toxic to be used alone can be rendered therapeutically useful. Effective immunoconjugates will be generated by: a) substituting the moderately cytotoxic anti-neoplastic agents in current use in antibody- drug conjugates with CC-1065 analogs which are 100 to 1000-fold more potent and b) linking these CC-1065 analogs to antibodies via disulfide bonds that should be stable in circulation, but efficiently cleaved inside the cell to release fully active drug. In order to realize this goal, new disulfide-containing CC-1065 analogs will be synthesized without affecting the high cytotoxicity of the parent drug. Preliminary experiments indicate that the presence of a disulfide functionality preserves the potency of the drug. The most cytotoxic of these drugs will be linked to antibodies via disulfide bonds and the in vitro cytotoxicity and specificity of these conjugates will be determined. the antibodies we propose to use in this study are already being used in human clinical trials.