herceptin conjugates linked by edc boost direct tumor cell death via programmed tumor cell necrosis赫赛汀配合与edc提高直接通过肿瘤细胞程序性坏死肿瘤细胞死亡.pdfVIP

Herceptin Conjugates Linked by EDC Boost Direct Tumor Cell Death via Programmed Tumor Cell Necrosis 1. 2. 1 3 4 1 1 Jiemiao Hu , Xinli Liu , Dennis Hughes , Francisco J. Esteva , Bolin Liu , Joya Chandra , Shulin Li * 1 Department of Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 2 Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America, 3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America, 4 Department of Pathology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States of America Abstract Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride), are capable of engendering human epidermal growth factor receptor 2 (Her2) positive tumor cells death. Using a high-performance liquid chromatography (HPLC) system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also