Catholic University of the Sacred Heart, Department of Gynecologic Oncology, Rome, Italy.
Expert Opin Investig Drugs. 2009 Dec;18(12):1939-46. doi: 10.1517/13543780903401284.
Brostallicin (PNU-166196), a-bromo-acrylamido tetra-pyrrole derivative, showed high cytotoxic potency and myelotoxicity dramatically reduced compared with other minor groove DNA-binding agents. In the presence of high intracellular glutathione concentrations, which are associated with resistance to chemotherapy, brostallicin performs a DNA minor groove attack leading to alkylation of DNA nucleophilic functions. In preclinical models, the antitumor activity of brostallicin has been tested in ovarian cancer xenografts, L1210 murine leukemia models, renal, colon and prostatic cancer cells and glutathione-S-transferase (GST) transfected human breast carcinoma cells. In clinical setting, the antitumor activity of brostallicin has been tested in ovarian cancer and in soft tissue sarcoma patients. A clear therapeutic advantage is also observed in preclinical models when brostallicin is combined with anticancer agents such as cisplatin (CDDP), doxorubicin, irinotecan and docetaxel. Brostallicin was also tested in combination with gefitinib, imatinib and bevacizumab in in vitro and in vivo studies, documenting a synergistic effect and with cetuximab showing an additive effect. Preliminary results of activity and toxicities of brostallicin in Phase I and II studies will be provided.
布罗他滨（PNU-166196），一种溴代丙烯酰胺四吡咯衍生物，与其他小沟 DNA 结合剂相比，具有较高的细胞毒性和显著降低的骨髓毒性。在与化疗耐药相关的高细胞内谷胱甘肽浓度存在下，布罗他滨对 DNA 小沟进行攻击，导致 DNA 亲核功能的烷化。在临床前模型中，已在卵巢癌异种移植、L1210 白血病模型、肾、结肠和前列腺癌细胞以及谷胱甘肽-S-转移酶（GST）转染的人乳腺癌细胞中测试了布罗他滨的抗肿瘤活性。在临床环境中，已在卵巢癌和软组织肉瘤患者中测试了布罗他滨的抗肿瘤活性。当布罗他滨与顺铂（CDDP）、阿霉素、伊立替康和多西他赛等抗癌药物联合使用时，在临床前模型中也观察到明显的治疗优势。布罗他滨还在体外和体内研究中与吉非替尼、伊马替尼和贝伐单抗联合进行了测试，证明具有协同作用，与西妥昔单抗联合具有相加作用。将提供布罗他滨在 I 期和 II 期研究中的活性和毒性的初步结果。
