Hammond L A, Davidson K, Lawrence R, Camden J B, Von Hoff D D, Weitman S, Izbicka E
Institute for Drug Development, Cancer Therapy & Research Center, 8122 Datapoint Drive 650, San Antonio, TX 78229, USA.
J Cancer Res Clin Oncol. 2001 May;127(5):301-13. doi: 10.1007/s004320000212.
FB642(methyl-2-benzimidazolecarbamate, carbendazim) is a systemic fungicide belonging to the benzimidazole family with antitumor activity against a broad spectrum of tumors both in vitro and in vivo such as pancreas, prostate, colon, and breast. Although the preclinical antitumor activity of FB642 has been well explored, its mechanism of action has not been as well delineated. Previous studies indicate that FB642 may interfere with mitosis and thus may disrupt or inhibit microtubule function resulting in apoptosis. This study seeks to determine if FB642 is a sufficiently novel agent worthy of further development by examining the effect of FB642 on apoptosis, the cell cycle, p53-positive and -negative tumors, and drug-resistant and MDR cell lines. The results of this present study indicate that FB642 increases the degree of apoptosis in all examined tumor cell lines, may induce G2/M uncoupling, may selectively kill p53 abnormal cells, and exhibits antitumor activity in drug- and multidrug-resistant cell lines. The induction of apoptosis by FB642, particularly in p53-deficient cells, its impressive in vivo activity against a broad spectrum of murine and human tumors, as well as an acceptable toxicity profile in animals, make FB642 an excellent candidate for further evaluation in clinical trials in cancer patients.
FB642（甲基-2-苯并咪唑氨基甲酸酯，多菌灵）是一种系统性杀菌剂，属于苯并咪唑类，在体外和体内对多种肿瘤具有抗肿瘤活性，如胰腺癌、前列腺癌、结肠癌和乳腺癌。尽管FB642的临床前抗肿瘤活性已得到充分研究，但其作用机制尚未完全阐明。先前的研究表明，FB642可能干扰有丝分裂，从而可能破坏或抑制微管功能，导致细胞凋亡。本研究旨在通过检测FB642对细胞凋亡、细胞周期、p53阳性和阴性肿瘤以及耐药和多药耐药细胞系的影响，确定FB642是否是一种值得进一步开发的新型药物。本研究结果表明，FB642可增加所有检测肿瘤细胞系的凋亡程度，可能诱导G2/M期解偶联，可选择性杀死p53异常细胞，并在耐药和多药耐药细胞系中表现出抗肿瘤活性。FB642诱导细胞凋亡，特别是在p53缺陷细胞中，其在体内对多种小鼠和人类肿瘤具有令人印象深刻的活性，以及在动物中可接受的毒性特征，使FB642成为癌症患者临床试验中进一步评估的优秀候选药物。
