Rouleau Cecile, Menon Krishna, Boutin Paula, Guyre Cheryl, Yoshida Hitoshi, Kataoka Shiro, Perricone Michael, Shankara Srinivas, Frankel Arthur E, Duesbery Nicholas S, Vande Woude George, Biemann Hans-Peter, Teicher Beverly A
Genzyme Corporation, Framingham, MA 01701, USA.
Int J Oncol. 2008 Apr;32(4):739-48.
Two of the three components of anthrax toxin, protective antigen (PA) and lethal factor (LF), together known as lethal toxin (LeTx), reportedly show anti-tumor activity in melanoma in vitro and in vivo. The growth inhibitory activity of LeTx in culture was determined in nine human cancer cell lines, including melanoma, neuroblastoma and adenocarcinoma cells, as well as in human umbilical vein endothelial cells (HUVEC). The contribution of the two known PA receptor proteins, ANTXR1/TEM8 and ANTXR2/CMG2, to the sensitivity of the cells was assessed. The efficacy of LeTx was evaluated in vivo in the SK-N-AS neuroblastoma and SK-MEL-28 melanoma tumor xenograft models. Sensitivity to LeTx in vitro was observed in the neuroblastoma and colorectal adenocarcinoma cells and HUVEC, as well as melanoma cells. ANTXR1/TEM8 and ANTXR2/CMG2 protein expression studies suggested that a certain threshold of the PA receptor protein level must be met for sensitivity to LeTx to be observed. However, although the SK-N-AS neuroblastoma cells expressed the highest levels of receptor proteins and achieved the lowest IC50 in vitro (0.1 ng/ml), we observed no correlation between either the ANTXR1/TEM8 or ANTXR2/CMG2 protein levels and sensitivity to LeTx in vitro. In vivo, LeTx was an active anti-tumor agent when administered intravenously to mice bearing the human SK-N-AS or SK-MEL-28 tumor xenografts. The tumor growth delays were 6-8 days with a lower dose regimen and 14-16 days with a higher dose regimen for the two tumor models. These in vitro data suggest that LeTx may have broad therapeutic indications in cancer and the in vivo studies demonstrate that LeTx has systemic efficacy in neuroblastoma as well as melanoma. The therapeutic potential of LeTx needs to be further investigated in non-melanoma tumor models expressing the ANTXR1/TEM8 and/or ANTXR2/CMG2 protein.
炭疽毒素的三个组成部分中的两个，即保护性抗原（PA）和致死因子（LF），合称为致死毒素（LeTx），据报道在体外和体内的黑色素瘤中均显示出抗肿瘤活性。在包括黑色素瘤、神经母细胞瘤和腺癌细胞以及人脐静脉内皮细胞（HUVEC）在内的九种人类癌细胞系中测定了LeTx在培养物中的生长抑制活性。评估了两种已知的PA受体蛋白，即ANTXR1/TEM8和ANTXR2/CMG2对细胞敏感性的贡献。在SK-N-AS神经母细胞瘤和SK-MEL-28黑色素瘤肿瘤异种移植模型中对LeTx的体内疗效进行了评估。在神经母细胞瘤、结肠直肠腺癌细胞、HUVEC以及黑色素瘤细胞中均观察到了对LeTx的体外敏感性。ANTXR1/TEM8和ANTXR2/CMG2蛋白表达研究表明，要观察到对LeTx的敏感性，PA受体蛋白水平必须达到一定阈值。然而，尽管SK-N-AS神经母细胞瘤细胞表达的受体蛋白水平最高，且在体外达到了最低的半数抑制浓度（IC50，0.1纳克/毫升），但我们并未观察到ANTXR1/TEM8或ANTXR2/CMG2蛋白水平与体外对LeTx的敏感性之间存在相关性。在体内，当向携带人SK-N-AS或SK-MEL-28肿瘤异种移植的小鼠静脉注射LeTx时，它是一种有效的抗肿瘤药物。对于这两种肿瘤模型，较低剂量方案的肿瘤生长延迟为6 - 8天，较高剂量方案的肿瘤生长延迟为14 - 16天。这些体外数据表明LeTx在癌症治疗中可能具有广泛的适应症，而体内研究表明LeTx在神经母细胞瘤和黑色素瘤中均具有全身疗效。LeTx的治疗潜力需要在表达ANTXR1/TEM8和/或ANTXR2/CMG2蛋白的非黑色素瘤肿瘤模型中进一步研究。
