Ogawa T, Mimura Y, Isowa K, Kato H, Mitsuishi M, Toyoshi T, Kuwayama N, Morimoto H, Murakoshi M, Nakayama T
Safety Research Department, Teikoku Hormone Manufacturing Co., Ltd., 1604 Shimosakunobe, Takatsu-ku, Kawasaki-shi, 213-8522, Kanagawa, Japan.
Toxicol Lett. 2001 Apr 30;121(2):97-106. doi: 10.1016/s0378-4274(01)00327-7.
One of the major dose-limiting toxicities induced by antimicrotubule antitumor agents such as vinca alkaloids and taxanes is peripheral neuropathy. The neurotoxicity of TZT-1027 (a dolastatin 10 derivative antimicrotubule agent) was thus assessed using the animal models for antimicrotubule agent-induced neurotoxicity. Rabbits were intravenously given TZT-1027 or vincristine weekly for 5 weeks. In the mouse study, TZT-1027, vincristine or paclitaxel was intravenously given every 2 days and/or weekly. Despite the neuropathologic evidence such as myelinated axonal and fiber degeneration in the peripheral nerves and in the sensory tracts of the spinal cord following the treatment with vincristine or paclitaxel, no drug-induced alteration was observed in the TZT-1027 groups. Although there are reports that some other dolastatin derivatives with antimicrotubule activity showed no neurotoxic potential in humans, the present study represents the first demonstration in experimental animals that a dolastatin derivative has no, or at least a lower, neurotoxic potential compared to other antimicrotubule agents.
诸如长春花生物碱和紫杉烷类等抗微管抗肿瘤药物所引发的主要剂量限制性毒性之一是周围神经病变。因此，使用抗微管药物诱导神经毒性的动物模型评估了TZT-1027（一种多拉司他汀10衍生物抗微管药物）的神经毒性。兔子每周静脉注射TZT-1027或长春新碱，持续5周。在小鼠研究中，每2天和/或每周静脉注射TZT-1027、长春新碱或紫杉醇。尽管在用长春新碱或紫杉醇治疗后，周围神经和脊髓感觉束出现了有髓轴突和纤维变性等神经病理学证据，但在TZT-1027组中未观察到药物诱导的改变。虽然有报道称其他一些具有抗微管活性的多拉司他汀衍生物在人类中未显示出神经毒性潜力，但本研究首次在实验动物中证明，与其他抗微管药物相比，一种多拉司他汀衍生物没有神经毒性潜力，或至少具有较低的神经毒性潜力。
