Characterization of the Interaction of TZT‐1027, a Potent Antitumor Agent, with Tubulin

• DOI: 10.1111/j.1349-7006.2000.tb01007.x
• Publication Date: 2005-08-23T08:51:55Z
• Authors: Tsugitaka Natsume; Jun‐ichi Watanabe; Satoru Tamaoki; Nami Fujio; Katsuhiko Miyasaka; Motohiro Kobayashi
• Keywords: Vinca; Microtubule polymerization; IC50

TZT‐1027, a derivative of dolastatin 10 isolated from the Indian Ocean sea hare Dolabella auricularia in 1987 by Pettit et al. , is potent antimicrotubule agent. We have compared activity TZT‐1027 with that as well vinca alkaloids vinblastine (VLB), vincristine (VCR) and vindesine (VDS). inhibited microtubule polymerization concentration‐dependently at 1–100 μ M IC 50 values 2.2±0.6 2.3±0.7 respectively. VLB, VCR VDS 1–3 2.7±0.6, 1.6±0.4 1.6±0.2 respectively, but showed slight decrease inhibitory effect concentrations or more. also monosodium glutamate‐induced tubulin 0.3–10 an 1.2 whereas VLB was only effective 0.3–3 0.6 caused so‐called “aggregation” M. Scatchard analysis binding data for [ 3 H]VLB suggested one site (K d 0.2±0.04 B max 6.0±0.26 n /mg protein), while H]TZT‐1027 two sites, high affinity 0.2±0.01 1.7±0.012 protein) other low 10.3±1.46 11.6±0.83 protein). completely displaced incompletely VLB. TZT‐1027. Furthermore, prevented to non‐competitive manner according Lineweaver‐Burk analysis. concentrationdependently both H]guanosine 5′‐triphosphate (GTP) GTP hydrolysis on tubulin. lesser extent than no H]GTP evident even 100 . Thus, affected tubulin, its not identical had differed mode action against polymerization.