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Jpn J Cancer Res. 2000 Jul;91(7):737-47.

Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin.

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  • 1Teikoku Hormone Mfg. Co., Ltd., Takatsu-ku, Kawasaki, Kanagawa 213-8522, Japan.


TZT-1027, a derivative of dolastatin 10 isolated from the Indian Ocean sea hare Dolabella auricularia in 1987 by Pettit et al., is a potent antimicrotubule agent. We have compared the activity of TZT-1027 with that of dolastatin 10 as well as the vinca alkaloids vinblastine (VLB), vincristine (VCR) and vindesine (VDS). TZT-1027 and dolastatin 10 inhibited microtubule polymerization concentration-dependently at 1 - 100 microM with IC50 values of 2.2 +/- 0.6 and 2.3 +/- 0.7 microM, respectively. VLB, VCR and VDS inhibited microtubule polymerization at 1 - 3 microM with IC50 values of 2.7 +/- 0.6, 1.6 +/- 0.4 and 1.6 +/- 0.2 microM, respectively, but showed a slight decrease in inhibitory effect at concentrations of 10 microM or more. TZT-1027 also inhibited monosodium glutamate-induced tubulin polymerization concentration-dependently at 0.3 - 10 microM, with an IC50 of 1.2 microM, whereas VLB was only effective at 0.3 - 3 microM, with an IC50 of 0.6 microM, and caused so-called "aggregation" of tubulin at 10 microM. Scatchard analysis of the binding data for [(3)H]VLB suggested one binding site (Kd 0.2 +/- 0.04 microM and Bmax 6.0 +/- 0.26 nM / mg protein), while that for [(3)H]TZT-1027 suggested two binding sites, one of high affinity (Kd 0.2 +/- 0.01 microM and Bmax 1.7 +/- 0.012 nM / mg protein) and the other of low affinity (Kd 10. 3 +/- 1.46 microM and Bmax 11.6 +/- 0.83 nM / mg protein). [(3)H]TZT-1027 was completely displaced by dolastatin 10 but only incompletely by VLB. [(3)H]VLB was completely displaced by dolastatin 10 and TZT-1027. Furthermore, TZT-1027 prevented [(3)H]VLB from binding to tubulin in a non-competitive manner according to Lineweaver-Burk analysis. TZT-1027 concentration-dependently inhibited both [(3)H]guanosine 5'-triphosphate (GTP) binding to and GTP hydrolysis on tubulin. VLB inhibited the hydrolysis of GTP on tubulin concentration-dependently to a lesser extent than TZT-1027, but no inhibitory effect of VLB on [(3)H]GTP binding to tubulin was evident even at 100 microM. Thus, TZT-1027 affected the binding of VLB to tubulin, but its binding site was not completely identical to that of VLB. TZT-1027 had a potent inhibitory effect on tubulin polymerization and differed from vinca alkaloids in its mode of action against tubulin polymerization.

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