DOLASTATIN-10, A POWERFUL CYTOSTATIC PEPTIDE DERIVED FROM A MARINE ANIMAL - INHIBITION OF TUBULIN POLYMERIZATION MEDIATED THROUGH THE VINCA ALKALOID BINDING DOMAIN
DOLASTATIN-10, A POWERFUL CYTOSTATIC PEPTIDE DERIVED FROM A MARINE ANIMAL - INHIBITION OF TUBULIN POLYMERIZATION MEDIATED THROUGH THE VINCA ALKALOID BINDING DOMAIN
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DOI：
10.1016/0006-2952(90)90613-p
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发表时间：
1990-06-15
影响因子：
5.8
通讯作者：
HAMEL, E
中科院分区：
文献类型：
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作者：
BAI, R;PETTIT, GR;HAMEL, E
多拉司他丁10是一种含有几个独特氨基酸亚单位的细胞生长抑制肽，从海洋无壳软体动物Dolabella auricularia中分离出来（Pettit GR，Kamano Y，Herald CL，Tuinman AA，Boettner FE，Kizu H，施密特JM，Baczynskyj L，Tomer KB和Bontems RJ，J. Am Chem Soc 109：6883-6885，1987）。由于我们的初步研究表明，海兔毒素10抑制微管蛋白聚合和放射性标记的长春碱与微管蛋白的结合，海兔毒素10的性质的初步表征包括与干扰长春花生物碱与微管蛋白结合的其他抗有丝分裂药物（长春碱、美登素、根霉素和根视蛋白A）的比较。多拉司他汀10抑制培养的L1210小鼠白血病细胞的生长，伴随有丝分裂指数的一致升高，其对细胞生长的IC 50值为0.5 nM。其它药物的可比值为美登素0.5nM、根霉素1 nM、长春碱20 nM和视根蛋白A 7 μ M。还获得了纯化的微管蛋白在谷氨酸盐中聚合的IC 50值：海兔毒素10为1.2 μ M，根视蛋白A为1.4 μ M，长春碱为1.5 μ M，美登素为3.5 μ M，根霉素为6.8 μ M。多拉司他丁10和长春碱在依赖于微管相关蛋白的微管组装上的作用是相当的。初步研究表明，多拉司他汀10，如长春碱，在较高的药物浓度下引起冷稳定的微管蛋白聚集体的形成。我们证实，根霉毒素，phomopsin A，美登素也抑制放射性标记的长春碱和长春新碱微管蛋白的结合。Dolastatin 10和phomopsin A是这些反应的最强抑制剂，而rhizoxin最弱。海兔毒素10，phomopsin A，美登素，长春碱，和rhizoxin都抑制微管蛋白依赖的GTP水解。用海兔毒素10和根视蛋白A观察到最大的水解抑制，用根霉素观察到最小的抑制。
Dolastatin 10, a cytostatic peptide containing several unique amino acid subunits, was isolated from the marine shell-less mollusk Dolabella auricularia (Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB and Bontems RJ, J. Am Chem Soc 109: 6883-6885, 1987). Since our preliminary studies demonstrated that dolastatin 10 inhibited tubulin polymerization and the binding of radiolabeled vinblastine to tubulin, an initial characterization of the properties of dolastatin 10 included a comparison to other antimitotic drugs interfering with vinca alkaloid binding to tubulin (vinblastine, maytansine, rhizoxin, and phomopsin A). Dolastatin 10 inhibited the growth of L1210 murine leukemia cells in culture, with a concordant rise in the mitotic index, and its IC50 value for cell growth was 0.5 nM. Comparable values for the other drugs were 0.5 nM for maytansine, 1 nM for rhizoxin, 20 nM for vinblastine, and 7 .mu.M for phomopsin A. IC50 values were also obtained for the polymerization of purified tubulin in glutamate: 1.2 .mu.M for dolastatin 10, 1.4 .mu.M for phomopsin A, 1.5 .mu.M for vinblastine, 3.5 .mu.M for maytansine, and 6.8 .mu.M for rhizoxin. Dolastatin 10 and vinblastine were comparable in their effects on microtubule assembly dependent on microtubule-associated proteins. Preliminary studies indicated that dolastatin 10, like vinblastine, causes formation of a cold-stable tubulin aggregate at higher drug concentrations. We confirmed that rhizoxin, phomopsin A, and maytansine also inhibit the binding of radiolabeled vinblastine and vincristine to tubulin. Dolastatin 10 and phomopsin A were the strongest inhibitors of these reactions, and rhizoxin the weakest. Dolastatin 10, phomopsin A, maytansine, vinblastine, and rhizoxin all inhibited tubulin-dependent GTP hydrolysis. The greatest inhibition of hydrolysis was observed with dolastatin 10 and phomopsin A, and the least inhibition with rhizoxin.