Crampton S L, Adams E G, Kuentzel S L, Li L H, Badiner G, Bhuyan B K
Cancer Res. 1984 May;44(5):1796-801.
Didemnins are a new class of cyclic depsipeptides in which didemnin A is the major component, didemnin B the minor component, and a trace of didemnin C is present. Didemnin B was more potent than was didemnin A against B16 melanoma and P388 leukemia in vivo, and B was also approximately 20 times more cytotoxic than was didemnin A in vitro. Therefore, didemnin B was studied in greater detail for its biochemical and cellular effects. Didemnin B inhibited the in vitro growth of B16 greater than L1210 greater than V-79 cells = human foreskin fibroblast = 9L greater than Chinese hamster ovary cells. Didemnin B was more lethal to exponentially growing B16 cells (50% lethal dose for a 2-hr exposure, 17.5 ng/ml) than to plateau-phase cells (50% lethal dose for a 2-hr exposure, 100 ng/ml). After a 24-hr exposure, the 50% lethal dose for exponential- and plateau-phase B16 cells was 8.8 and 59.6 ng/ml, respectively. Chinese hamster ovary cells were not killed even at 25,000 ng/ml. Mitotic cells were the least sensitive to didemnin B, and cells became more sensitive as they progressed into G1 and S phase. However, since cells in all phases were killed, didemnin B cannot be considered a phase-specific agent. Didemnin B inhibited the synthesis of protein more than that of DNA, with much less inhibition of RNA synthesis. Cell progression studies showed that high doses (300 ng/ml for 2 hr or 100 ng/ml for 24 hr) of didemnin B "froze" the cells in their respective phases with complete inhibition of cell progression or growth. At low doses (10 ng/ml for 2 hr or 3 ng/ml for 24 hr), the cells were blocked at the G1-S border thereby increasing the percentage of G1 cells and decreasing the percentage of S-phase cells. Cells continued to progress from S phase to G2 + M and from G2 + M to G1. The cytotoxicity to different cell lines and inhibition of macromolecule synthesis by didemnin A is also reported.
海兔素是一类新型环缩肽，其中海兔素A是主要成分，海兔素B是次要成分，还存在微量的海兔素C。在体内，海兔素B对B16黑色素瘤和P388白血病的活性比海兔素A更强，在体外，海兔素B的细胞毒性也比海兔素A大约高20倍。因此，对海兔素B的生化和细胞效应进行了更详细的研究。海兔素B对体外培养的B16细胞生长的抑制作用大于L1210细胞大于V - 79细胞 = 人包皮成纤维细胞 = 9L细胞大于中国仓鼠卵巢细胞。海兔素B对指数生长期的B16细胞（2小时暴露的半数致死剂量，17.5纳克/毫升）比对平台期细胞（2小时暴露的半数致死剂量，100纳克/毫升）更具致死性。暴露24小时后，指数生长期和平台期B16细胞的半数致死剂量分别为8.8和59.6纳克/毫升。即使在25000纳克/毫升的浓度下，中国仓鼠卵巢细胞也未被杀死。有丝分裂细胞对海兔素B最不敏感，随着细胞进入G1期和S期，敏感性增加。然而，由于所有阶段的细胞都会被杀死，所以海兔素B不能被认为是一种阶段特异性药物。海兔素B对蛋白质合成的抑制作用大于对DNA合成的抑制作用，对RNA合成的抑制作用则小得多。细胞进程研究表明，高剂量（2小时300纳克/毫升或24小时100纳克/毫升）的海兔素B会使细胞“停滞”在各自的阶段，完全抑制细胞进程或生长。在低剂量（2小时10纳克/毫升或24小时3纳克/毫升）下，细胞被阻滞在G1 - S边界，从而增加G1期细胞的百分比并降低S期细胞的百分比。细胞继续从S期进入G2 + M期，再从G2 + M期进入G1期。还报道了海兔素A对不同细胞系的细胞毒性和对大分子合成的抑制作用。
