Ali S, Ahmad I, Peters A, Masters G, Minchey S, Janoff A, Mayhew E
The Liposome Company, Inc., One Research Way, Princeton, NJ 08540, USA.
Anticancer Drugs. 2001 Feb;12(2):117-28. doi: 10.1097/00001813-200102000-00004.
A series of taxane prodrugs with 2-bromoacyl chains attached at the 2'-position of the paclitaxel side chain, varying from six, eight, 12, 14 to 16 carbons in length, were synthesized, characterized and evaluated against human breast MCF-7 cancer cell line for their growth inhibitory (GI50) activities. The GI50 is the drug concentration required to inhibit cell growth by 50%. For comparison, hydrophobic taxanes varying in acyl chain lengths from six to 16 carbons were also synthesized and compared for their G050s with taxanes having equivalent bromoacyl chain lengths. The bromoacyl taxanes bearing six, eight and 12 carbon acyl chain lengths had GI50 values very similar to parent paclitaxel. The GI50 was 3 nM for three taxanes versus 1 nM for paclitaxel on the MCF-7 cell line. Increasing the acyl chain length to 14 or 16 carbons resulted in a significant decrease in cytotoxicity and an increase in the GI50 to 20 or 70 nM, respectively. In general, the GI50 values were directly related to the bromoacyl chain lengths in cultured tumor cells. Unlike bromoacyl taxanes, the taxanes lacking bromine in their acyl chain composition were 50- to 250-fold less active, suggesting that the heteroatom facilitated the hydrolysis of acyl chains to yield free paclitaxel. These differences in growth inhibitory activities may indirectly reflect differences in the susceptibility of the acyl chain to bromine-induced hydrolysis after association of the derivative with cell membranes. Liposome formulations of 2-bromoacyl taxanes bearing six, eight, 12 and 16 carbons were prepared and tested in SCID mice against a xenografted human ovcar-3 ovarian tumor. In vivo results showed that bromoacyl taxanes with a longer chain were therapeutically more efficacious than those with a short chain, presumably due to slow hydrolysis of the prodrug followed by sustained delivery of paclitaxel to the tumor.
合成了一系列在紫杉醇侧链2'-位连接有2-溴酰基链的紫杉烷前药，其碳链长度从6、8、12、14到16个碳不等，并对其进行了表征，还针对人乳腺癌MCF-7细胞系评估了它们的生长抑制（GI50）活性。GI50是抑制细胞生长50%所需的药物浓度。为作比较，还合成了酰基链长度从6到16个碳不等的疏水紫杉烷，并将它们的GI50与具有等效溴酰基链长度的紫杉烷进行比较。碳链长度为6、8和12个碳的溴酰基紫杉烷的GI50值与母体紫杉醇非常相似。在MCF-7细胞系上，三种紫杉烷的GI50为3 nM，而紫杉醇为1 nM。将酰基链长度增加到14或16个碳会导致细胞毒性显著降低，GI50分别增加到20或70 nM。一般来说，GI50值与培养的肿瘤细胞中的溴酰基链长度直接相关。与溴酰基紫杉烷不同，酰基链组成中缺乏溴的紫杉烷活性低50至250倍，这表明杂原子促进了酰基链的水解以产生游离紫杉醇。这些生长抑制活性的差异可能间接反映了衍生物与细胞膜结合后酰基链对溴诱导水解的敏感性差异。制备了碳链长度为6、8、12和16个碳的2-溴酰基紫杉烷的脂质体制剂，并在SCID小鼠中针对异种移植的人卵巢癌ovcar-3肿瘤进行了测试。体内结果表明，链较长的溴酰基紫杉烷在治疗上比链较短的更有效，这可能是由于前药水解缓慢，随后紫杉醇持续递送至肿瘤。
