Enhancement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment: effect of treatment schedule.
Enhancement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment: effect of treatment schedule.
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发表时间：
2001-03
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通讯作者：
Hoon Seong;M. Jang;Jessie L Guillaume Wientjes;S. Au
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作者：
Hoon Seong;M. Jang;Jessie L Guillaume Wientjes;S. Au
紫杉醇对实体瘤的渗透性有限，可能会限制其治疗效果。我们最近发现了实体肿瘤间质间隙的增加和药物输送的增强之间的相关性。本研究评估了这一观察结果是否可以用于开发一种治疗策略，即使用紫杉醇诱导细胞凋亡的预处理来增强其自身对实体瘤的输送。在人咽FaDu异种移植瘤的组织培养中，用1微米的非放射性标记紫杉醇预处理，可导致约25%的细胞凋亡和25%的细胞密度下降，从而提高[(3)H]紫杉醇的渗透率。同样，将总的药物暴露分为两个处理，分开一个间隔以允许细胞凋亡发生，与连续给予相同的药物暴露相比，导致更高的药物渗透率和累积。在移植有前列腺癌Mat-LyLu肿瘤的大鼠身上也得到了类似的结果；分次给药方法包括：1)预先给予产生足够和临床相关的血浆浓度以诱导细胞凋亡；2)按选定的间隔进行第二次给药，以允许细胞凋亡和肿瘤细胞密度降低，与使用相同总剂量但不包括诱导细胞凋亡的预处理或不允许细胞凋亡发生的其他治疗方法相比，第二次剂量可导致更高的肿瘤浓度。我们的结论是，紫杉醇的药理作用影响其自身对实体瘤的传递，并且修改紫杉醇的治疗方案可以增强对实体瘤的药物传递。
The limited penetration of paclitaxel into solid tumors may limit its therapeutic efficacy. We recently showed a correlation between an increase in interstitial space and an enhancement of drug delivery in solid tumors. The present study evaluated whether this observation can be used to develop a treatment strategy, where an apoptosis-inducing pretreatment with paclitaxel is used to enhance its own delivery to solid tumors. In histocultures of human pharynx FaDu xenograft tumors, pretreatment with 1 microM nonradiolabeled paclitaxel, which resulted in approximately 25% apoptosis and a 25% reduction in cell density, enhanced the penetration rate of [(3)H]paclitaxel. Likewise, dividing a total drug exposure to two treatments, separated by an interval to allow apoptosis to occur, resulted in higher drug penetration rate and accumulation compared with giving the same drug exposure continuously. Similar results were obtained in rats bearing subcutaneously implanted prostate MAT-LyLu tumors; fractionation of the dose, to include 1) a pretreatment that yielded sufficient and clinically relevant plasma concentration to induce apoptosis and 2) a second dose given at an interval selected to allow apoptosis and reduction in tumor cell density to occur, resulted in higher tumor concentration compared with other treatments using the same total dose but either did not include an apoptosis-inducing pretreatment or did not allow for apoptosis to occur. We conclude that the pharmacological effect of paclitaxel affects its own delivery to solid tumors and that modifications of the paclitaxel treatment schedule can enhance drug delivery in solid tumors.