Kuh H J, Jang S H, Wientjes M G, Weaver J R, Au J L
College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
J Pharmacol Exp Ther. 1999 Aug;290(2):871-80.
The present study examined the determinants of the penetration and accumulation of [(3)H]paclitaxel (12-12,000 nM) in three-dimensional histocultures of patient tumors and of a human xenograft tumor in mice. The results showed 1) significant and saturable drug accumulation in tumors, 2) extensive drug retention in tumors, and 3) a slower penetration but a more extensive accumulation in the xenograft tumor compared with patient tumors. Drug penetration was not rate-limited by drug diffusion from medium through the matrix supporting the histocultures. The difference in the expression of the mdr1 P-glycoprotein did not fully account for the difference in the drug accumulation in xenograft and patient tumors. Autoradiography and imaging were used to evaluate the spatial relationship between tumor architecture, tumor cell distribution, and drug distribution as a function of time and initial drug concentration in culture medium. The tumor cell density and the kinetics of drug-induced apoptosis were also evaluated. The results indicate that a high tumor cell density is a barrier to paclitaxel penetration and that the apoptotic effect of paclitaxel enhances its penetration in solid tumor. These factors are responsible for the time- and concentration-dependent drug penetration rate, with drug penetration confined to the periphery until apoptosis and reduction of epithelial cell density occurred at 24 h, after which time paclitaxel penetrated the inner parts of the tumor.
本研究检测了[(3)H]紫杉醇（12 - 12,000 nM）在患者肿瘤的三维组织培养物以及小鼠体内人异种移植肿瘤中的渗透和蓄积的决定因素。结果显示：1）肿瘤中存在显著且可饱和的药物蓄积；2）药物在肿瘤中大量滞留；3）与患者肿瘤相比，异种移植肿瘤中的药物渗透较慢，但蓄积更广泛。药物渗透并非由药物从培养基通过支持组织培养的基质扩散所限速。mdr1 P - 糖蛋白表达的差异并不能完全解释异种移植肿瘤和患者肿瘤中药物蓄积的差异。利用放射自显影和成像技术评估肿瘤结构、肿瘤细胞分布与药物分布之间的空间关系，该关系是时间以及培养基中初始药物浓度的函数。还评估了肿瘤细胞密度以及药物诱导凋亡的动力学。结果表明，高肿瘤细胞密度是紫杉醇渗透的障碍，且紫杉醇的凋亡作用增强了其在实体瘤中的渗透。这些因素导致了药物渗透速率的时间和浓度依赖性，在24小时凋亡和上皮细胞密度降低发生之前，药物渗透局限于周边区域，此后紫杉醇渗透到肿瘤内部。
