RT Journal Article
SR Electronic
T1 Determinants of Paclitaxel Penetration and Accumulation in Human Solid Tumor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 871
OP 880
VO 290
IS 2
A1 Hyo-Jeong Kuh
A1 Seong H. Jang
A1 M. Guillaume Wientjes
A1 Jean R. Weaver
A1 Jessie L.-S. Au
YR 1999
UL http://jpet.aspetjournals.org/content/290/2/871.abstract
AB The present study examined the determinants of the penetration and accumulation of [3H]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 themdr1 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. The American Society for Pharmacology and Experimental Therapeutics