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Vol. 290, Issue 2, 871-880, August 1999
College of Pharmacy, The Ohio State University, Columbus, Ohio
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 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.
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