Determinants of paclitaxel penetration and accumulation in human solid tumor

The present study examined the determinants of the penetration and accumula tion of [H-3]paclitaxel (12-12,000 nM) in three-dimensional histocultures o f patient tumors and of a human xenograft tumor in mice. The results showed 1) significant and saturable drug accumulation in tumors, 2) extensive dru g retention in tumors, and 3) a slower penetration but a more extensive acc umulation in the xenograft tumor compared with patient tumors. Drug penetra tion 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 accumul ation in xenograft and patient tumors. Autoradiography and imaging were use d to evaluate the spatial relationship between tumor architecture, tumor ce ll distribution, and drug distribution as a function of time and initial dr ug 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 th e apoptotic effect of paclitaxel enhances its penetration in solid tumor. T hese factors are responsible for the time- and concentration-dependent drug penetration rate, with drug penetration confined to the periphery until ap optosis and reduction of epithelial cell density occurred at 24 h, after wh ich time paclitaxel penetrated the inner parts of the tumor.