Determinants of Paclitaxel Uptake, Accumulation and Retention in Solid Tumors
Tóm tắt
This report addresses the determinants ofthe rate and extent of paclitaxelaccumulation in tumors. In a 2-dimensionalsystem such as monolayers where the drug isdirectly in contact with tumor cells, drugaccumulation is determined by theextracellular-to-intracellularconcentration gradient, the drug binding toextracellular and intracellularmacromolecules, the presence of the mdr1p-glycoprotein (Pgp), and thetime-dependent and drugconcentration-dependent changes in tubulinsand cell density. Intracellularpharmacokinetic models were developed todepict the effects of these parameters.Computer simulation results indicate thatat the clinically relevant concentrationrange of 1 to 1,000 nM, (a) the bindingaffinity and the number of intracellularsaturable drug binding sites are importantfor drug accumulation at low and highextracellular concentrations, respectively,(b) saturation in the drug binding to thehigh affinity intracellular binding sites(e.g., tubulin/microtubule) occurs atextracellular drug concentration above 100nM, (c) treatment with 1,000 nM paclitaxelfor ≥4 hr results in increased levels oftubulin/microtubule and consequentlyincreased intracellular drug accumulation,whereas the continued cell proliferationafter treatment with low drugconcentrations results in reducedintracellular accumulation, and (d)saturation of Pgp in mdr1-transfectedcells occurs at the high end of theclinically relevant concentration range. Ina 3-dimensional system such as the solidtumor histocultures, which contain tumorcells as well as stromal cells, the drugaccumulation into the inner cell layers isdetermined by the unique properties ofsolid tumors, including tumor cell densityand spatial arrangement of tumor andstromal tissues. Most interestingly, drugpenetration is modulated by thedrug-induced apoptosis; the reduced celldensity due to apoptosis results in anenhancement of the rate of drug penetrationinto the inner cell layers of solid tumors.In conclusion, the uptake, accumulation,and retention of paclitaxel in solid tumorsare determined by (a) factors that areindependent of biological changes in tumorcells induced by paclitaxel, i.e., ratio ofextracellular and intracellularconcentrations, and drug binding toextracellular and intracellularmacromolecules, and (b) factors that aredependent on the time- and drugconcentration-dependent biological changesinduced by paclitaxel, i.e., induction ofapoptosis, enhancement oftubulin/microtubule production, andinduction of Pgp expression.
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