Determinants of paclitaxel uptake, accumulation and retention in solid tumors

This report addresses the determinants of the rate and extent of paclitaxel accumulation in tumors. In a 2-dimensional system such as monolayers where the drug is directly in contact with tumor cells, drug accumulation is det ermined by the extracellular-to-intracellular concentration gradient, the d rug binding to extracellular and intracellular macromolecules, the presence of the mdr1 p-glycoprotein (Pgp), and the time-dependent and drug concentr ation-dependent changes in tubulins and cell density. Intracellular pharmac okinetic models were developed to depict the effects of these parameters. C omputer simulation results indicate that at the clinically relevant concent ration range of 1 to 1,000 nM, (a) the binding affinity and the number of i ntracellular saturable drug binding sites are important for drug accumulati on at low and high extracellular concentrations, respectively, (b) saturati on in the drug binding to the high affinity intracellular binding sites (e. g., tubulin/microtubule) occurs at extracellular drug concentration above 1 00 nM, (c) treatment with 1,000 nM paclitaxel for greater than or equal to4 hr results in increased levels of tubulin/microtubule and consequently inc reased intracellular drug accumulation, whereas the continued cell prolifer ation after treatment with low drug concentrations results in reduced intra cellular accumulation, and (d) saturation of Pgp in mdr1-transfected cells occurs at the high end of the clinically relevant concentration range. In a 3-dimensional system such as the solid tumor histocultures, which contain tumor cells as well as stromal cells, the drug accumulation into the inner cell layers is determined by the unique properties of solid tumors, includi ng tumor cell density and spatial arrangement of tumor and stromal tissues. Most interestingly, drug penetration is modulated by the drug-induced apop tosis; the reduced cell density due to apoptosis results in an enhancement of the rate of drug penetration into the inner cell layers of solid tumors. In conclusion, the uptake, accumulation, and retention of paclitaxel in so lid tumors are determined by (a) factors that are independent of biological changes in tumor cells induced by paclitaxel, i.e., ratio of extracellular and intracellular concentrations, and drug binding to extracellular and in tracellular macromolecules, and (b) factors that are dependent on the time- and drug concentration-dependent biological changes induced by paclitaxel, i.e., induction of apoptosis, enhancement of tubulin/microtubule productio n, and induction of Pgp expression.