PURPOSE: Limited drug penetration in solid tumors is a potential mechanism of resistance for many anticancer drugs. Taxanes represent a class of drugs that are currently undergoing a new round of development, but with little known of their ability to penetrate and distribute relative to blood vessels within solid tumors. EXPERIMENTAL DESIGN: We assessed the tissue penetration of paclitaxel and docetaxel in HCT-116 tumor xenografts and in multilayered cell culture (MCC), a three-dimensional cell culture model of the tumor extravascular compartment. In xenografts, taxanes were mapped relative to blood vessels to obtain drug profiles as a function of distance from vasculature. For MCC, cultures were exposed to stirred drug reservoirs and taxanes measured as a function of depth into tissue. RESULTS: Both taxanes exhibited limited penetration, with little drug reaching further than 100 microm into the tissue. Of the two, paclitaxel exhibited up to 2-fold greater penetration than docetaxel. Mapping tumor cell proliferation following treatment allowed the consequences of limited drug penetration to be assessed. In tumor xenografts where reduced drug exposure to cells far from vasculature is one of several factors influencing response to treatment, up to a 75% reduction in S-phase cells was achieved in cells nearest the vessels, but only 50% reduction was observed in the tissue 150 microm away. In MCC-based data, where the influence of reduced cell proliferation with depth into tissue was circumvented, a 5-fold (paclitaxel) and 10-fold (docetaxel) increase in reservoir drug concentration was required to produce a response in cells 150 microm into the tissue equivalent to that seen in cells directly exposed to the drug. CONCLUSION: These results indicate that limited distribution is an important mechanism of tumor resistance to taxanes.
PURPOSE: Limited drug penetration in solid tumors is a potential mechanism of resistance for many anticancer drugs. Taxanes represent a class of drugs that are currently undergoing a new round of development, but with little known of their ability to penetrate and distribute relative to blood vessels within solid tumors. EXPERIMENTAL DESIGN: We assessed the tissue penetration of paclitaxel and docetaxel in HCT-116 tumor xenografts and in multilayered cell culture (MCC), a three-dimensional cell culture model of the tumor extravascular compartment. In xenografts, taxanes were mapped relative to blood vessels to obtain drug profiles as a function of distance from vasculature. For MCC, cultures were exposed to stirred drug reservoirs and taxanes measured as a function of depth into tissue. RESULTS: Both taxanes exhibited limited penetration, with little drug reaching further than 100 microm into the tissue. Of the two, paclitaxel exhibited up to 2-fold greater penetration than docetaxel. Mapping tumor cell proliferation following treatment allowed the consequences of limited drug penetration to be assessed. In tumor xenografts where reduced drug exposure to cells far from vasculature is one of several factors influencing response to treatment, up to a 75% reduction in S-phase cells was achieved in cells nearest the vessels, but only 50% reduction was observed in the tissue 150 microm away. In MCC-based data, where the influence of reduced cell proliferation with depth into tissue was circumvented, a 5-fold (paclitaxel) and 10-fold (docetaxel) increase in reservoir drug concentration was required to produce a response in cells 150 microm into the tissue equivalent to that seen in cells directly exposed to the drug. CONCLUSION: These results indicate that limited distribution is an important mechanism of tumor resistance to taxanes.
Authors: Pieter Colin; Lieselotte De Smet; Chris Vervaet; Jean-Paul Remon; Wim Ceelen; Jan Van Bocxlaer; Koen Boussery; An Vermeulen Journal: Pharm Res Date: 2014-05-22 Impact factor: 4.200
Authors: Greg M Thurber; Thomas Reiner; Katherine S Yang; Rainer H Kohler; Ralph Weissleder Journal: Mol Cancer Ther Date: 2014-02-19 Impact factor: 6.261
Authors: Greg M Thurber; Katy S Yang; Thomas Reiner; Rainer H Kohler; Peter Sorger; Tim Mitchison; Ralph Weissleder Journal: Nat Commun Date: 2013 Impact factor: 14.919