Abstract
Abstract
One consequence of elevated interstitial fluid pressures (IFP) within solid tumours is disruption to the normal process of convective fluid flow (CFF) from the vasculature into the interstitium. Loss of convective fluid flow in tumours has a significant effect on reducing drug delivery and is recognised as a major factor that contributes to the drug resistant phenotype of many solid tumours. Experimental models of IFP and CFF have traditionally relied upon in vivo tumour models but here, we describe an in vitro assay which could be used to evaluate strategies designed to manipulate convective fluid flow. The model is based upon a conventional transwell model for assessing drug penetration across multicell layers which has been modified to allow the fluid level in top chamber to be raised above that in the bottom chamber. The difference in hydrostatic pressure across the multicell layer drives convective fluid flow, the rate of which can be varied by increasing or decreasing the height of fluid in the top chamber and/or by using multicell layers of different thicknesses. When CFF was 0.19 ml/min, the penetration of gefitinib, imatinib and doxorubicin across DLD-1 human colon carcinoma multicell layers was significantly enhanced compared to similar experiments where CFF was zero. The enhancement of penetration rates was 75 fold for doxorubicin, 53 fold for gefitinib and 62 fold for imatinib. The magnitude of these effects has potential therapeutic significance and support the proposal that strategies aimed at reducing tumour IFP and increasing CFF may enhance the efficacy of chemotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4455. doi:10.1158/1538-7445.AM2011-4455