Penetration of anticancer drugs through tumour tissue as a function of cellular packing density and interstitial fluid pressure and its modification by bortezomib

Background: Limited penetration of anticancer drugs in solid tumours is a probable cause of drug resistance. Our previous results indicate that drug penetration depends on cellular packing density and adhesion between cancer cells. Methods: We used epithelioid and round cell variants of the HCT-8 human colon carcinoma cell lines to generate tightly and loosely packed xenografts in nude mice. We measured packing density and interstitial fluid pressure (IFP) and studied the penetration of anti-cancer drugs through multilayered cell cultures (MCC) derived from epithelioid HCT-8 variants, and the distribution of doxorubicin in xenografts with and without pre-treatment with bortezomib. Results: We show lower packing density in xenografts established from round cell than epithelioid cell lines, with lower IFP in xenografts. There was better distribution of doxorubicin in xenografts grown from round cell variants, consistent with previous data in MCC. Bortezomib pre-treatment reduced cellular packing density, improved penetration, and enhanced cytotoxcity of several anticancer drugs in MCC derived from epithelioid cell lines. Pre-treatment of xenografts with bortezomib enhanced the distribution of doxorubicin within them. Conclusions: Our results provide a rationale for further investigation of agents that enhance the distribution of chemotherapeutic drugs in combination with conventional chemotherapy in solid tumours.