HIGH INTERSTITIAL FLUID PRESSURE REGULATES TUMOR GROWTH AND DRUG UPTAKE IN HUMAN GLIOBLASTOMA

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Abstract

BACKGROUND: (blind field). METHODS: We developed methodology to measure IFP in human GBM xenografts and mechanical compression in 3D-cultures. We used a cell counter and calcein-AM-loaded cells to measure cell volume following treatment with temozolomide and/or blockade of NKCC1 activity. Fluorescent MQAE-loaded cells were recorded to measure intracellular chloride levels. To study uptake of chemotherapy following IFP-reduction in GBM xenografts following AF-induction or treatment with bumetanide, we injected doxorubicin and measured fluorescent doxorubicin levels in tissue sections. RESULTS: Elevated compression increased proliferation in GBM cultures and IFP levels rapidly increased during the exponential growth phase in GBM xenografts. In contrast to Avastin that targets the vasculature, SPC diet induced AF expression only in tumor cells. In addition to reducing IFP levels, AF-induction also inhibited proliferation, induced apoptosis, and increased survival in mice xenografted with human GBM cells. SPC diet and intranasal injection of AF increased uptake of doxorubicin in GBM xenografts. In vitro, AF augmented TMZ-induced apoptosis and reduced proliferation at both baseline and increased hydrostatic compression. CONCLUSIONS: In contrast to IFP-reducing therapies targeting the vasculature, treatments that reduced osmotic pressure in GBM cells effectively reduced tumor growth and invasion in vivo. AF and bumetanide increased uptake and cytotoxic response from chemotherapies by inhibiting NKCC1 activity in GBM cells. Our studies suggest that elevated IFP promotes tumor growth, reduces drug uptake, and limits therapy-response in GBM. AF-induction represents an attractive strategy to reduce invasion, inhibit tumor growth, increase drug uptake, and ultimately improve the survival of GBM patients. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.

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