Abstract
BackgroundHypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix.MethodsOne group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO2 = 2 bar, 4 exposures à 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO2 = 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors.ResultsThe uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake.ConclusionWe showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO2.
Highlights
Hypoxia is associated with increased resistance to chemo- and radiation-therapy
A tumor is comprised of cancer cells as well as stromal cells that are embedded in an extracellular matrix (ECM) and nourished by vasculature
As hypoxia reduces the response of chemotherapeutic agents, we aimed to study the effect of enhanced oxygenation on drug-uptake in mammary tumors, by using hyperbaric oxygen (HBO)
Summary
Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. Solid tumors have a pathologically increased interstitial fluid pressure (Pif) and a dense ECM that make transport of chemotherapeutic agents difficult [3,4,5,6,7]. Increased Pif leads to decreased transcapillary transport, and thereby hinders efficient uptake of chemotherapy [8], while the fibrotic nature of the dense ECM in solid tumors have been shown to impede transport of molecules in the tumor interstitium, and thereby decrease the effect of cytostatic drugs [9,10,11]. Since Pif can be lowered and the structure of the tumor interstitium can be altered, this could have the potential to enhance the efficiency of drugbased treatment of solid malignancies
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