Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma

One 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.The 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.We 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.A tumor is comprised of cancer cells as well as stromal cells (fibroblasts, immune cells) that are embedded in an extracellular matrix (ECM) and nourished by vasculature. Because of irregular and tortuous tumor blood vessels with impaired blood flow and high proliferation rate, tumors have large hypoxic areas, especially in the central parts. It is now widely accepted that hypoxia induces tumor growth and enhances both radiation- and chemo-resistance of cancer cells [1].Inefficiency of chemotherapy can partly be explained by development of multidrug resistance to different chemotherapeutic agents. However, the causes of hypoxia-med