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Carbogen Breathing Increases 5-Fluorouracil Uptake and Cytotoxicity in Hypoxic Murine RIF-1 Tumors: A Magnetic Resonance Study in Vivo¹

Cancer Research Campaign Biomedical Magnetic Resonance Research Unit, Department of Cellular and Molecular Sciences [P. M. J. M., S. P. R., A. S. E. O., J. R. G.], and Department of Pharmacology [M. B. C.], St. George's Hospital Medical School, London SW17 0RE, United Kingdom; Cancer Research Campaign Clinical Magnetic Resonance Research Group [P. M. J. M., A. S. E. O., M. O. L.] and Cancer Research Campaign Centre for Cancer Therapeutics [P. M. J. M., A. S. E. O., I. R. J.], Institute of Cancer Research and Royal Marsden National Health Service Trust, Surrey SM2 5PT, United Kingdom; and Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 [E. O. A.]

The purpose of this study was to examine the effect of carbogen gas (95% O₂-5% CO₂) on uptake and metabolism of 5-fluorouracil (5FU) in murine RIF-1 tumors and their growth in vivo. In addition, we have explored the mechanisms by which carbogen can transiently affect the physiology of RIF-1 tumors.

After i.p. injection of 1 mmol/kg 5FU into C3H mice, the uptake and metabolism of the drug by s.c. RIF-1 tumors was followed for 2 h noninvasively using ¹⁹F-magnetic resonance spectroscopy (MRS). In all animals, irrespective of tumor size, carbogen caused a significant increase in the half-life (t) of the elimination of 5FU by the tumor and a significant increase in growth inhibition. In 2–3-g tumors (group II), carbogen also caused increased 5FU uptake and metabolism to the cytotoxic 5-fluoronucleotides, whereas in 0.8–1.5-g tumors (group I), only the t was slightly increased. These results suggested that tumor size was an important factor in the effect of carbogen on tumor physiology.

Measurements of RIF-1 tumor vascular and necrotic volume showed no significant differences between group I and group II tumors. However, ¹H-MR images of RIF-1 tumors showed that carbogen caused a transient decrease in signal intensity, which correlated positively (P = 0.02) with tumor size, suggesting that larger tumors responded to carbogen by transiently increasing O₂ uptake from the blood. ¹⁹F-MRS was used to measure RIF-1 tumor retention of the fluorinated nitroimidazole SR-4554. These studies also showed a positive correlation (P = 0.001) with tumor size, implying greater hypoxia in larger tumors. We propose that carbogen may transiently open nonfunctional blood vessels in the tumor, allowing increased leakage of 5FU from the plasma into the extracellular space. 5FU transport is known to be pH dependent. Intra- and extracellular tumor pH was measured using ³¹P- and ¹⁹F-MRS, which showed that carbogen caused a significant decrease in the extracellular pH of 0.1 unit in group II tumors and a consequent increase in the negative pH gradient across the tumor plasma membrane, which can cause increased 5FU uptake. The pH gradient was unaffected in group I tumors.

We conclude that carbogen breathing can increase tumor uptake of 5FU by two independent mechanisms involving changes in tumor blood flow and pH, which consequently cause increased formation of 5-fluoronucleotides and cytotoxicity. The effect seems more pronounced in hypoxic tumors, implying that carbogen would be a valuable aid in clinical chemotherapy.

¹ This work was supported by the Cancer Research Campaign Programme Grants SP1971/0404 and SP1971/0502.

² To whom requests for reprints should be addressed, at Department of Cellular and Molecular Sciences, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, United Kingdom.

Received 11/19/97. Accepted 1/29/98.

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