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Effect of Radiation on Interstitial Fluid Pressure and Oxygenation in a Human Tumor Xenograft¹

Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213 [C. A. Z.]; Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 [M. R., M. W. E.]; Department of Radiation Medicine, Evanston Hospital Corp., Evanston, Illinois 60201 [W. D. B.]; and Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114 [Y. B., R. K. J.]

Elevated interstitial fluid pressure (IFP) is a pathophysiological characteristic of most human and experimental tumors and may be responsible, in part, for the poor distribution of blood-borne therapeutic agents and low blood flow rate in tumors. Recent data in cervical carcinomas in patients suggest that fractionated radiation can lower tumor IFP and increase oxygen partial pressure (pO₂) in some patients. The goals of this study were to find the minimum dose of radiation required to modulate IFP and pO₂ and to determine the time course of IFP changes due to radiation in a preclinical model. Xenografts of the LS174T human colon adenocarcinoma were grown in the right flank of nude (BALB/c) mice. IFP and pO₂ were measured before and 24 h after graded doses of irradiation. The mean ± SD initial IFP in untreated tumors was 12.9 ± 0.5 mm Hg (n = 109), and the range was 3.0 to 40.3 mm Hg. The mean ± SD and median initial pO₂ were 20.2 ± 2.4 and 11.9 mm Hg, respectively (n = 37). IFP and pO₂ were independent of tumor size. Fractionated radiation lowered IFP by 2.5 mm Hg when the total dose was 10 or 15 Gy (P < 0.05), but IFP did not change in the controls or the 5-Gy radiation group (P < 0.05). Irradiation increased the proportion of tumors at higher oxygen tensions when compared to control tumors. The IFP and tumor volumes were followed for up to 10 days after a single dose of 10, 20, or 30 Gy of irradiation. IFP decreased for all treatment groups. The decrease was most significant for the group receiving 30 Gy. On day five following irradiation, the IFP had decreased by 35%. The changes in IFP and pO₂ occurred before any macroscopic changes in tumor volume could be observed. The radiation-induced decrease in IFP could be, in part, responsible for the increased uptake of monoclonal antibodies following single or fractionated radiation that has been reported in the literature.

¹ This work was supported by a grant from the Claude Worthington Benedum Foundation (to W. D. B.) and by Outstanding Investigator Grant R35-CA-56591 (to R. K. J.).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Cox 7, Massachusetts General Hospital, Boston, MA 02114.

Received 12/27/95. Accepted 1/24/96.

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