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Angiogenesis Determines Blood Flow, Metabolism, Growth Rate, and ATPase Kinetics of Tumors Growing in an Irradiated Bed: ³¹P and ²H Nuclear Magnetic Resonance Studies¹

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Experimental tumors growing in irradiated tissue have been used to study the biological differences characteristic of locally recurrent tumors. Since the hypoxic cell fraction of tumors growing in irradiated tissue is increased and growth rate is slowed, these tumors are assumed to be metabolically deprived with hypoperfusion. In this study, we directly measured the effect of tumor bed irradiation on blood flow, growth rate, rate of nucleoside triphosphate (NTP) turnover, and metabolic state using ³¹P and ²H nuclear magnetic resonance, and an intradermal assay for angiogenesis. (NTP turnover refers to ATP-synthetase mediated NTP turnover that is visible to ³¹P nuclear magnetic resonance using the technique of saturation transfer.) A decrease in the number of small blood vessels perfusing tumors in a preirradiated bed was found. Most of the decrease was due to a loss of vessels with diameters less than 0.04 mm. When tumors growing in preirradiated tissue reached 100 mm³ in volume, a high frequency of gross and microscopic necrosis and hemorrhage was already observed in most tumors. Consistent with these observations, the phosphocreatine/inorganic phosphate and nucleoside triphosphate/inorganic phosphate ratios were significantly lower in the tumors growing in a preirradiated bed compared with tumors in a nonirradiated bed. The blood flow rate was similar to control for tumors less than 100 mm³ (45.8 versus 40.5 ml/100 g/min, P = not significant), but was significantly lower than control for tumors greater than 100 mm³ (40.4 versus 12.2 ml/100 g/min, P < 0.01). The NTP turnover rates correlated (P < 0.005, r = 0.66) with the volume doubling rate (1/tumor volume doubling time), but for tumors 100 mm³ in size neither the volume doubling rate nor the NTP turnover rate of tumors growing in an irradiated bed was statistically lower than control [NTP turnover: 14 ± 3%/s versus 9 ± 2%/s; volume doubling rate: 0.47 ± 0.07/day versus 0.33 ± 0.04/day (mean ± SE)]. A large intertumor variability of all metabolic parameters was observed.

¹ This work was supported in part by NIH Grants CA48096, CA13311, and RR00995, as well as an American Cancer Society Career Development Award and Research Grant PDT-313, and the Deutscher Akademischer Austauschdienst.

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

³ Present address: Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114.

⁴ Present address: Francis Bitter National Magnetic Laboratory, Massachusetts Institute of Technology, 170 Albany Street, Cambridge, MA 02139.

⁵ Present address: Institute of Physiology and Pathophysiology, Pathophysiology Division, University of Mainz, D-6500 Mainz, Federal Republic of Germany.

Received 8/28/90. Accepted 4/ 1/91.

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