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Nicotinamide Can Lower Tumor Interstitial Fluid Pressure: Mechanistic and Therapeutic Implications¹

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

Several investigators have shown that nicotinamide (NA) may increase the tumor blood flow and/or alleviate temporal fluctuations in tumor blood flow and, consequently, increase pO₂. However, the mechanisms of these changes in tumor blood flow are not understood, especially because NA lowers the mean arterial blood pressure in mice. Our hypothesis is that NA may decrease flow resistance in tumors, which would lower vascular pressure and tumor interstitial fluid pressure (TIFP). To test this hypothesis, we measured the physiological parameters: mean arterial blood pressure, TIFP, tumor water content, and hematocrit in C3H mice bearing FSall tumors, before and after treatment with 500 mg/kg of NA. In control animals, TIFP increased with tumor growth up to 400 mm³, reached a plateau, and then decreased when the tumor size was above 1000 mm³ (n = 135). Tumor water content correlated significantly with TIFT (for tumors <500 mm³) (n = 26). NA caused approximately a 15% decrease in mean arterial blood pressure (P < 0.05) and a 35% decrease in TIFP (P < 0.001) at 2 h postinjection, without any change in hematocrit. The change in TIFP was found to be tumor size dependent. Specifically, NA decreased the TIFP by 47% (P < 0.001) and 39% (P < 0.001) in medium (200 to 500 mm³) and large (500 to 800 mm³) tumors, respectively. The decrease in TIFP in small (<200 mm³) and very large (>800 mm³) tumors was not statistically significant (P > 0.1). Our results may explain the size-dependent enhancement in pO₂ and radiation response reported by I. Lee and C. W. Song (Radiat. Res., 130: 65–71, 1992) for this tumor line. If our results could be confirmed in human tumors in situ, they would have significant implications in noninvasive measurements of TIFP using NMR and in cancer treatment using radiation, chemotherapy, and immunotherapy.

¹ This work was supported by grants from the National Cancer Institute (CA-37239, CA-49792, and CA-13311). Presented at the 40th Radiation Research Society Meeting, Salt Lake City, UT, March 14–18, 1992.

Received 2/25/92. Accepted 4/15/92.

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