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Nicotinamide can lower tumor interstitial fluid pressure: mechanistic and therapeutic implications
1Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Abstract:
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 FSaII 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 less than 500 mm3) (n = 26). NA caused approximately a 15% decrease in mean arterial blood pressure (P less than 0.05) and a 35% decrease in TIFP (P less than 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 less than 0.001) and 39% (P less than 0.001) in medium (200 to 500 mm3) and large (500 to 800 mm3) tumors, respectively. The decrease in TIFP in small (less than 200 mm3) and very large (greater than 800 mm3) tumors was not statistically significant (P greater than 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.
Insights
Nicotinamide (NA) reduces tumor interstitial fluid pressure (TIFP) in a size-dependent manner, potentially by decreasing tumor blood flow resistance. This finding may explain NA
Area of Science:
- Oncology
- Physiology
- Biomedical Engineering
Background:
- Nicotinamide (NA) has been observed to increase tumor blood flow and oxygenation.
- The underlying mechanisms for NA's effects on tumor hemodynamics remain unclear, particularly given its hypotensive effect.
Purpose of the Study:
- To investigate the hypothesis that NA decreases tumor blood flow resistance, leading to reduced vascular and interstitial fluid pressure.
- To quantify the impact of NA on tumor interstitial fluid pressure (TIFP) and related physiological parameters.
Main Methods:
- Measurements of mean arterial blood pressure, TIFP, tumor water content, and hematocrit were performed in C3H mice bearing FSaII tumors.
- Mice were treated with 500 mg/kg of NA, and physiological parameters were assessed before and after treatment.
- Tumor size was categorized into small, medium, large, and very large for analysis.
Main Results:
- NA administration resulted in a significant decrease in mean arterial blood pressure (approx. 15%) and TIFP (approx. 35%) at 2 hours post-injection.
- The reduction in TIFP was dependent on tumor size, with significant decreases observed in medium (200-500 mm3) and large (500-800 mm3) tumors.
- No significant changes in TIFP were observed in small (<200 mm3) or very large (>800 mm3) tumors, nor was hematocrit affected.
Conclusions:
- NA effectively reduces TIFP in a tumor size-dependent manner, likely by decreasing vascular resistance.
- These findings provide a potential explanation for previously observed size-dependent enhancements in tumor oxygenation and radiation response.
- The results suggest implications for noninvasive TIFP measurements and cancer treatment strategies involving radiation, chemotherapy, and immunotherapy.