Elevated interstitial fluid pressure (IFP) in solid
tumors may reduce the effect of systemically administered anticancer drugs. Modulation of the
tumor extracellular matrix might reduce the elevated IFP. To study the influence of the microenvironment, the IFP was measured in human
osteosarcoma xenografts grown both subcutaneously and orthotopically. The IFP response was recorded in xenografts grown at both sites after direct intratumoral injection of bovine testicular
hyaluronidase (500 or 1600 units in 50 microliters saline). Control
tumors received 50 microliters saline alone or 10%
bovine serum albumin in saline. IFP was measured centrally in the
tumors using the wick-in-needle technique, and mean arterial blood pressure was monitored after carotid cannulation.
Tumor tissue sections were stained with hyaluronectin and analyzed for
hyaluronan content using confocal
laser scanning fluorescence microscopy. The baseline IFP was significantly higher in orthotopic (30 +/- 9 mmHg,
n = 30) compared with subcutaneous
tumors (17 +/- 6 mmHg, n = 11) of comparable sizes (p < 0.001). Injection of
hyaluronidase reduced the IFP in both
tumor models to 61-81% compared with controls 1 h after injection (p < 0.05), without affecting the mean arterial blood pressure significantly. The
hyaluronan staining intensity increased in subcutaneous
tumor sections, but remained unchanged in orthotopic
tumor sections 1 h after injection of 1600 units of
hyaluronidase. The IFP was restored within 48 h after
hyaluronidase injection. Interestingly, IFP increased with
tumor volume in orthotopic
tumors, but not in subcutaneous
tumors. In conclusion, intratumoral
hyaluronidase injection reduces the IFP transiently in solid
osteosarcoma xenografts. Furthermore, this study emphasizes that physiological parameters might differ significantly between human
osteosarcoma xenografts grown subcutaneously versus orthotopically in nude mice.