Effect of angiotensin II on immunotoxin uptake in tumor and normal tissue.

Abstract

To investigate the effect of the sarcosine analog of human angiotensin II ([sar]ATII) on the uptake and spatial distribution of immunotoxins (MW 210000 Da) in RD rhabdomyosarcoma xenografts in mice. This analog has a pressor activity similar to native angiotensin II (ATII) but a longer duration of action. A period of elevated blood pressure of approximately 80 min, measured by noninvasive photoplethysmography, was achieved by a 40-min continuous i.p. infusion of [sar]ATII at 0.07 microg/min. Tumor-bearing animals were injected i.v. with 125I-labeled specific and 131I-labeled nonspecific immunotoxins and made hypertensive by i.p. infusion of [sar]ATII. Radioactivity was measured in plasma, tumor, liver, kidney and muscle at 2, 6 and 24 h. Plasma radioactivity was subtracted from tissue values to calculate tissue uptake. To assess the spatial distribution of immunotoxin in the solid tumor, 125I-labeled specific immunotoxin was injected i.v. into tumor-bearing animals, and quantitative autoradiography was performed on tumor sections. The uptake of specific or nonspecific immunotoxins in tumor and normal tissues was not significantly different in [sar]ATII-hypertensive animals compared with saline-treated controls. In control animals. the spatial distribution of 125I-labeled specific immunotoxins was very heterogeneous and contained punctate accumulations throughout the tumor. Treatment with [sar]ATII did not affect this distribution qualitatively or quantitatively. To examine a possible reason for the lack of [sar]ATII effect, we measured the interstitial pressure of the RD tumor using a fluid-filled micropipette connected to a servo-null pressure transducer. The interstitial pressure in this solid tumor was unexpectedly low, only 0.6 +/- 0.9 mm Hg. The sustained period of [sar]ATII-induced hypertension had no effect on RD tumor or normal tissue uptake or tumor spatial distribution of immunotoxin. In saline-treated controls, the heterogeneity of immunotoxin distribution does not arise from an elevated interstitial pressure. Further studies are needed to determine whether a correlation exists between responsiveness to ATII-induced hypertensive chemotherapy using macromolecular drugs and tumor type and/or physiological properties.