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Effect of angiotensin II on immunotoxin uptake in tumor and normal tissue
1Biomedical Engineering and Instrumentation Program, National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892, USA.
Purpose:
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.
Method:
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.
Results:
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.
Conclusions:
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.