Observations in studies of quantitative kinetics of tritium labelled hematoporphyrin derivatives (HpDI and HpDII) in the normal and neoplastic rat brain model.
Increasing interest has developed in the use of the photodynamic agent, Hematoporphyrin derivative (HpD) for photoradiation therapy (PRT) as adjunctive therapy of malignant glial tumors of the brain. HpD, injected systemically, is preferentially taken up and retained by neoplastic tissue. Early studies of such uptake have largely relied on gross fluorescence as evidence of tissue uptake. In this study HpD was labelled with a tritiated radioisotope (3H) in order to quantify tissue uptake in visceral and in normal and neoplastic brain tissues in a rat brain model. 3H-HpD was injected intravenously at a 10 mg/kg dose into 30 Sprague-Dawley rats (Group A) without tumors in order to clarify method. Separately, 3H-HpD of like dosage was injected into 20 Fischer-344 rats (Group B), 5 control and 15 with a 9L gliosarcoma implanted in the left anterior cerebral cortex. Post injection sacrifice occurred at 6, 24 and 48 hours. From the Sprague-Dawley group multiple somatic and cerebral specimens were assayed. Differential areas within the brain showed no significant difference in uptake. The tumor area, peritumoral margin, and distant uninvolved areas of the Fischer-344 9L rats were likewise assayed. Definite uptake of normal visceral and cerebral tissue occurred with a markedly higher uptake differential in tumor areas. Such differential was relatively consistent from trial to trial, but multiple separate values obtained in the respective study groups were often unreliabe in their reproducibility and at variance with previously reported tissue level studies. These findings implied an instability of 3H-HpD, subsequently confirmed chromatographically as contamination probably due to time related degradation and exchange. Therefore, 3H-HpD appears to inherently carry such a risk for contamination. The compound Photofrin II (HpDII) represents a chromatographic fraction of HpD (HpDI), currently considered its most photodynamically active and purest component. Tritiated Photofrin II was used for quantification. An assay was performed with 5 Fischer-344 9L brain tumor rats (Group C), sacrificed at 24 hours. Photofrin II provided results more reliably reproducible. Contamination, degradation, and exchange of 3H-Photofrin II did not appear to occur. Neoplastic brain levels of the Photofrin II isotope were higher than in the HpD studies, and highly fluorescent. Normal brain values were consistently minimal and without fluorescence. The differential tumor/brain ratio in Photofrin II was consequently much higher. The isolated active substrate of HpDI and HpDII (Photofrin II) appears to be the compound DiHematoporphyrin Ether (DHE).(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D004355:Drug Stability; D005910:Glioma / Q000378:metabolism*; D017324:Hematoporphyrin Derivative; D006415:Hematoporphyrins / Q000378:metabolism*; D007700:Kinetics; D011838:Radiation-Sensitizing Agents / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014316:Tritium
D006415:Hematoporphyrins; D011838:Radiation-Sensitizing Agents; D014316:Tritium; D017324:Hematoporphyrin Derivative