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Title: Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside

Abstract

The perfluorochemical emulsion Fluosol-DA plus carbogen breathing has been shown to increase the effectiveness of radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly. The authors hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly. In the present study, the [alpha]/[beta] agonist ephedrine, the Ca[sup 2+] channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested. Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA [+-] carbogen antitumor effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus carbogen and the radiation plus Fluosol-DA/carbogen in both emulsion was given rapidly. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and carbogen breathing prior to and during radiation therapy using growthmore » delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses. These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by carbogen breathing and radiation therapy. 45 refs., 4 figs.« less

Authors:
; ; ; ;
Publication Date:
OSTI Identifier:
6936312
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; (United States); Journal Volume: 26:1
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; EPHEDRINE; RADIOSENSITIVITY EFFECTS; FLUORINE COMPOUNDS; NEOPLASMS; RADIOTHERAPY; VASODILATORS; MICE; ALKALOIDS; AMINES; ANIMALS; AUTONOMIC NERVOUS SYSTEM AGENTS; CARDIOVASCULAR AGENTS; DISEASES; DRUGS; HALOGEN COMPOUNDS; HYDROXY COMPOUNDS; MAMMALS; MEDICINE; NUCLEAR MEDICINE; ORGANIC COMPOUNDS; RADIOLOGY; RODENTS; SYMPATHOMIMETICS; THERAPY; VASOCONSTRICTORS; VERTEBRATES; 560152* - Radiation Effects on Animals- Animals

Citation Formats

Teicher, B.A., Holden, S.A., Northey, D., Dewhirst, M.W., and Herman, T.S. Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside. United States: N. p., 1993. Web. doi:10.1016/0360-3016(93)90179-Y.
Teicher, B.A., Holden, S.A., Northey, D., Dewhirst, M.W., & Herman, T.S. Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside. United States. doi:10.1016/0360-3016(93)90179-Y.
Teicher, B.A., Holden, S.A., Northey, D., Dewhirst, M.W., and Herman, T.S. 1993. "Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside". United States. doi:10.1016/0360-3016(93)90179-Y.
@article{osti_6936312,
title = {Therapeutic effect of infused Fluosol-DA/carbogen with ephedrine, flunarizine, or nitroprusside},
author = {Teicher, B.A. and Holden, S.A. and Northey, D. and Dewhirst, M.W. and Herman, T.S.},
abstractNote = {The perfluorochemical emulsion Fluosol-DA plus carbogen breathing has been shown to increase the effectiveness of radiation therapy in preclinical solid tumors when the emulsion was administered by i.v. bolus injection. Much of the enhancement in tumor radiation response was lost when the emulsion was administered slowly. The authors hypothesized that an increase in tumor perfusion resulted when Fluosol-DA was administered rapidly. In the present study, the [alpha]/[beta] agonist ephedrine, the Ca[sup 2+] channel blocker flunarizine and the nitric oxide producing vasodilating drug nitroprusside have been tested. Ephedrine administration resulted in a decrease in the radiation plus Fluosol-DA [+-] carbogen antitumor effects in both the Lewis lung carcinoma and FSaIIC tumor systems. In contrast, flunarizine administration resulted in an increase in the efficacy of the radiation plus carbogen and the radiation plus Fluosol-DA/carbogen in both emulsion was given rapidly. Even with flunarizine administration Fluosol-DA delivered slowly was less effective than when the emulsion was given rapidly. Flunarizine with Fluosol-DA infused i.v. over 30 min followed by carbogen breathing prior to and during radiation therapy resulted in a 1.7-1.6-fold increase in response compared with 2.4-2.2-fold with Fluosol-DA administered by injection i.v. and carbogen breathing prior to and during radiation therapy using growth delay of the Lewis lung carcinoma. The effects of nitroprusside were complex. This drug had considerably more effect at 10 Gy than at higher radiation doses. These studies suggest that Fluosol-DA given by i.v. injection may increase tumor perfusion and that a drug like flunarizine may be beneficial if the Fluosol-DA is administered slowly followed by carbogen breathing and radiation therapy. 45 refs., 4 figs.},
doi = {10.1016/0360-3016(93)90179-Y},
journal = {International Journal of Radiation Oncology, Biology and Physics; (United States)},
number = ,
volume = 26:1,
place = {United States},
year = 1993,
month = 4
}
  • A series of heterogeneous catalysts for asymmetric Michael additions was synthesized based on ephedrine chemically bound to the surface of silica. The length of the hydrocarbon chain binding the active center to the support surface affects the sign of rotation of the reaction product from the asymmetric addition of thiophenol to benzylideneacetophenone. Grafting ephedrine to the silica surface via a short hydrocarbon chain results in a change in the configuration of the reaction product. Silanol groups on the silica surface are involved in the transition state, as evidenced by data obtained using silica which has been exhaustively treated with trimethylchlorosilane.more » The absolute specific rotation of 1,3-diphenyl-3-thiophenylpropan-1-one has been established.« less
  • Normal tissue effects in mice due to combinations of a perfluorochemical emulsion, Fluosol-DA 20%, 100% oxygen, and whole-body irradiation were investigated. Eight-to-10-week-old C57BL/6 male mice were injected via the tail vein with 10 ml/kg of Fluosol-DA with and without subsequent exposure to oxygen for 60 minutes. Animals then received graded doses of whole-body radiation (4 MV photons) at a dose rate of 2.85 +/- .015 Gy/minute. Using linear regression analysis, the lethal doses of radiation to 50% and 10% of the animals within 30 days in the absence of Fluosol-DA and oxygen were 8.35 Gy (95% c.l.:7.77-8.93 Gy) and 6.73more » Gy (95% cl.:6.21-7.25 Gy), respectively, and were unaffected by Fluosol-DA and/or oxygen pre-treatment. However, Fluosol-DA given alone or in combination with oxygen produced increased balding and decreased graying incidence in mice within 60 days, and resulted in depressed weight gain 15 to 60 days post-treatment. Normal tissue effects due to administration of Fluosol-DA and oxygen in combination with whole-body irradiation have been demonstrated but appear minimal compared to other anti-tumor modalities currently under investigation.« less
  • Previous studies revealed that administration of 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) to calcium (Ca)-deficient rats causes a dose-dependent reduction in markedly elevated serum 1,25-(OH)2D3 level. Although the results suggested that the metabolism of 1,25-(OH)2D3 was accelerated by 24,25-(OH)2D3, those experiments could not define whether the enhanced metabolism of 1,25-(OH)2D3 played a role in the reduction in the serum 1,25-(OH)2D3 level. In the present study, in order to address this issue more specifically, serum 1,25-(OH)2D3 was maintained solely by exogenous administration through miniosmotic pumps of 1,25-(OH)2D3 into vitamin D-deficient rats. Thus, by measuring the serum 1,25-(OH)2D3 concentration, the effect of 24,25-(OH)2D3 on themore » MCR of 1,25-(OH)2D3 could be examined. Administration of 24,25-(OH)2D3 caused a dose-dependent enhancement in the MCR of 1,25-(OH)2D3, and 1 microgram/100 g rat.day 24,25-(OH)2D3, which elevated serum 24,25-(OH)2D3 to 8.6 +/- 1.3 ng/ml, significantly increased MCR and suppressed serum levels of 1,25-(OH)2D3. The effect of 24,25-(OH)2D3 on 1,25-(OH)2D3 metabolism developed with a rapid time course, and the recovery of iv injected (1 beta-3H)1,25-(OH)2D3 in blood was significantly reduced within 1 h. In addition, there was an increase in radioactivity in the water-soluble fraction of serum as well as in urine, suggesting that 1,25-(OH)2D3 is rapidly degraded to a water-soluble metabolite(s). Furthermore, the reduction in serum 1,25-(OH)2D3 was associated with a reduction in both serum and urinary Ca levels. Because the conversion of (3H)24,25-(OH)2D3 to (3H)1,24,25-(OH)2D3 or other metabolites was minimal in these rats, 24,25-(OH)2D3 appears to act without being converted into other metabolites. These results demonstrate that 24,25-(OH)2D3 rapidly stimulates the metabolism of 1,25-(OH)2D3 and reduces its serum level.« less