Perfluorochemicals attracted widespread attention in 1966, when Clark and Gollan showed that mice could survive for prolonged periods when completely immersed in liquid perfluorochemicals equilibriated with O2 at atmospheric pressure. The exceptional O2-carrying capacity of perfluorochemicals has provided the basis for using physiolologic emulsions of perfluorochemicals as O2-transport fluids after hemorrhage or during surgery when blood transfusions are impossible or refused. Treatment with perfluorochemical emulsions (PFCE's) and O2-breathing also reduces myocardial damage after coronary artery occlusion, protects against acute focal cerebral ischemia after ligation of the cerebral artery, and minimizes injury after spinal cord compression, reflecting improving O2 delivery into ischemic tissues. Solid tumors have abnormal, insufficient vasculatures and, as a result, contain areas which are hypoxic because of transient or chronic deficiencies in blood flow. Hypoxic cells are very resistant to the cytotoxic effects of ionizing radiation and limit the efficacy of radiotherapy in achieving local control of some solid tumors. We found that administration of a perfluorochemical emulsion and a high-oxygen atmosphere increases the response of BAlll2 rat rhabdomyosarcomas and EMT6 mouse mammary tumors to radiation. This was shown to reflect a decrease in the proportion of hypoxic tumor cells, rather than a direct toxic or radiosensitizing effect of the PFCE. This project will examine further the clinical potential of this effect, using solid EMT6, KHJJ, and BAlll2 tumors to test the effects of PFCE's and O2-breathing on tumor cell survival curves, tumor growth, tumor cure, and tumor oxygenation. The effect of treatment with PFCE's on the efficacy of fractionated radiotherapy and chronic low dose rate irradiation will also be examined. The effects of exchange transfusions, producing high flurocrits and low hematocrits, will be tested. The toxicities and physiological effects of the PFCE/O2 treatments and the effects of the treatments on tumor growth and metastasis will also be examined. The effects of PFCE's on the radiation responses of several normal tissues (including lung, skin, liver, and the hematopoetic system) will also be studied. These data will be used to determine whether therapeutic gain can be obtained by adjunctive treatment with PFCE's and oxygen, to assess further the clinical potential of PFCE's as adjuncts to radiotherapy, and to identify any problems which may be encountered in the clinical use of these adjuvants.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035215-06
Application #
3172837
Study Section
Radiation Study Section (RAD)
Project Start
1984-05-01
Project End
1992-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Rockwell, S (1994) Perfluorochemical emulsions and radiation therapy. Artif Cells Blood Substit Immobil Biotechnol 22:1097-108
Rockwell, S; Kelley, M; Irvin, C G (1992) Effects of the perfluorochemical emulsion FMIQ on the radiation response of EMT6 tumours. Int J Radiat Biol 61:833-9
Rockwell, S; Irvin, C G; Kelley, M et al. (1992) Effects of hyperbaric oxygen and a perfluorooctylbromide emulsion on the radiation responses of tumors and normal tissues in rodents. Int J Radiat Oncol Biol Phys 22:87-93
Sostman, H D; Rockwell, S; Sylvia, A L et al. (1991) Evaluation of BA1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy. Magn Reson Med 20:253-67
Rockwell, S; Kelley, M; Irvin, C G et al. (1991) Modulation of tumor oxygenation and radiosensitivity by a perfluorooctylbromide emulsion. Radiother Oncol 22:92-8
Rockwell, S; Hughes, C S; Kennedy, K A (1991) Effect of host age on microenvironmental heterogeneity and efficacy of combined modality therapy in solid tumors. Int J Radiat Oncol Biol Phys 20:259-63
Morton, J D; Porter, E; Yabuki, H et al. (1990) Effects of a perfluorochemical emulsion on the response of BA1112 rat rhabdomyosarcomas to continuous low-dose-rate irradiation. Radiat Res 124:178-82
Rockwell, S; Moulder, J E (1990) Hypoxic fractions of human tumors xenografted into mice: a review. Int J Radiat Oncol Biol Phys 19:197-202
Suit, H D; Rockwell, S; Zeitman, A et al. (1989) Quantitative transplantation assays of the rat rhabdomyosarcoma BA1112 isografts into the WAG/Rij Y rat and xenotransplantation into the athymic NCr (nu/nu) nude mouse. Eur J Cancer Clin Oncol 25:1463-6
Rockwell, S; Kelley, M (1989) Radiation enhancement of lung nodule formation in mice is not potentiated by treatment with a perfluorochemical emulsion and carbogen. Radiother Oncol 14:49-53

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