Non-invasive determination of tumor oxygen tension and local variation with growth.

PURPOSE The objective was to develop and demonstrate a novel noninvasive technique of measuring regional pO2 in tumors. The method is based on measuring 19F nuclear magnetic resonance spin-lattice relaxation rate (R1 = 1/T1) of perfluorocarbon (PFC) emulsion discretely sequestered in a tumor. METHODS AND MATERIALS We have examined pO2 in the Dunning prostate tumor R3327-AT1 implanted in a Copenhagen rat. Oxypherol blood substitute emulsion was administered intravenously and became sequestered in tissue. Proton magnetic resonance imaging (MRI) showed tumor anatomy and correlated 19F MRI indicated the distribution of perfluorocarbon. Fluorine-19 spectroscopic relaxometry was used to measure pO2 in the tumor and repeated measurements over a period of 3 weeks showed the variation in local pO2 during tumor growth. RESULTS Perfluorocarbon initially resided in the vascularized peripheral region of the tumor: 19F nuclear magnetic resonance R1 indicated pO2 approximately 75 torr in a small tumor (approximately 1 cm) in an anesthetized rat. As the tumor grew, the sequestered PFC retained its original distribution. When the tumor had doubled in size the residual PFC was predominantly in the core of the tumor and the pO2 of this region was approximately 1 torr indicating central tumor hypoxia. CONCLUSION We have demonstrated a novel noninvasive approach to monitoring regional tumor pO2. Given the critical role of oxygen tension in tumor response to therapy this may provide new insight into tumor physiology, the efficacy of various therapeutic approaches, and ultimately provide a clinical technique for assessing individual tumor oxygenation.

[1]  D. Carney,et al.  Perfluorooctylbromide as a contrast agent for CT and sonography: preliminary clinical results. , 1993, AJR. American journal of roentgenology.

[2]  R K Jain,et al.  Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. , 1991, Cancer research.

[3]  D. Delpy,et al.  19F NMR imaging of blood oxygenation in the brain , 1988, Magnetic resonance in medicine.

[4]  C. Song,et al.  Increase in pO2 and radiosensitivity of tumors by Fluosol-DA (20%) and carbogen. , 1986, Cancer research.

[5]  R. Martino,et al.  Fluosol 43 intravascular persistence in mice measured by 19F nmr , 1984, The Journal of pharmacy and pharmacology.

[6]  H C Charles,et al.  Evaluation of ba1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy , 1991, Magnetic resonance in medicine.

[7]  L. H. Gray,et al.  The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. , 1953, The British journal of radiology.

[8]  K. Yokoyama,et al.  Oxygenation effect of fluosol-DA on hypoxic tumor tissue and retention of PFCs in the tumor-bearing rats. , 1988, Biomaterials, artificial cells, and artificial organs.

[9]  B. Teicher,et al.  Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. , 1981, Cancer research.

[10]  M. Trotter,et al.  Evidence for intermittent radiobiological hypoxia in experimental tumour systems. , 1989, Biomedica biochimica acta.

[11]  C. J. Koch,et al.  A novel technique for measuring human tissue pO2 at the cellular level. , 1986, British Journal of Cancer.

[12]  C. Song,et al.  The oxygenation of murine tumor isografts and human tumor xenografts by nicotinamide. , 1992, Radiation research.

[13]  P. Vaupel,et al.  Intracapillary HbO2 saturation in malignant tumors during normoxia and hyperoxia. , 1979, Microvascular research.

[14]  J. Ackerman,et al.  NMR T1 measurements in inhomogeneous B1 with surface coils , 1983 .

[15]  I. Silver,et al.  Quantitative measurements of oxygen tension in normal tissues and in the tumours of patients before and after radiotherapy. , 1960, Acta radiologica.

[16]  P. Hees,et al.  Assessment of changes in murine tumor oxygenation in response to nicotinamide using 19F NMR relaxometry of a perfluorocarbon emulsion , 1993, Magnetic resonance in medicine.

[17]  Akber Sf.  Correlation between oxygen tension and spin-lattice relaxation rate in tumors. , 1989 .

[18]  F. Lohr,et al.  Response of the rat Dunning R3327-AT1 prostate tumor to treatment with fractionated fast neutrons. , 1992, Radiation research.

[19]  P. Antich,et al.  A novel editing technique for 19F MRI: molecule-specific imaging. , 1990, Magnetic resonance imaging.

[20]  P. Okunieff,et al.  Estimation of tumor oxygenation and metabolic rate using 31P MRS: correlation of longitudinal relaxation with tumor growth rate and DNA synthesis. , 1988, International journal of radiation oncology, biology, physics.

[21]  P Peschke,et al.  Isolated tumor growth in a surgically formed skin pedicle in the rat: a new tumor model for NMR studies. , 1993, Magnetic resonance imaging.

[22]  M. Graham,et al.  31P magnetic resonance spectroscopy is sensitive to tumor hypoxia: Perfusion and oxygenation of rat 9L gliosarcoma after treatment with BCNU , 1991, NMR in biomedicine.

[23]  P Vaupel,et al.  Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. , 1991, Cancer research.

[24]  P Okunieff,et al.  Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma. , 1989, Radiation research.

[25]  P. Antich,et al.  Oxygent: a novel probe of tissue oxygen tension. , 1992, Biomaterials, artificial cells, and immobilization biotechnology : official journal of the International Society for Artificial Cells and Immobilization Biotechnology.

[26]  Stanton A. Glantz,et al.  Primer of biostatistics : statistical software program version 6.0 , 1981 .

[27]  R. Sutherland.  Cell and environment interactions in tumor microregions: the multicell spheroid model. , 1988, Science.

[28]  R. Steen,et al.  31P NMR spectroscopic and near infrared spectrophotometric studies of effects of anesthetics on In vivo RIF‐1 tumors. relationship to tumor radiosensitivity , 1989, NMR in biomedicine.

[29]  P Vaupel,et al.  Pathophysiological approaches to identifying tumor hypoxia in patients. , 1991, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[30]  P. Antich,et al.  Tissue oxygenation: A novel determination using 19F surface coil NMR spectroscopy of sequestered perfluorocarbon emulsion , 1991, Magnetic resonance in medicine.

[31]  P. Joseph,et al.  In vivo measurements of vascular oxygen tension in tumors using MRI of a fluorinated blood substitute. , 1989, Investigative radiology.

[32]  M. McPhee,et al.  The radiation sensitivities of R3327-H and R3327-AT rat prostate adenocarcinomas. , 1985, The Journal of urology.

[33]  P. Naylor,et al.  The effect of oxygen breathing and radiotherapy upon the tissue oxygen tension of some human tumours , 1963 .

[34]  J. Handa,et al.  Perfluorocarbon temperature measurements using 19F NMR , 1992, NMR in biomedicine.

[35]  R. Damadian.  Tumor Detection by Nuclear Magnetic Resonance , 1971, Science.

[36]  C. Jaffe,et al.  Reduction of myocardial ischemia during percutaneous transluminal coronary angioplasty with oxygenated Fluosol. , 1990, The American journal of cardiology.

[37]  J. Griffiths,et al.  Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by 19F magnetic resonance spectroscopy in vivo. , 1989, International journal of radiation oncology, biology, physics.

[38]  P. Okunieff,et al.  Effects of Oxygen on the Metabolism of Murine Tumors Using in Vivo Phosphorus‐31 NMR , 1987, American journal of clinical oncology.

[39]  B. Teicher,et al.  A clinical trial of Fluosol DA 20% in advanced squamous cell carcinoma of the head and neck. , 1986, International journal of radiation oncology, biology, physics.

[40]  C. M. J. Van Uijen,et al.  Driven‐equilibrium radiofrequency pulses in NMR imaging , 1984, Magnetic resonance in medicine.

[41]  L. Kwock,et al.  Evaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by 19F magnetic resonance spectroscopy and immunohistochemistry. , 1992, Radiation research.

[42]  R. Coombes,et al.  Monitoring Cancer Therapy by NMR Spectroscopy a , 1987, Annals of the New York Academy of Sciences.

[43]  C. Lewa,et al.  Temperature relationships of proton spin-lattice relaxation time T1 in biological tissues. , 1980, Bulletin du cancer.

[44]  S. Rockwell,et al.  Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. , 1984, International journal of radiation oncology, biology, physics.

[45]  P. Antich,et al.  Perfluorocarbon imaging in vivo: a 19F MRI study in tumor-bearing mice. , 1989, Magnetic resonance imaging.

[46]  P. Antich,et al.  In vivo oxygen tension and temperature: Simultaneous determination using 19F NMR spectroscopy of perfluorocarbon , 1993, Magnetic resonance in medicine.

[47]  D. S. Coffey,et al.  Animal models of the hormone-sensitive and -insensitive prostatic adenocarcinomas, Dunning R-3327-H, R-3327-HI, and R-3327-AT. , 1978, Cancer research.

[48]  R. Gatenby,et al.  Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. , 1988, International journal of radiation oncology, biology, physics.

[49]  R. London,et al.  Quantitative determination of the partial oxygen pressure in the vitrectomized rabbit eye in Vivo using 19F NMR , 1991, Magnetic resonance in medicine.

[50]  B. Fenton,et al.  31P nuclear magnetic resonance spectroscopy studies of tumor energy metabolism and its relationship to intracapillary oxyhemoglobin saturation status and tumor hypoxia. , 1988, Cancer research.

[51]  C. Coleman,et al.  Hypoxia in tumors: a paradigm for the approach to biochemical and physiologic heterogeneity. , 1988, Journal of the National Cancer Institute.

[52]  R. Steen.  Characterization of tumor hypoxia by 31P MR spectroscopy. , 1991, AJR. American journal of roentgenology.