Relative volume‐average murine tumor blood flow measurement via deuterium nuclear magnetic resonance spectroscopy

A deuterium NMR spectroscopic method to determine relative tumor blood flow (TBF) by measuring the increase in tumor HOD concentration after intravenous injection of 100 μl D2O (0.9% NaCl) is presented. An integration approach analogous to that validated for positron emission tomographic measurement of cerebral blood flow was implemented. Computer simulations indicated that integration from 30 to 120 s minimizes the sensitivity of the uptake integral to the shape of the arterial input function, which cannot be assessed in each mouse, while maintaining both a nearly linear relationship between TBF and the integral and high NMR signal‐to‐noise. A strong positive linear correlation was observed between the uptake integral and TBF measured by D2O clearance in both untreated tumors (n = 19; P < 0.001) and tumors after hyperthermia (n = 16; P < 0.001). This method can measure relative TBF in tumors with heterogeneous blood flow and is ideally suited to concurrent or interleaved measurement of TBF and metabolism via multinuclear NMR spectroscopy. © 1991 Academic Press. Inc.

[1]  Deuterium NMR cerebral imaging in Situ , 1988, Magnetic resonance in medicine.

[2]  I. Kanno,et al.  Error Analysis of a Quantitative Cerebral Blood Flow Measurement Using H215O Autoradiography and Positron Emission Tomography, with Respect to the Dispersion of the Input Function , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  F. Gibbs,et al.  Capillary blood flow in murine tumors, feet, and intestines during localized hyperthermia. , 1983, Radiation research.

[4]  J. Evelhoch,et al.  Deuterium nuclear magnetic resonance imaging of tracer distribution in D2O clearance measurements of tumor blood flow in mice. , 1990, Cancer research.

[5]  S. G. Kim,et al.  Quantitative determination of tumor blood flow and perfusion via deuterium nuclear magnetic resonance spectroscopy in mice. , 1988, Cancer research.

[6]  M D Ginsberg,et al.  Emission tomographic measurement of local cerebral blood flow in humans by an in vivo autoradiographic strategy , 1984, Annals of neurology.

[7]  J. Gray,et al.  A new mouse tumor model system (RIF-1) for comparison of end-point studies. , 1980, Journal of the National Cancer Institute.

[8]  A C GUYTON,et al.  Adjustments of the circulatory system following very rapid transfusion or hemorrhage. , 1951, The American journal of physiology.

[9]  J. Evelhoch,et al.  Flavone acetic acid (NSC 347512)-induced modulation of murine tumor physiology monitored by in vivo nuclear magnetic resonance spectroscopy. , 1988, Cancer research.

[10]  C. Song,et al.  Tumor reoxygenation and postirradiation vascular changes. , 1978, Radiology.

[11]  P. Tofts,et al.  Noninvasive measurement of molar concentrations of 31P metabolites in vivo, using surface coil NMR spectroscopy , 1988, Magnetic resonance in medicine.

[12]  T. Ng,et al.  Shielded solenoidal probe for in Vivo NMR studies of solid tumors , 1985, Magnetic resonance in medicine.

[13]  C. Song,et al.  Continuous and non-invasive quantification of heat-induced changes in blood flow in the skin and RIF-1 tumour of mice by laser Doppler flowmetry. , 1987, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[14]  K. Aukland,et al.  Distribution of blood flow in the dog kidney. I. Saturation rates for inert diffusible tracers, 125I-iodoantipyrine and tritiated water, versus uptake of microspheres under control conditions. , 1979, Acta physiologica Scandinavica.

[15]  N. Lifson,et al.  Kinetics concerned with distribution of isotopic water in isolated perfused dog heart and skeletal muscle. , 1952, The American journal of physiology.

[16]  M. Mintun,et al.  Brain blood flow measured with intravenous H2(15)O. II. Implementation and validation. , 1983, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[17]  F. Gibbs,et al.  RIF-1 tumor treatment in anesthetized mice with minimal effects on blood flow and hypoxia. , 1988, Radiation research.

[18]  G. Denardo,et al.  Blood flow in irradiated mouse sarcoma as determined by the clearance of xenon-133. , 1972, Cancer research.

[19]  D. I. Hoult,et al.  The NMR receiver: A description and analysis of design , 1978 .

[20]  Keith R Thulborn,et al.  Absolute molar concentrations by NMR in inhomogeneous B1. A scheme for analysis of in vivo metabolites , 1983 .

[21]  R A Koeppe,et al.  Examination of assumptions for local cerebral blood flow studies in PET. , 1987, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  M. Raichle,et al.  Brain blood flow measured with intravenous H2(15)O. I. Theory and error analysis. , 1983, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  C. Babbs,et al.  Hydralazine-enhanced selective heating of transmissible venereal tumor implants in dogs. , 1982, European journal of cancer & clinical oncology.

[24]  S. Kety The theory and applications of the exchange of inert gas at the lungs and tissues. , 1951, Pharmacological reviews.

[25]  T. Ng,et al.  Direct relationship between high-energy phosphate content and blood flow in thermally treated murine tumors. , 1985, Journal of the National Cancer Institute.

[26]  R. A. Norman,et al.  Dynamics of water-isotope distribution. , 1972, The American journal of physiology.

[27]  J. Ackerman,et al.  Multicompartment analysis of blood flow and tissue perfusion employing D2O as a freely diffusible tracer: A novel deuterium NMR technique demonstrated via application with murine RIF‐1 tumors , 1988, Magnetic resonance in medicine.

[28]  R. Jain,et al.  Viscous resistance to blood flow in solid tumors: effect of hematocrit on intratumor blood viscosity. , 1989, Cancer research.

[29]  D. Doddrell,et al.  Preliminary studies on the potential of in vivo deuterium NMR spectroscopy. , 1986, Biochemical and biophysical research communications.

[30]  R. Jirtle,et al.  Measurement of mammary tumor blood flow in unanesthetized rats. , 1978, Journal of the National Cancer Institute.

[31]  H. Reinhold,et al.  Tumour microcirculation as a target for hyperthermia. , 1986, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.

[32]  J. Finley,et al.  Evaluation of nuclear magnetic resonance spectroscopy for determination of deuterium abundance in body fluids: application to measurement of total-body water in human infants. , 1987, The American journal of clinical nutrition.

[33]  R. Reed,et al.  Interstitial fluid pressure in DMBA-induced rat mammary tumours. , 1982, Scandinavian journal of clinical and laboratory investigation.

[34]  Douglas A. Wolfe,et al.  Nonparametric Statistical Methods , 1973 .

[35]  J. Ackerman,et al.  Deuterium nuclear magnetic resonance measurements of blood flow and tissue perfusion employing 2H2O as a freely diffusible tracer. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. M. Thompson,et al.  Regional tissue uptake of D2O in perfused organs: rat liver, dog heart and gastrocnemius. , 1959, The American journal of physiology.

[37]  M E Raichle,et al.  Evidence of the Limitations of Water as a Freely Diffusible Tracer in Brain of the Rhesus Monkey , 1974, Circulation research.

[38]  R. Hill,et al.  Effect of tumor blood flow manipulations on radiation response. , 1983, International journal of radiation oncology, biology, physics.

[39]  J. Bassingthwaighte,et al.  Circulatory Transport of Iodoantipyrine and Water in the Isolated Dog Heart , 1970, Circulation research.