title: Effect of RSR13, an allosteric hemoglobin modifier, on oxygenation in murine tumors: an in vivo electron paramagnetic resonance oximetry and bold MRI study.
abstract: OBJECTIVE
  RSR13, an allosteric modifier of hemoglobin, reduces hemoglobin-oxygen binding affinity facilitating oxygen release from hemoglobin, resulting in increases in tissue pO(2). The purpose of this study was noninvasively to monitor the time course and effect of RSR13 on tumor oxygenation, directly using in vivo electron paramagnetic resonance (EPR oximetry), and indirectly using blood oxygen level dependent magnetic resonance imaging (BOLD MRI).
  
  
  METHODS
  The study was performed in transplanted radiation-induced fibrosarcoma tumors (RIF-1) in 18 female C3H/HEJ mice, which had two lithium phthalocyanine (LiPc) deposits implanted in the tumor when the tumors reached about 200-600 mm(3). Baseline EPR measurements were made daily for 3 days. Then, for 6 consecutive days and after an initial baseline EPR measurement, RSR13 (150 mg/kg) or vehicle (same volume) was injected intraperitoneally, and measurements of intratumoral oxygen were made at 10-min intervals for the next 60 min. In each mouse, every third day, instead of EPR oximetry, BOLD MRI measurements were made for 60 min after administration of the RSR13.
  
  
  RESULTS
  Based on EPR measurements, RSR13 produced statistically significant temporal increases in tumor pO(2) over the 60-min time course, which reached a maximum at 35-43 min postdose. The average time required to return to the baseline pO(2) was 70-85 min. The maximum increase in tumor tissue pO(2) values after RSR13 treatment from Day 1 to Day 5 (8.3-12.4 mm Hg) was greater than the maximum tumor tissue pO(2) value for Day 6 (4.7 mm Hg, p < 0.01). The maximum increase in pO(2) occurred on Day 2 (12.4 mm Hg) after RSR13 treatment. There was little change in R(2)*, indicating that the RSR13 had minimal detectable effects on total deoxyhemoglobin and hemoglobin-oxygen saturation.
  
  
  CONCLUSIONS
  The extent of the increase in tumor pO(2) achieved by RSR13 would be expected to lead to a significant increase in the effectiveness of tumor radiotherapy. The lack of a change in the BOLD MRI signal suggests that the tumor physiology was largely unchanged by RSR13. These results illustrate a unique and useful capability of in vivo EPR oximetry and BOLD MRI to obtain repeated measurements of tumor oxygenation and physiology. The dynamics of tumor pO(2) after RSR13 administration may be useful for the design of clinical protocols using allosteric hemoglobin effectors.
authors.affiliation: Department of Diagnostic Radiology, EPR Center for the Study of Viable Systems, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Huagang
authors.initials: H
authors.lastname: Hou
authors.forename: Nadeem
authors.initials: N
authors.lastname: Khan
authors.forename: Julia A
authors.initials: JA
authors.lastname: O'Hara
authors.forename: Oleg Y
authors.initials: OY
authors.lastname: Grinberg
authors.forename: Jeff F
authors.initials: JF
authors.lastname: Dunn
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Abajian
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Wilmot
authors.forename: Malek
authors.initials: M
authors.lastname: Makki
authors.forename: Eugene
authors.initials: E
authors.lastname: Demidenko
authors.forename: Shiyi
authors.initials: S
authors.lastname: Lu
authors.forename: Robert P
authors.initials: RP
authors.lastname: Steffen
authors.forename: Harold M
authors.initials: HM
authors.lastname: Swartz
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism; D006441:Hemoglobin A / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008809:Mice, Inbred C3H; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism*; D010092:Oximetry / Q000379:methods; D010100:Oxygen / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000814:Aniline Compounds; D011422:Propionates; D011838:Radiation-Sensitizing Agents; D006441:Hemoglobin A; C067396:efaproxiral; D010100:Oxygen