RSR13, a synthetic allosteric modifier of hemoglobin, as an adjunct to radiotherapy: Preliminary studies with EMT6 cells and tumors and normal tissues in mice

Rockwell, Sara; Kelley, Marianne

doi:10.1002/(sici)1520-6823(1998)6:5<199::aid-roi1>3.3.co;2-4

Cited by 7 publications

(9 citation statements)

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“…A number of single-dose studies have shown that efaproxiral plus oxygen breathing increases the delivery of oxygen to hypoxic tumors and that this increase in tumor oxygenation enhances the effectiveness of radiotherapy (14,15). Efaproxiral plus oxygen breathing increased the effectiveness of radiation on EMT6 mammary tumors in BALB/c mice and reduced the hypoxic fraction to 9% from 24% found in either air-breathing or oxygen-breathing mice (16). When administered on days 4 through 18 after tumor implantation, efaproxiral was a highly effective an-219 EFAPROXIRAL, RADIATION AND OXYGENATION IN MURINE TUMORS timetastatic agent in animals bearing Lewis lung carcinoma (17).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Efaproxyn™ (Efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy-Mediated Inhibition of Tumor Growth in Mice

Hou¹,

Khan²,

Grinberg³

et al. 2007

Radiation Research

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Efaproxiral, an allosteric modifier of hemoglobin, reduces hemoglobin-oxygen binding affinity, facilitating oxygen release from hemoglobin, which is likely to increase tissue pO(2). The purpose of this study was to determine the effect of efaproxiral on tumor oxygenation and growth inhibition of RIF-1 tumors that received X radiation (4 Gy) plus oxygen breathing compared to radiation plus oxygen plus efaproxiral daily for 5 days. Two lithium phthalocyanine (LiPc) deposits were implanted in RIF-1 tumors in C3H mice for tumor pO(2) measurements using EPR oximetry. Efaproxiral significantly increased tumor oxygenation by 8.4 to 43.4 mmHg within 5 days, with maximum increases at 22-31 min after treatment. Oxygen breathing alone did not affect tumor pO(2). Radiation plus oxygen plus efaproxiral produced tumor growth inhibition throughout the treatment duration, and inhibition was significantly different from radiation plus oxygen from day 3 to day 5. The results of this study provide unambiguous quantitative information on the effectiveness of efaproxiral to consistently and reproducibly increase tumor oxygenation over the course of 5 days of treatment, modeling the clinical use of efaproxiral. Also, based on the tumor growth inhibition, the study shows the efaproxiral-enhanced tumor oxygenation was radiobiologically significant. This is the first study to demonstrate the ability of efaproxiral to increase tumor oxygenation and to increase the tumor growth inhibition of radiotherapy over 5 days of treatment.

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Section: Introductionmentioning

confidence: 99%

The Effects of Efaproxyn™ (Efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy-Mediated Inhibition of Tumor Growth in Mice

Hou¹,

Khan²,

Grinberg³

et al. 2007

Radiation Research

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“…RSR4 was a stronger effector than RSR13 in Hb solution studies and about equipotent in whole blood studies. [13][14][15][16][17] However, RSR13 was chosen as the candidate for phase I clinical trials with the rationale that the phenyl methyl substitution might be better tolerated in vivo in animal studies. This proved to be correct.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of Chiral Allosteric Modifiers of Hemoglobin

et al. 2000

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A series of allosteric effectors of hemoglobin, 2-(aryloxy)-2-alkanoic acids, was prepared to investigate the effect of the stereocenter on allosteric activity. The chiral analogues were based on the lead compound, RSR13 (3b), with different alkyl/alkanoic and cycloalkyl/cycloalkanoic groups positioned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 were selected for resolution based on structure-activity relationships. One chiral analogue, (-)-(1R,2R)-1-[4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentane carbox ylic acid (11), exhibited greater in vitro activity in hemoglobin solutions than its antipode, racemate, and RSR13. Compound (-)-(1R, 2R)-11 was equipotent with RSR13 in whole blood, is a candidate for in vivo animal studies, and if efficacious and safe has a potential for use in humans. In general, it was found that chirality affects allosteric effector activity with measurable differences observed between enantiomers and the racemates.

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“…This pharmacodynamic (PD) effect is measured either as a decrease in standard cutaneous pulse oximetry (SpO 2 ) or as an increase in the partial pressure of O 2 (pO 2 ) to produce 50% saturation of Hb (p50). Nonclinical pharmacology (Khandelwal et al, 1996;Teicher et al, 1996;Rockwell and Kelley, 1998;Amorino et al, 2001) studies have demonstrated that efaproxiral can enhance the oxygenation of hypoxic tumours and function as a radiation sensitiser, increasing the effectiveness of RT.…”

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confidence: 99%

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

et al. 2006

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Efaproxiral (Efaproxynt, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O 2 ) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction Â 10 days), plus supplemental O 2 (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (X483 mg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

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RSR13, a synthetic allosteric modifier of hemoglobin, as an adjunct to radiotherapy: Preliminary studies with EMT6 cells and tumors and normal tissues in mice

Cited by 7 publications

References 0 publications

The Effects of Efaproxyn™ (Efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy-Mediated Inhibition of Tumor Growth in Mice

The Effects of Efaproxyn™ (Efaproxiral) on Subcutaneous RIF-1 Tumor Oxygenation and Enhancement of Radiotherapy-Mediated Inhibition of Tumor Growth in Mice

Synthesis and Structure−Activity Relationships of Chiral Allosteric Modifiers of Hemoglobin

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

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