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

Abstract

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.

Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

“…These AEHs have potential therapeutic applications in treating ischemia-related cardiovascular diseases, such as angina, myocardial ischemia, stroke, trauma, where more O 2 is needed to heal tissue or organs. 54–59 A second class of AEHs, which includes several aromatic aldehydes, on the contrary, bind to Hb to increase its O 2 affinity by preferentially stabilizing the R-state relative to the T-state (Fig. 2B).…”

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

“…25-28 Right-shifters encompass both covalent binders, such as aromatic aldehydes, 29,30 and non-covalent binders, e.g. aromatic propionates.…”

Dynamic changes in oxygenation of intracranial tumor and contralateral brain during tumor growth and carbogen breathing: A multisite EPR oximetry with implantable resonators

“…Once introduced in the tissue of interest, they allow repeated measurement of pO 2 at the same site for up to years after implantation. Based on extensive pre-clinical and some clinical studies [26–30], EPR oximetry with particulate paramagnetic materials has shown several advantages, especially for the repetitive and accurate measurement of localized tissue pO 2 . However, these studies have also indicated the areas in which progress is needed, particularly the need for technological developments that can enable measurements in tissues at depths of greater than 10 mm.…”