Efaproxiral

Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb–O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb–O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb–O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.

Radiation therapy (RT) is the cornerstone of management of malignant brain tumors, but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review, we provide an overview of radiosensitizers developed for malignant brain tumors, summarize their safety and efficacy, and evaluate areas for possible improvement.

Following PRISMA guidelines, PubMed, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT. Articles reporting clinical evidence of nonantineoplastic radiosensitizers with RT for malignant central nervous system tumors were included. Data of interest were presumed mechanism of action, median overall survival (OS), progression-free survival (PFS), and adverse events.

Twenty-two unique radiosensitizers were identified. Only 2/22 agents (fluosol with oxygen, and efaproxiral) showed improvement in OS in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. Improved PFS was reported with use of metronidazole, sodium glycididazole, and chloroquine. There was a wide range of toxicities, which prompted change of schedule or complete discontinuation of 9 agents.

Progress in radiosensitizers for malignant CNS tumors has been limited. Only 2 radiosensitizers have shown limited improvement in survival. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Use of drug development strategies using new technologies to overcome past challenges is necessary.