Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment

Introduction: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. Methods: Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunofluorescent determination of phosphorylated histone H2AX ($\gamma$H2AX) foci, $\beta$-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model. Results: Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T-oligo was associated with increased formation and/or delayed resolution of $\gamma$H2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions. Conclusions: Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects

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

Efaproxiral (Efaproxyn™, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O2) 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 × 10 days), plus supplemental O2 (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 (⩾483 μg/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

RSR13 e modificação alostérica da afinidade hemoglobina-oxigênio: abuso entre atletas RSR13 and allosteric change in the hemoglobin-oxygen afinity: abuse among athletes

O ácido metilpropiônico (RSR13) é um modificador alostérico da hemoglobina, com a qual se liga de forma não-covalente, diminuindo sua afinidade pelo oxigênio de modo dose-dependente e, conseqüentemente, aumentando a oxigenação periférica. O objetivo deste artigo é apresentar brevemente as evidências científicas acerca das características farmacológicas e funcionais, indicações médicas e efeitos adversos do uso do RSR13 por atletas, a mais recente alternativa de aumento artificial do desempenho. Estudos experimentais preliminares verificaram algum efeito positivo do RSR13 sobre a recuperação do miocárdio isquêmico e sobre a extensão da isquemia cerebral, mas as principais indicações estudadas atualmente são a cirurgia com hipotermia e cardioplegia durante circulação extracorpórea e o uso como agente coadjuvante potenciador da radioterapia para certos tumores sólidos. Somente um estudo em modelo canino mostrou aumento do consumo máximo de oxigênio em músculo isolado, não existindo evidências de que o RSR13 possa efetivamente melhorar o desempenho em humanos. Em realidade, já foram descritos efeitos adversos, como diminuição da perfusão sanguínea, elevação da pressão arterial e diminuição da função renal. Antecipando o potencial aumento da utilização do RSR13 por atletas, métodos já foram desenvolvidos para sua detecção em amostras de urina humana.<br>Methylpropionic acid (RSR13) is an allosteric hemoglobin modifier to which it binds in a non-covalent manner, reducing its affinity to oxygen in a dose-dependent fashion, and consequently, increasing peripheral oxygenation. The purpose of this article is to briefly present scientific evidence concerning pharmacological and functional characteristics, medical indications, and adverse effects of RSR13 use by athletes, the most recent alternative to enhance performance artificially. Preliminary experimental studies have verified some positive effect of RSR13 on the recovery of ischemic myocardium and on the extension of cerebral ischemia. However, the main indications currently under study are surgery with hypothermia and cardioplegia during extra-corporeal circulation and the use as a radiotherapy enhancing agent for certain solid tumors. One single study with a canine model has shown increased maximal oxygen consumption in isolated muscles, there existing no evidence that RSR13 can effectively enhance performance in humans. Actually, adverse effects such as reduced blood perfusion, increased arterial blood pressure, and impaired renal function have been described. As an anticipation of the potential increased use of RSR13 by athletes, methods have been developed for its detection in human urine samples