Potentiation of radiation-induced regrowth delay by isosorbide dinitrate in FSaII murine tumors (original) (raw)
Related papers
International Journal of Radiation Oncology*Biology*Physics, 2000
Purpose: In an effort to improve radiotherapy treatments, methods aimed at increasing the quantity of oxygen delivered to tumors were investigated. The aim of this study was to evaluate the effect of one nitric oxide (NO) donor (isosorbide dinitrate) on pO 2 and blood flow in a murine tumor model. The effect was compared to carbogen, used as a reference treatment. Methods and Materials: Thirty-six liver tumors implanted in mouse thighs were imaged using magnetic resonance imaging (MRI) at 4.7 Tesla with dynamic Gd-DTPA and blood oxygen level-dependent (BOLD) contrast-enhanced imaging after administration of isosorbide dinitrate or carbogen. The effect on the pO 2 was also tested by EPR oximetry (1.1 GHz) on 52 mice.
International Journal of Cancer, 2004
Different nitric oxide (NO)-mediated treatments (e.g., isosorbide dinitrate, insulin and electrical stimulation of the host tissue) have been investigated for their effects on tumor oxygenation and radiation sensitivity. We further address the issue of the role played by modulation of the NO-pathway in tumor radiosensitivity. For this purpose, the local concentration of NO was monitored after treatment in FSaII tumors and a comparison between the sensitivity of LLC tumors implanted both on eNOS ؊/؊ and wild-type (WT) mice was carried out. First, we demonstrate the central role played by eNOS in the radiosensitizing effect after application of insulin treatment and electrical stimulation: a significant increase in tumor NO content is induced by these treatments and the increase in tumor oxygenation, as well as the radiosensitizing effect are abolished in eNOS knockout mice, in contrast to WT mice. Second, by comparing the level of oxygen and NO achieved in tumors after NO-mediated treatments and carbogen, we provide evidence that these NO-mediated treatments are not simply acting by a single oxygen effect. These treatments induced significant regrowth delays compared to carbogen, despite a smaller increase in tumor oxygenation. For the NO-mediated treatments, there was a direct correlation between the NO content and the radiosensitizing effect. These data strongly suggest that NO is a complementary factor additive to oxygen in determining the sensitivity to irradiation and we therefore propose that NO acts as an intrinsic radiosensitizer in vivo.
Biochemical and Biophysical Research Communications, 2013
Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO 2 in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10 Gy × 2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy.
Radiosensitization of hypoxic tumor cells in vitro by nitric oxide
International Journal of Radiation Oncology*Biology*Physics, 1996
Purpose: The effects of nitric oxide (NO) on the radiosensitivity of SCK tumor cells in oxic and hypoxic environments m vitro were studied. Methods and Mater-h& NO was delivered to cell suspensions using the NO donors 2,2-diethyl-l-nitroso-oxyhydrazine sodium a& (DEA/NO), and a spermhte/nitric oxide complex (SPER/NO), which release NO at h&lives of 2.1 mitt and 39 min at pH 7.4, respectively. The cells were suspended in media containing DEA./NO or SPBR/ NO for varying lengths of time under oxic or hypoxic conditions, irradiated, and the clonogenicity determined. Remits: Both compotmds markedly radiosensitized the hypoxic cells. The drug enhancement r&os (DBR) for 0.1, 1.0, and 2.0 mM DEA/NO were 2.0,2.3 and 3.0, respectively, and those for 0.1, 1.0, aud 2.0 mM SPER/NO were l&2.3, and Zg, respectively. Aerobic cells were not radiosensitized by DEMO or SPRIVNO. When DEA/ NO and SPERAUO were incubated in solution overnight to allow release of NO, they were found to have no radiosensitizing effect under hypoxic or oxic conditions indicating the sensitization by the NO donors was due to the NO molecule released from these drugs. At the higher concentrations, SPER/NO was found to be cytotoxic in aerobic conditions but not in hypoxic conditions. DEAN0 was only slightly toxic to the ceils in both aerobic and hypoxic conditions. Con&sions: NO released from NO donors DEA/NO and SPER/NO is as effective as oxygen to radiosensitize hvpoxic cells in vitro. Its application to the radiosensitization of hypoxic celb in solid tumors remains to be investigated. Copyright 0 1996 Elsevier Science Inc.
Cancer research, 2003
The combination of radiotherapy and antiangiogenic strategies has been shown to increase the tumor response in various experimental models. The rationale for this cotherapy was initially related to the expected gain in efficacy by acting on two different targets, e.g., tumor cells and endothelial cells (ECs). However, recent studies have documented more than additive effects due to apparent mutual potentiation of these approaches. In this study, we tested the hypothesis that these synergistic effects could stem from the stimulatory effects of ionizing radiations on angiogenesis, which would then need to be restrained to avoid tumor regrowth after irradiation. We found that irradiation dose-dependently induced the activation of the proangiogenic NO pathway in ECs through increases in endothelial nitric oxide synthase abundance and phosphorylation. Using 2- and 3-dimensional cultures of ECs and isolated mouse tumor arterioles, we documented that the irradiation-induced enhanced produc...
International Journal of Radiation Oncology*Biology*Physics, 2003
Purpose: Oxygen deficiency in tumors reduces the efficacy of nonsurgical treatment modalities. We tested the hypothesis that electrical stimulation of the sciatic nerve could modify the oxygenation status and the blood flow of tumors implanted in the thigh of mice. Methods and Materials: The sciatic nerve was electrically stimulated at 5 Hz. Local transplantable liver tumor (TLT) and fibrosarcoma (FSaII) tumor oxygen pressure (pO 2) and perfusion measurements were carried out using electron paramagnetic resonance (EPR) oximetry and the OxyLite/OxyFlo technique. The radiosensitizing effect of the protocol was assessed by irradiating FSaII tumors with X-rays. Results: Tumor pO 2 increased from ϳ3 mm Hg to ϳ8 mm Hg, and relative tumor blood flow was increased by 241% and 162% for TLT and FSaII tumor models, respectively. The effect on the tumor oxygenation was inhibited by a nitric oxide synthase (NOS) inhibitor, and an increase in the tumor nitric oxide (NO) content was observed using EPR spin-trapping. The tumor oxygen consumption rate was decreased after the stimulation protocol. In addition, the electrical stimulation of the host tissue increased regrowth delays by a factor of 1.65. Conclusions: This increase in tumor oxygenation is due to the temporary increase in tumor blood flow, but particularly to a decrease in the tumor oxygen consumption rate (inhibition of respiration) that is mediated by a local production of NO during the protocol. Those tumor hemodynamic changes resulted in a radiosensitizing effect.
Intravascular oxygen distribution in subcutaneous 9L tumors and radiation sensitivity
Journal of applied physiology (Bethesda, Md. : 1985), 1997
Phosphorescence quenching was evaluated as a technique for measuring PO2 in tumors and for determining the effect of increased PO2 on sensitivity of the tumors to radiation. Suspensions of cultured 9L cells or small pieces of solid tumors from 9L cells were injected subcutaneously on the hindquarter of rats, and tumors were grown to between 0.2 and 1.0 cm in diameter. Oxygen-dependent quenching of the phosphorescence of intravenously injected Pd-meso-tetra-(4-carboxyphenyl) porphine was used to image the in vivo distribution of PO2 in the vasculature of small tumors and surrounding tissue. Maps (512 x 480 pixels) of tissue oxygen distribution showed that the PO2 within 9L tumors was low (2-12 Torr) relative to the surrounding muscle tissue (20-40 Torr). When the rats were given 100% oxygen or carbogen (95% O2-5% CO2) to breathe, the PO2 in the tumors increased significantly. This increase was variable among tumors and was greater with carbogen compared with 100% oxygen. Based on irr...
Tumors growing in irradiated tissue: Oxygenation, metabolic state, and pH
International Journal of Radiation Oncology*Biology*Physics, 1991
Experimental tumors growing in irradiated tissue have been used to study the biological differences characteristic of locally recurrent tumors. Animal tumors were early generation isotransplants of a spontaneous fibrosarcoma in a C3lWSed mouse, designated FSa-II. Since the hypoxic cell fraction of tumors growing in irradiated tissue is increased, these tumors are assumed to be metaboiicaily deprived with hypoperfusion and acidosis. In thii study we directly measured the oxygen partial pressure (~0~) distribution, metabolic state, and pi-l of tumors growing in an irradiated tumor bed using oxygen sensitive electrodes and "P-NMR. The results confirmed a threefold increase in the number of p0, readings 5 2.5 mml-lg and also showed increased acidosis with a 0.17 unit decrease in pH,,. When tumors growing in pre-irradiated tissue reached-100 mm' in volume, a high frequency of gross and microscopic necrosis and hemorrhage was already observed. Consistent with these observations, the phosphocreatine/inorganic phosphate (PCr/P,) and nucleoside triphosphatelinorganic phosphate (NTP/P,) ratios were significantly lower in the tumors in a pre-irradiated bed compared to tumors in a non-irradiated bed (PWP,: 0.51 vs 0.79, p < 0.05; and NTP/P,: 0.64 vs 0.93, p < 0.05). The longitudinal relaxation time (T,) of Pi was numerically shorter in control tumors (consistent with the better tissue oxygenation), but this did not reach statistical significance (2.09 f .ll set vs 2.25 +-16 see).