ABSTRACT
Radiation therapy is an extensively applied cancer treatment methods in clinic. Radiation therapy can be conducted by either administrating/implanting radioactive isotope agents into the patients to irradiate tumors from inside, or using external beams (e.g. X-ray beams) to irradiate the tumor from the outside. It is well known that oxygen molecules play an important role in enhancing radiation-induced cancer cell killing. However, as most of solid tumors possess hypoxic tumor microenvironment, the tumor hypoxia is well recognized as one of important reasons that lead to the resistance of tumors to radiation therapies. In recent years, owing to the rapid development of biomaterials and nanotechnology, many different strategies have been reported to effectively modulate and reverse the hypoxic tumor microenvironment. In this article, we will summarize various types of nano-biomaterials for tumor hypoxia relief and their application in radiotherapy sensibilization, as well as the future clinical translation.
ABSTRACT
The therapeutic effect of tumor photodynamic therapy is severely limited by the hypoxic tumor microenvironment. Inhibiting tumor celloxygen consumption is a more effective way than increasing its oxygen supply to overcome the tumor hypoxia and enhance photodynamic therapy. To carry out this strategy, the supramolecular nanoparticles VER-ATO-SMN loaded with photosensitizer verteporfin (VER), oxygen-consuming inhibitor atovaquone (ATO), and stabilizer polyvinylpyrrolidone (PVP)-K30 were prepared by the nanoprecipitation method, and the optimal prescription was screened and optimized by single factor experiments. The results showed that the optimal prescription for VER-ATO-SMN was ATO∶VER (w/w) = 1∶1, PVP-K30 = 100 mg, N,N-dimethylformamide∶water (v/v) = 1∶10. The morphology, particle size, particle dispersion index and encapsulation efficiency of supramolecular nanoparticles were characterized. The VER-ATO-SMN showed a spherical morphology and was well dispersed. The hydrodynamic size of VER-ATO-SMN was 101.21 ± 4.30 nm as determined by dynamic light scattering (DLS). The encapsulation efficiencies of VER and ATO in VER-ATO-SMN prepared with the optimal prescription were 70.86% and 77.52%, respectively. The VER-ATO-SMN exhibited good laser stability and also showed high stability in conditions which simulated the physiological solution. Compared with free VER and VER liposome, VER-ATO-SMN performed enhanced therapeutic effect at the cell level. The mechanism was that VER-ATO-SMN could effectively incorporate into cells and improving the intracellular oxygen concentration by reducing the oxygen consumption of tumor cells could increase the amount of reactive oxygen species generated by VER mediated photodynamic therapy. The in vivo anticancer efficacy results of tumor-bearing mice suggested that VER-ATO-SMN could effectively inhibit the tumor growth or even completely eliminate the tumor. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of 900 Hospital of the Joint Logistics Team.
ABSTRACT
Hypoxia is a serious impediment to current treatments of many malignant tumors. Catalase, an antioxidant enzyme, is capable of decomposing endogenous hydrogen peroxide (H
ABSTRACT
The improvement of hypoxia of tumor cells can effectively reduce their resistance to radiation and chemotherapy and im-prove the cure rate of the tumor. Recently, the compounds which are used to improve hypoxia of tumor cells and reduce radiation resist-ance are no longer just the original electrophilic radiosensitizers, and many potential targets as radiosensitizer for hypoxia also become research focus. Based on the mechanism of tumor hypoxia, the paper summarized the study progresses in four different radiosensitizers including new targeted agents, electrophilic radiotherapy sensitization agents, biological reductants and natural plant extracts.
ABSTRACT
Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, efforts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting.
Subject(s)
Humans , Hypoxia , Genetic Phenomena , Neoplasm Metastasis , Oxygen , Prognosis , Transcription FactorsABSTRACT
Hypoxia, defined as a decrease of tissue oxygen levels, represents a fundamental pathophysiological condition in the microenvironment of solid tumors. Tumor hypoxia is known to be associated with radio/chemo-resistance and metastasis that eventually lead to cancer progression contributing to poor prognosis in cancer patients. Among transcription factors that accumulated under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that has received the most intense attention in this field of research due to its capacity to modulate several hundred genes. With a clearer understanding of the HIF-1 pathway, efforts are directed at manipulation of this complex genetic process in order to ultimately decrease cellular HIF-1 levels. Some novel agents have been shown to have HIF-1 inhibition activity through a variety of molecular mechanisms and have provided promising results in the preclinical setting.
Subject(s)
Humans , Hypoxia , Genetic Phenomena , Neoplasm Metastasis , Oxygen , Prognosis , Transcription FactorsABSTRACT
Hypoxic cells that exist in nasopharyngeal cancer can not be killed easily and they are the underlying cause for recurrence and metastasis. In radiotherapy for nasopharyngeal cancer, the application of Qi-benefiting and blood-supplementing Chinese medicines can improve blood circulation, increase oxygenation of tumor body, and ameliorating the status of hypoxic cells. Besides medical ozone can promote oxygen-carrying ability of hemoglobin and releasing of oxygen capacity and improve oxygen supplying. If the method of radiotherapy combined with ozone and Chinese medicines can solve the problem of resistance of hypoxic cells to radiation and promote the oxygen effect in radiation and the interaction between organisms, then it will play an important role in the treatment of nasopharyngeal cancer.
ABSTRACT
PURPOSE: Tumor cells are known to express hypoxia-related proteins such as glucose transporter-1 (Glut-1). These hypoxia-induced changes may allow tumor cells to survive under sustained hypoxic microenvironments, and the surviving tumor cell under hypoxia may develop a more aggressive phenotype and so result in a poor prognosis. MATERIALS AND METHODS: The Glut-1 expression was analyzed by immunohistochemistry, and its association with the prognosis was assessed in 60 patients with squamous cell carcinoma of the tongue. RESULTS: The Glut-1 expression was diffuse with a membranous pattern, and the median percentage of Glut-1 positive tumor cells was 60% (range: 0.0~90.0%). A high Glut-1 expression (the percentage of positive tumor cells > or = the median value, 60%) was associated with the location of primary lesion, lymph node metastasis status and disease stage (p<0.05). The expression of Glut-1 was correlated with the Ki-67 expression (r=0.406, p=0.001). Microvessel density, as represented by CD31 staining, was also correlated with the Glut-1 expression although its significance is weak (r=0.267, p=0.039). On the univariate analysis, the group with a high Glut-1 expression showed poorer overall survival than the group with a low Glut-1 expression (p<0.05). However, the Glut-1 expression failed to show any independent prognostic significance on the multivariate analysis. CONCLUSION: The expression of Glut-1 may be useful for predicting the prognosis and determining the treatment strategy for the management of squamous cell carcinoma of the tongue.
Subject(s)
Humans , Hypoxia , Carcinoma, Squamous Cell , Glucose , Immunohistochemistry , Lymph Nodes , Microvessels , Multivariate Analysis , Neoplasm Metastasis , Phenotype , Prognosis , TongueABSTRACT
Hypoxia, one major characteristic of malignant solid tumors, not only changes the biological characteristics of tumor cells, but also is the main cause of the failure for conventional chemotherapy and radiotherapy. This paper summarizes the implications of tumor hypoxia and the corresponding techniques,then we present the change in tumor biological characteristics induced by hypoxia. Next we analyze the cause of tumor resistance to chemotherapy and radiotherapy. And finally,We discuss the three antitumor strategies targeting hypoxia, which opens a new path to conquer cancer.[
ABSTRACT
PURPOSE: Tumor hypoxia can be overcome with hypoxic cytotoxin. In mouse tumor, tirapazamine's efficacy of the potentiating radiation effect was tested by the tumor oxygenation status combined with hyperfactionated radiotherapy. MATERIALS AND METHODS: The control and hypoxic mouse tumors were established by inoculation of RIF-1 tumor cells into the normal or previously irradiated back and thigh of C3H mice. When the tumors reached a proper size, both the control and hypoxic tumors were given hyperfractionated treatments (8 fractions/4 days) with saline (0.02 ml/g), tirapazamin (0.08 mM/0.02 ml/kg), irradiation (2.5 Gy), irradiation combined with tirapazamine given 30 minutes prior to each irradiation. The response was evaluated by the growth delay assay by measuring tumor size from day 0 (12 hrs prior to the first fractionation) to the day when the volume had 4-fold increase or cross sectional area had 2-fold increase. RESULTS: Overall growth pattern showed that tirapazamine potentiated radiation effect in back and thigh tumors grew in the normal and preirradiated tumor bed. With growth delay assay using reference point of initial tumor volume or cross sectional area, tirapazamine potentiated radiation effect 1.9 times for the control and 2.4 times for the hypoxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. With reference of 4-fold increase of the initial volume or 2-fold increase of the cross sectional area, tirapazamine potentiated radiation effect 1.48 times for the control and 2.02 times for the hypxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. CONCLUSION: Present result indicated that radiation response of hypoxic tumors was potentiated by tirapazamine in the back or thigh tumors grew in the control or preirradiated tumor bed, and potentiation of the hypoxic tumors was equal to or greater than that of the control tumors in the back or thigh.
Subject(s)
Animals , Mice , Hypoxia , Mice, Inbred C3H , Oxygen , Radiation Effects , Radiotherapy , Thigh , Tumor BurdenABSTRACT
urpose: Misonidazole is a radiosensitizer that binds in hypoxic cells. The purpose of this study was to find out the feasibility of I-131-Iodomisonidazole (IMISO) for imaging of tumor hypoxia. MATERIALS AND METHODS: Tosyl precursor was dissolved in acetonitrile and I-131-NaI was added to synthesize IMISO. Balb/c mice inoculated with CT-26 adenocarcinoma were injected with IMISO. Mice were sacrificed at 1,2,4,24 hr and % of injected dose per gram of tissue (%ID/g) was determined. For scintigraphy and MRI, mouse bearing CT-26 adenocarcinoma was administered with IMISO and imaging was performed 4 hr after. Then, mouse body was fixed and microtomized slice was placed on radiographic film for autoradiography. RESULTS: %ID/g of tumor was 1.64 (1h), 0.98 (2h), 0.85 (4h) and 0.20 (24h), respectively. At 24h, %ID/g of tumor was higher than that of all other tissues except thyroid. Tumor to muscle ratio increased with time and tumor to blood ratio also increased with time and reached 1.53 at 24 hr. On autoradiogram, tumor was well visualized as an increased activity in central hypoxic area of the tumor which corresponds to the area of high signal intensity on T2-weighted MR image. On scintigraphy, tumor uptake was visualized. CONCLUSION:: This RESULTS suggest that IMISO may have a potential for tumor hypoxia imaging in mouse model. However, further study is needed to improve it's localization in tumor tissue and to achieve acceptable images of tumor hypoxia.