高压氧与肿瘤放射治疗

高压氧可抑制肿瘤生长和转移，提高肿瘤组织氧合，并诱导肿瘤细胞周期同步化，是一种安全、有效的放射增敏措施，与放疗联合应用可提高疗效。同时，高压氧也是治疗晚期放射性损伤的主要方法之一，但对放射并发症的预防作用尚需进一步研究。     

放射增敏剂与肿瘤治疗

放射增敏剂已经使用很多年了,目前主要用于增敏乏氧细胞。肿瘤组织中有乏氧细胞存在,过去曾用高压氧使乏氧细胞增敏,但不同的试验结果不尽一致。因为动物全身长时间高压氧处理产生的生理反应使血管闭合,从而影响氧的增敏效果。后来有人试图用负π介子和中子来解决乏氧细胞的问题,虽有一定作用但未能完全使乏氧细胞增敏,而且设备非常昂贵。因此,Gray实验室开始着手化学放射增敏剂的研究。Adams研究了许多带有机环结构的化合物,目前已有甲硝哒唑(metronidazole)、misonidazole和9963等放射增敏剂。一种化合物是否有放射增敏作用,主要看其治疗增益,即对肿瘤组织的增敏是否比正常组织增敏大,否则就起不到放射增敏的作用。肿瘤组织中存有许多乏氧细胞,而正常组织中都没有。因此,增敏剂能提高肿瘤组织的放射敏感性。     

高压氧对迟发性放射损伤的作用

放射疗法是一种对肿瘤和周围正常组织均有显著作用的物理疗法,在放疗的同时,不可避免地会损伤正常组织导致放射损伤,特别是迟发性放射损伤,这将严重影响患者的生存质量。随着时间的推移迟发性放射损伤会发展得更加严重,甚至致死,因此限制了临床治疗时的放射剂量,目前这一问题并未得到解决。笔者主要就高压氧治疗对迟发性放射损伤的影响作一综述。     

高压氧在肿瘤放疗中的实验研究及临床应用现状

恶性肿瘤因乏氧细胞的存在引起放射抗拒现象。经研究发现高压氧可以明显提高组织氧分压,使缺氧的肿瘤细胞供氧得以改善,增加了肿瘤细胞对氧的敏感性。高压氧对乏氧程度较高的恶性肿瘤有明显的增强放疗的作用,并且在放射损伤的治疗中也有很好的效果。     

高压氧后低氧放疗对Lewis肺癌小鼠效应初探

目的 观察高压氧后低氧放疗对小鼠肿瘤组织和正常组织的影响。方法 实验用C57 BL／6小鼠，共设5组：空白对照组，单纯放疗组(单放组)，单纯低氧放疗组(LO组)，单纯高压氧放疗组(HBO组)，高压氧后低氧放疗组(HBO LO组)。单次大剂量6MeV电子束一次给予20Gy，高压氧条件为2．5个绝对大气压，100min。低氧条件为10．5％的低氧混合气，各组小鼠均经鼠尾静脉注射5．55mBq／0．2ml^99mTc-HL91后120min进行ECTγ显像。结果 (1)HBO组和HBO LO组的小鼠肿瘤平均生长延迟天数明显长于其他各组，对肿瘤抑制作用相近。(2)LO组和HBO LO组的小鼠平均存活天数明显长于其他各组，保护正常组织，延长寿命效应相近。(3)HBO组和HBO LO组乏氧组织显像剂放射性计数比值明显低于其他各组，两组间差异无显著性。结论 高压氧后低氧放疗对小鼠肿瘤组织有放射增敏作用而且对正常组织有放射防护作用。     

肿瘤放射增敏药物的研究进展

放射治疗是临床肿瘤治疗的重要手段之一.肿瘤细胞的放射敏感性是影响肿瘤放疗疗效的关键因素.放射增敏药物能够增强机体的放射敏感性,通过提高肿瘤细胞的放射敏感性达到降低照射剂量、提高放疗疗效、降低正常组织损伤的目的.现有的放射增敏药物主要分为细胞毒类药物、靶向药物以及中药制剂3大类.该文将对肿瘤放射增敏药物的作用机制、现状及相关研究进展进行综述.     

抗癌基因与放射敏感性关系研究进展

提高肿瘤放射敏感性是放射治疗的关键。从总体角度,细胞水平研究肿瘤放射敏感性未能给临床提供足够的信息。抗癌基因,特别是P~(53)及其相关基因与放射敏感性关系的研究为提高放射治疗效果提供了新的思路和方法。     

癌干细胞与肿瘤的放射抗性

有关癌干细胞及其生物学特性研究信息的不断积累,推动了放射肿瘤生物学的发展。近年来的研究发现,癌干细胞和静止期癌细胞可能是导致肿瘤放射抗性增加和肿瘤放射治疗后复发的主要细胞学基础,有关这两种癌细胞亚群的放射敏感性及其机制的研究进展迅速,为提高肿瘤对放射治疗敏感性的措施研究提供了新的学术思路。该文将就癌细胞亚群的放射分子生物学特性,分析讨论肿瘤放射抗性的细胞学基础和相关分子机制。     

放射肿瘤学：抗癌基因与放射敏感性关系研究进展

提高肿瘤放射敏感性是放射治疗的关键。从总体角度，细胞水平研究肿瘤放射敏感性未能给临床提供足够的信息。抗癌基因，特别是Ｐ＾５３及其相关基因与放射敏感性关系的研究为提高放射治疗效果提供了新的思路和方法。     

放射增敏剂在肿瘤治疗中的应用

放射治疗是治疗恶性肿瘤的重要手段之一。临床上常因正常组织耐受剂量的限制而不能给予肿瘤足够的照射剂量,而造成治疗失败,因此,如何提高肿瘤对射线的敏感性是临床肿瘤放疗面临的突出问题。放射增敏剂作为一种增强肿瘤放疗敏感性、提高放疗疗效的药物,通过增加辐射诱导的氧自由基及DNA损伤、调控放疗关键分子靶点以达到放射增敏目的。本文结合放射增敏剂在放射治疗中的应用,概述了放射增敏剂的发展现状及相关领域的研究进展,并对多种放射增敏剂的作用机制进行了简要综述,以期为进一步研究放射增敏调控的分子机制、促进放射增敏剂的研发,以及设计新的策略改善放射治疗结果提供帮助。     

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy

PURPOSE: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.     

Influence of Pretreatment Polarographically Measured Oxygenation Levels in Spontaneous Canine Tumors Treated with Radiation Therapy

BACKGROUND AND PURPOSE: The level of hypoxia in primary tumors has been described to influence response to treatment. The aim of the present study was to investigate the impact of pretreatment oxygen level measurements in spontaneous canine tumors on treatment outcome. MATERIALS AND METHODS: Data of pretreatment tumor oxygenation status and local tumor response after primary radiation therapy in a group of spontaneously occurring tumors in dogs (n=52) was collected. Radiation therapy was given with curative (14-17x3-3.5 Gy) or palliative intent (3x8 Gy or 4-5x6 Gy). Progression-free interval and overall survival were correlated to polarographically measured tumor oxygenation status. RESULTS: In the curatively irradiated group, tumors with median pO2 values相似文献   

Evaluation of BA1112 rhabdomyosarcoma oxygenation with microelectrodes, optical spectrophotometry, radiosensitivity, and magnetic resonance spectroscopy.

We studied tumor tissue oxygenation in the BA1112 rhabdomyosarcoma using micro-electrode pO2 measurements, optical spectrophotometry, analyses of cell survival after irradiation, and 31P magnetic resonance spectroscopy (MRS). Studies were carried out in WAG/Rij/Y rats breathing normoxic, hypoxic, and hyperoxic gas mixtures with and without iv administration of perfluorochemical. Significant changes in tissue oxygenation and metabolic status were found when pO2 values, optical measurements of hemoglobin saturation and cytochrome a, a3 reduction-oxidation, radiation cell survival determinations, and MRS measurements of phosphometabolite ratios were obtained in rats breathing different gas mixtures. Inhalation of 100% O2 caused increases in tumor pO2, hemoglobin saturation, cytochrome a, a3 oxidation, tumor radiosensitivity, and PCr/Pi, NTP/Pi, and PDE/Pi ratios. Such changes were augmented by pretreatment with iv perfluorochemicals. Inhalation of hypoxic gas mixtures resulted in reductions in the above parameters. These results indicate that tissue oxygenation can be manipulated reproducibly in the BA1112 rhabdomyosarcoma and suggest that 31P MRS can be used to monitor changes in tumor oxygenation in this model system.     

Effect of Carbogen Breathing on the Radiation Response of a Human Glioblastoma Xenograft

BACKGROUND AND PURPOSE: The aim of these experiments was to study the relationship between the previously demonstrated efficacy of carbogen breathing on tumor oxygenation status and the response to radiation assessed by a growth delay assay. This study was also developed to investigate the microenvironmental changes caused by combined treatment compared to irradiation only in regrowing tumors. MATERIAL AND METHODS: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without carbogen breathing. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after immunohistochemical staining. Tumor growth delay was monitored for up to 120 days after treatment. RESULTS: In general, there was no benefit of combined treatment. However, a small subgroup with good response to combined radiation and carbogen treatment was identified showing little hypoxia and mainly necrosis in the regrowing tumors. These microenvironmental characteristics were not seen in tumors of the other treatment groups. CONCLUSION: The observations suggest that a subgroup of patients, who could potentially benefit from the combined carbogen and radiation treatment, might be identified. However, the heterogeneous response to treatment illustrates the need for selection of patients before start of treatment.     

Increased uptake of99mTc-HL91 in tumor cells exposed to X-ray radiation

99mTc-HL91, a hypoxic marker, may be a predictor of tumor response to radiotherapy and an indicator of tumor oxygenation in the course of treatment. In this study, serial changes in 99mTc-HL91 uptake were observed in the normoxic condition in a human bladder cancer cell line exposed to a single dose or a fractionated dose of 10 Gy with an x-ray beam. The uptake per cell increased during cell growth retardation induced by the irradiation. This finding indicates that 99mTc-HL91 uptake is affected by injury to cells due to radiation; it may therefore be difficult to correctly assess the tissue oxygenation status during radiotherapy with 99mTc-HL91.     

Tumor R2* is a prognostic indicator of acute radiotherapeutic response in rodent tumors

PURPOSE: To test the prognostic potential of tumor R2* with respect to radiotherapeutic outcome. Blood oxygenation level dependent (BOLD) MRI images are sensitive to changes in deoxyhemoglobin concentration through the transverse MRI relaxation rate R2* of tissue water, hence the quantitative measurement of tumor R2* may be related to tissue oxygenation. METHODS AND MATERIALS: Tumor growth inhibition in response to radiation was established for both GH3 prolactinomas and RIF-1 fibrosarcomas with animals breathing either air or carbogen during radiation. In a separate cohort, the baseline R2* and carbogen (95% O2, 5% CO2)-induced DeltaR2* of rat GH3 prolactinomas and murine RIF-1 fibrosarcomas were quantified using multigradient echo (MGRE) MRI prior to radiotherapy, and correlated with subsequent tumor growth inhibition in response to ionizing radiation, while the animals breathed air. RESULTS: A radiation dose of 15 Gy caused pronounced growth delay in both tumor models and transient regression of the GH3 prolactinomas. When the animals breathed carbogen during radiation, the growth delay/regression was enhanced only in the GH3 prolactinomas. The GH3 prolactinomas, which exhibit a relatively fast baseline R2* and large DeltaR2* in response to carbogen breathing prior to radiotherapy, showed a substantial reduction in normalized tumor volume to 66 +/- 3% with air breathing and 36 +/- 5% with carbogen seven days after 15 Gy irradiation. In contrast, the effect of 15 Gy on the RIF-1 fibrosarcomas, which give a relatively slow baseline R2* and negligible DeltaR2* response to carbogen prior to treatment, showed a much smaller growth inhibition (143 +/- 3% with air, 133 +/- 12% with carbogen). CONCLUSION: Quantitation of tumor R2* and carbogen-induced DeltaR2* by MGRE MRI provides completely noninvasive prognostic indicators of a potential acute radiotherapeutic response.     

Oxygenation of Tumor Recurrences Following Fractionated Radiotherapy of Primary Tumors

BACKGROUND AND PURPOSE: Tumor oxygenation is well recognized as a major factor of tumor response to radiotherapy. In this respect, a number of studies have examined the response of primary tumors, whereas little is known about the oxygenation of tumor recurrences after radiotherapy. It was the aim of this study to investigate the oxygenation of tumor recurrences after preceding irradiation of the primary tumor. MATERIAL AND METHODS: Tumor oxygenation in primary tumors and recurrences of rat rhabdomyosarcomas R1H was measured by using pO(2) probes and Eppendorf pO(2) histography. Primary tumors were irradiated at a (60)Co radiotherapy facility with a total dose of 75 Gy, given in 30 fractions over 6 weeks. Oxygenation was measured in R1H tumors before and directly after completion of irradiation. In R1H recurrences oxygenation was determined, when they reached the same size as the previously treated primary tumors (V(o) = 3.1 +/- 0.5 cm(3)). Additionally, tumor microvessel density and the intercapillary distance of tumor blood vessels were determined on histological sections using a counting grid. RESULTS: Tumor oxygenation in R1H recurrences was significantly lower when compared to primary R1H tumors. In primary tumors a median pO(2) of 17 +/- 7 mmHg was measured. By contrast, the median pO(2) in R1H recurrences was only 5 +/- 5 mmHg (p < 0.05). The high frequency of pO(2) values < 5 mmHg indicated that R1H recurrences were significantly more hypoxic (58 +/- 5%) in comparison to primary tumors (22 +/- 4%). The histological sections of the R1H recurrences showed a higher heterogeneity in their tissue structure than primary nonirradiated tumors. The morphometric studies demonstrated a reduced microvessel density (91 +/- 21/9.04 mm(2) in the tumor periphery; p = 0.0001) compared with recurrent tumors (68 +/- 26) and an enhanced mean distance of tumor blood vessels, especially in the center of the R1H recurrences (184 +/- 20 vs. 243 +/- 70 mm; p = 0.0001). CONCLUSION: In R1H rhabdomyosarcomas tumor oxygenation in recurrent tumors following radiation therapy is significantly lower than in primary tumors. This observation has to be taken into account in cases of tumor recurrences where repeated radiotherapy, chemotherapy or combined treatment modalities are used.     

Characterization of response to radiation mediated gene therapy by means of multimodality imaging

Imaging techniques are under development to facilitate early analysis of spatial patterns of tumor response to combined radiation and antivascular gene therapy. A genetically modified, replication defective adenoviral vector (Ad.EGR‐TNFα), injected intratumorally, mediates infected cells to express tumor necrosis factor alpha (TNFα), which is increased after exposure to radiation. The goal of this study was to characterize an image based “signature” for response to this combined radiation and gene therapy in mice with human prostate xenografts. This study is part of an imaged guided therapy project where such a signature would be useful in guiding subsequent treatments. Changes in the tumor micro‐environment were assessed using MRI registered with electron paramagnetic resonance imaging which provides images of tissue oxygenation. Dynamic contrast‐enhanced MRI was used to assess tissue perfusion. When compared with null vector (control) treatment, the ratio of contrast agent (Gd‐DTPA‐BMA) washout rate to uptake rate was lower (P = 0.001) after treatment, suggesting a more balanced perfusion. Concomitantly, oxygenation significantly increased in the treated animals and decreased or did not change in the control animals (P < 0.025). This is the first report of minimally invasive, quantitative, absolute oxygen measurements correlated with tissue perfusion in vivo. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Technical Improvement of pO2 Measurements in Breast Cancer

PURPOSE: Investigating tumor oxygenation in breast cancer with the Eppendorf device is hampered by the deep location and inadequate fixation of the tumor within the breast. In order to ensure the correct site of pO(2) measurements, guiding aids were introduced and the reliability of the refined method was evaluated. MATERIAL AND METHODS: For guidance of the needle electrode, a metal trocar was inserted up to the tumor rim. Its positioning and all transtumoral tracks of the needle electrode were monitored continuously by ultrasonography. Thus, 150 tumor measurements in 148 patients were evaluated. In a phantom, the possible influence of the metal trocar was assessed and the measurements of two histographs with five different needle electrodes were compared. RESULTS: In 88% of measurements (132/150) complete or partial sonographic demarcation of the tumor was possible. 83.2% of the tracks (437/525) could be controlled by ultrasonography. Overall, in 60% of measurements (90/150) all values derived reliably from within the tumor. In vitro, an influence of the metal trocar on the measurements could be excluded. Differences between histographs were in accordance with tolerance limits. CONCLUSION: From theoretical considerations and the phantom experiments a significant negative impact of the technical modifications could be excluded. Instead, the method described here showed to be beneficial in measuring tumor oxygenation in breast tumors. The authors strongly advise to consider exclusively intratumoral pO(2) values as proven by ultrasonography for oxygenation profiling, as in 40% of all measurements the origin of single pO(2) values or tracks was questionable.