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。     

放射增敏药物研究的现状及其趋向

放射增敏药物研究的现状及其趋向胡璧肿瘤临床治疗中，放疗是一个非常重要的措施，在总的治疗中占７０％、然而肿瘤放疗效果不尽理想，如果采用正常组织可耐受的照射剂量进行治疗，肿瘤的平均治愈率仅４０％，用放射增敏药，可以提高射线对肿瘤细胞的敏感性。因此，国内外...     

放射增敏剂AK和MISO的临床药物动力学和疗效比较研究

放射增敏剂ＡＫ和ＭＩＳＯ的临床药物动力学和疗效比较研究骆传环，鲍云华，王作华，王友茹，俞受程肿瘤组织中的乏氧细胞对射线敏感性低，限制了放疗效果。因此，人们研制了放射增敏剂，以提高肿瘤的放疗效果，并打破肿瘤治疗中的不良循环。目前研究最多的是硝基咪唑类化...     

金纳米簇放射治疗增敏作用的研究进展

目前恶性肿瘤的放射治疗疗效仍欠满意,放疗增敏剂是提高放疗疗效的有效手段。金纳米材料因其高原子序数可有效增加肿瘤细胞的放疗敏感性。金纳米簇因其更小的尺寸有更加优良的放射生物学、放射物理学特性。本文综述了金纳米簇特殊的放射生物学、放射物理学特性,并详细地介绍了其对外照射放疗、放射性核素治疗、X射线诱导的光动力治疗的增敏作用。     

靶向放射增敏剂的研究进展

放射增敏剂研究的先驱者Adamst[1]对放射增敏剂按照作用机制进行了分类.其中亲电子放射增敏剂由于对多种肿瘤细胞的体外增敏作用较强而受到广泛关注,其中效果较好的药物是眯嗦硝唑(misonidazo,MISO)但临床试验表明,该药物合并常规放疗无明显增敏效果,主要原因是肿瘤组织药物浓度低,不能产生明显的增敏效果,又因其不良反应较大,影响患者接受更大剂量来提高增敏效果[2].     

靶向放射增敏剂的研究进展

放射增敏剂研究的先驱者Adamst[1]对放射增敏剂按照作用机制进行了分类.其中亲电子放射增敏剂由于对多种肿瘤细胞的体外增敏作用较强而受到广泛关注,其中效果较好的药物是眯嗦硝唑(misonidazo,MISO)但临床试验表明,该药物合并常规放疗无明显增敏效果,主要原因是肿瘤组织药物浓度低,不能产生明显的增敏效果,又因其不良反应较大,影响患者接受更大剂量来提高增敏效果[2].     

无机纳米材料介导的肿瘤放疗增敏的研究进展

放疗作为一种肿瘤治疗手段,可通过电离辐射对肿瘤细胞造成直接或间接的损伤,但电离辐射对正常组织的损伤和肿瘤的放疗抵抗等问题会影响放疗的疗效。肿瘤放疗增敏是近年来的研究热点,其旨在增强肿瘤对放疗的敏感性,从而克服放疗的缺陷,提高放疗的疗效。无机纳米材料介导的肿瘤放疗增敏主要通过增加细胞内的辐射能量沉积、催化产生活性氧自由基和调控肿瘤微环境等方式提高放疗的疗效。笔者就无机纳米材料介导的肿瘤放疗增敏的研究进展进行综述。     

化学药物对恶性肿瘤和正常组织放射敏感性的影响

药物应用到肿瘤放疗临床时,需要了解对恶性肿瘤及正常组织的放射反应。本文介绍了放射防护剂、放射增敏剂及肿瘤化疗药物对以上两种组织放射敏感性的影响,开展这方面的研究对提高肿瘤放疗效果具有重要意义。     

放射增敏剂的研究现状及其在肿瘤放疗中的前景

在恶性肿瘤的放疗中,经常会遇到放疗后肿瘤复发的问题,这主要是由于抗放射的肿瘤细胞,其中很重要的是缺氧肿瘤细胞残留。而在大多数临床治疗的肿瘤,总存在1—30%的缺氧细胞。卅多年来,人们尝试各种方法来提高缺氧肿瘤细胞的放射敏感性,放射增敏剂就是其中研究的一个重要方面。一、定义和基本理论     

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。     

Hypoxia-selective Radiosensitization of Mammalian Cells by Nitracrine,an Electron-affinic DNA Intercalator

Summary

The radiosensitizing ability of the 1-nitroacridine nitracrine (NC) is of interest since it is an example of a DNA intercalating agent with an electron-affinic nitro group. NC radiosensitization was evaluated in Chinese hamster ovary cell (AA8) cultures at 4°C in order to suppress the rapid metabolism and potent cytotoxicity of the drug. Under hypoxic conditions, submicromolar concentrations of NC resulted in sensitization (SER = 1·6 at 1 µmol dm^?3). Sensitization was also seen under aerobic conditions but a concentration more than 10-fold higher was required. In aerobic cultures NC radiosensitization was independent of whether cells were exposed before and during, or after, irradiation. Postirradiation sensitization was not observed under hypoxic conditions. The time dependence of NC uptake and the development of radiosensitization were similar (maximal at 30 min at 4°C under hypoxia) suggesting that sensitization, unlike cytotoxicity, is due to unmetabolized drug. NC is about 1700 times more potent as a radiosensitizer than misonidazole. This high potency is adequately accounted for by the electron affinity of NC (E(1) value at pH 7 of ?275mV versus NHE) and by its accumulation in cells to give intracellular concentrations approximately 30 times greater than in the medium. However, concentrations of free NC appear to be low in AA8 cells, presumably because of DNA binding. If radiosensitization by NC is due to bound rather than free drug, it suggests that intercalated NC can interact very efficiently with DNA target radicals. This is despite a binding ratio in the cell estimated as less than 1 NC molecule/400 base pairs under conditions providing efficient sensitization. This work suggests a new approach in the search for more effective clinical radiosensitizers, and poses questions on the means by which intercalated drugs can interact with DNA damage.     

HSV-TK/GCV自杀基因系统联合γ射线放射治疗宫颈癌的实验研究

目的 探讨HSV-TK／GCV自杀基因系统协同^60Coγ射线放射治疗对人宫颈癌细胞系的体内外联合杀伤作用，以及HSV-TK／GCV对放射治疗的增敏作用。方法 分别以HSV-TK／GCV、^60Coγ射线放射治疗及两者联合治疗人宫颈癌HeLa细胞系和裸鼠宫颈癌移植瘤模型，比较治疗效果；利用增敏效应比值（E／O）、克隆形成实验评价体内外HSV-TK／GCV对放射敏感性的影响。结果 在体外实验中，自杀基因对宫颈癌HeLa细胞生长的抑制率为45．8％，单纯放疗的抑制率为42．4％，而基因治疗与放疗联用的抑制率为87．5％，与前两者比较，差异有统计学意义（P〈0．01）；且联合治疗组对射线敏感性较单独治疗组明显增加，克隆形成率明显下降（P〈0．05）；在体内实验中，单纯基因治疗与放疗对HeLa细胞裸鼠皮下移植瘤生长的抑瘤率分别为39．5％和35．8％，而基因治疗放疗联用的抑瘤率达到87．9％，与前两者比较，差异均有统计学意义（P〈0．01）；增敏效应比值（E／O）为3．2（〉1．4），提示HSV-TK／GCV对放疗具有增敏作用。结论 HSV-TK／GCV自杀基因系统具有放射增敏作用，二者联合治疗可作为宫颈癌综合治疗的有效补充方法。     

Aerobic radiosensitization by SR 4233 in rodent and human cells: mechanistic and therapeutic implications.

Mammalian cells surviving exposure to the bioreductive, cytotoxic agent SR 4233 under hypoxic conditions are sensitized to X-irradiation under aerobic conditions (and in the absence of drug). Fits of both the single-hit, multi-target and linear-quadratic expressions to survival data, as well as direct measurement of surviving fractions after a dose of 2 Gy, indicate that the aerobic radiosensitization produced by SR 4233 can increase both the initial and final 'slopes' of the X-ray survival curve. The amount of radiosensitization produced, and whether the modification is principally in the slope or shoulder region of the survival curve, varies from cell line to cell line. Rodent cells are radiosensitized equally whether the drug treatment is given immediately before or after, the irradiation, but human cells are only sensitized for SR 4233 exposure administered before irradiation. Using rodent CHO cells, time-course experiments for SR 4233 and X-rays given in sequence, in which an interval of up to 2 h was interposed between the treatments, reveal different kinetics for the loss of radiosensitization depending on whether the hypoxic drug exposure was given before or after the aerobic irradiation. When SR 4233 treatment is given pre-irradiation, the radiosensitization effect persists for at least 2 h, but it does not when drug is given after irradiation. Taken together, the finding of a difference between rodent and human cells with respect to post-irradiation sensitization by SR 4233, and the differing time-course kinetics for this effect as a function of how the drug and radiation are sequenced, suggest that while SR 4233 behaves in a radiomimetic manner in most respects, there may be subtle differences in the nature of the lesions produced by the drug, the important cellular targets for this damage, and/or the cell's management of the damage.     

Radiosensitization by Cisplatin of RIF1 Tumour Cells in Vitro

Summary

the ability of cis-diamminedichloroplatinum (II) (c-DDP) to enhance radiation-induced cell killing was tested on oxic RIF1 tumour cells in monolayer culture. Marked radiosensitization of the survivors of a 1 h drug treatment was found with all c-DDP doses tested, with enhancement ratios increasing from 1·2 to 2·2 with increasing drug dose. Isobologram analyses showed that the interactions of c-DDP with X-rays were supra-additive.

To test whether part of the enhancement was due to a selection of subpopulations, the diploid and tetraploid RIF1 cells, which normally coexist in culture, were separated by (a) unit gravity velocity sedimentation, and (b) by developing diploid and tetraploid clones. Both methods showed that there was little differnce in either drug sensitivity or radiation sensitivity between diploid and tetraploid cells. DNA histograms obtained by flow cytometry showed little or no cycle progression during the 1 h drug treatment. These data indicate that the radiosensitization was not the result of the drug exposure leaving cells in a radiosensitive phase. The observed radiosensitization, therefore, appears to have resulted from a true drug/X-ray interaction.     

Structure-activity relationships for tumour radiosensitization by analogues of nicotinamide and benzamide.

Nicotinamide has been shown in our laboratory and those of other investigators to be an effective radiosensitizer of a variety of mouse tumours, while producing little or no radiosensitization of normal tissues. Its mechanism of action is different from classical electron-affinic compounds and appears to be the result of improved tumour oxygenation. In this study we have synthesized 29 analogues of nicotinamide and benzamide and characterized them for their tumour radiosensitization and acute toxicity in mice. The data show that a wide range of additions to the nicotinamide and benzamide ring produce tumour radiosensitization similar to that produced by equimolar doses of misonidazole, but that substitutions of the amide tend to reduce radiosensitization. Other structure-activity relationships are evident. Although some compounds produce similar tumour radiosensitization to nicotinamide at equimolar doses, and are comparably low in acute toxicity, none appears sufficiently superior to supplant nicotinamide itself as a candidate for clinical trials. Thus these data provide evidence that nicotinamide, because of the extensive experience with its use in man, is likely to be the best drug in the benzamide-nicotinamide series for development as a radiosensitizer of human tumours.     

Structure–activity Relationships for Tumour Radiosensitization by Analogues of Nicotinamide and Benzamide

Summary

Nicotinamide has been shown in our laboratory and those of other investigators to be an effective radiosensitizer of a variety of mouse tumours, while producing little or no radiosensitization of normal tissues. Its mechanism of action is different from classical electron-affinic compounds and appears to be the result of improved tumour oxygenation. In this study we have synthesized 29 analogues of nicotinamide and benzamide and characterized them for their tumour radiosensitization and acute toxicity in mice. The data show that a wide range of additions to the nicotinamide and benzamide ring produce tumour radiosensitization similar to that produced by equimolar doses of misonidazole, but that substitutions of the amide tend to reduce radiosensitization. Other structure–activity relationships are evident. Although some compounds produce similar tumour radiosensitization to nicotinamide at equimolar doses, and are comparably low in acute toxicity, none appears sufficiently superior to supplant nicotinamide itself as a candidate for clinical trials. Thus these data provide evidence that nicotinamide, because of the extensive experience with its use in man, is likely to be the best drug in the benzamide–nicotinamide series for development as a radiosensitizer of human tumours.     

Photon activation therapy

It is suggested here that significant advantages should accrue from the use of 40 keV photons from implanted sources of 145Sm. These energies should stimulate Auger electron cascades from IdUrd, as well as produce non-repairable damage from radiosensitization. The use of low dose rates (approximately 10 rd/hr) should allow repair in normal tissues exposed to the activating photons. Utilization of this technique with brain tumors should minimize problems associated with radiosensitization of normal tissues, as CNS tissues do not synthesize DNA. The deposition of high LET radiations selectively in tumor cells provides unique advantages not available to either conventional therapy or other forms of particle therapy (fast neutrons, protons, pions, heavy ions).     

Adriamycin: a possible indirect radiosensitizer of hypoxic tumor cells.

Multicellular spheroids grown in vitro provide a convenient model of nodular tumors for experimental tumor therapy studies. Adriamycin was found to inactivate cells grown as spheroids less efficiently than single cells, presumably due to enhanced cellular resistance analogous to the increased radioresistance observed when these cells are grown in close contact. Spheroid growth was retarded by a minimally toxic (0.005 mug/ml) chronic level of adriamycin; irradiation and exposure to that drug concentration were not found to be synergistic. Large adriamycin concentrations (0.5 mug/ml) present during radiation exposure produced a marked "radiosensitization," presumably due to the drug-inhibitng cellular oxygen consumption and thus permitting reoxygenation of the previously hypoxic spheroid cells.     

Radiobiology and Clinical Application of Halogenated Pyrimidine Radiosensitizers

Summary

Halogenated pyrimidines (HP) represent a unique class of non-hypoxic cell radiosensitizers currently under clinical re-investigation. In order for halogenated pyrimidines to sensitize cells to radiation, they must be incorporated into cellular DNA. In the case of human tumors, which have in general rather long cell cycle times, this may require many days of continuous drug infusion to achieve adequate replacement of the DNA base thymidine with HP. In vitro studies support the relationship between the extent of radiosensitization and the percentage of thymidine replacement. Recent clinical studies evaluating the role of iododeoxyuridine (IdUrd) as a radiation sensitizer in large unresectable sarcomas have been extremely encouraging. To support and expand upon these positive clinical findings more information and research is needed regarding: (1) the mechanism of HP-induced radiosensitization; (2) the percentage of HP thymidine replacement in human tumors achievable and how it relates to treatment outcome; (3) the means of increasing HP incorporation in tumor and minimizing incorporation in normal tissues; (4) a better understanding of optimal timing between HP administration and radiation treatment; and (5) methods to evaluate which tumors are appropriate candidates for HP therapy. While presently limited to use in conventional high dose-rate X-ray therapy, laboratory studies suggest that HP might also be effective in low dose-rate brachytherapy and for selected high LET clinical beams. HPs probably will not be ‘general’ non-hypoxic cell radiosensitizers for all tumor types, but with appropriate tumor-type/anatomical site selection and refinement in their administration, HPs may prove beneficial in cancer treatment.     

Gold nanoparticles in combination with megavoltage radiation energy increased radiosensitization and apoptosis in colon cancer HT-29 cells

Purpose: Gold nanoparticles (GNP) act as a radiosensitizer in radiation therapy. However, recent studies have shown contradictory evidence in terms of radiosensitization in the presence of GNP combined with X-ray megavoltage energy (MV) on different cell types. In this study, the effect of GNP on radiosensitization enhancement of HT-29 human colorectal cancer cells at MV X-ray energy was evaluated.

Materials and methods: The cytotoxicity and radiosensitization of GNP were evaluated in HT-29 human colorectal cancer cells by MTS-assay and multiple MTS-assay, respectively. Cellular uptake was assayed using graphite furnace atomic absorption spectrometry (GFAAS). Apoptosis and cell cycle progression were determined by an Annexin V-FITC/propidium iodide (PI) kit and PI/RNase solution with flow cytometry, respectively.

Results: Results showed that the cell viability of the HT-29 cells was not influenced by exposure to different concentrations of GNP (10–100 μM). GNP alone did not affect the cell cycle progression and apoptosis. In contrast, GNP, in combination with radiation (9?MV), induced more apoptosis. The interaction of GNP with MV energy resulted in a significant radiosensitization enhancement compared with irradiation alone.

Conclusion: It was concluded that GNP may work as bio-inert material on HT-29 cancer cells and their enhancement of radiosensitization may be due to increase in the absorbed irradiation dose.