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1.
Mechthild Krause Daniel Zips Howard D Thames Johann Kummermehr Michael Baumann 《Radiotherapy and oncology》2006,80(2):112-122
The combination of molecular-targeted agents with irradiation is a highly promising avenue for cancer research and patient care. Molecular-targeted agents are in themselves not curative in solid tumours, whereas radiotherapy is highly efficient in eradicating tumour stem cells. Recurrences after high-dose radiotherapy are caused by only one or few surviving tumour stem cells. Thus, even if a novel agent has the potential to kill only few tumour stem cells, or if it interferes in mechanisms of radioresistance of tumours, combination with radiotherapy may lead to an important improvement in local tumour control and survival. To evaluate the effects of novel agents combined with radiotherapy, it is therefore necessary to use experimental endpoints which reflect the killing of tumour stem cells, in particular tumour control assays. Such endpoints often do not correlate with volume-based parameters of tumour response such as tumour regression and growth delay. This calls for radiotherapy specific research strategies in the preclinical testing of novel anti-cancer drugs, which in many aspects are different from research approaches for medical oncology. 相似文献
3.
Shirmardi SP Gandomkar M Maragheh MG Shamsaei M 《Cancer biotherapy & radiopharmaceuticals》2011,26(3):309-316
Bombesin (BBN) is a peptide showing high affinity for the gastrin-releasing peptide receptor. Tumors such as prostate, small cell lung cancer, breast, gastric, and colon cancer are known to over express receptors to BBN and gastrin-releasing peptide (GRP). The goal of this study was to evaluate a new (67)Ga radiolabeled BBN analog based on the bifunctional chelating ligand DOTA (1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid), which could be used as a tool for diagnosis of GRP receptor-positive tumors. DOTA-GABA-BBN (7-14) NH(2) was synthesized using a standard Fmoc strategy. Labeling with (67)Ga was performed at 95°C for 30 minutes in ammonium acetate buffer (pH?=?4.8). Radiochemical analysis involved ITLC and HPLC methods. The stability of radiopeptide was examined in the presence of human serum at 37°C up to 24 hours. The receptor-bound internalization and externalization rates were studied in GRP receptor expressing PC-3 cells. Biodistribution of radiopeptide was studied in nude mice bearing PC-3 tumor. Labeling yield of >90% was obtained corresponding to a specific activity of approximatrly 2.6?MBq/nmol. Peptide conjugate showed good stability in the presence of human serum. The radioligand showed a good and specific internalization into PC-3 cells (16.13%?±?0.71% at 4 hours). After 4 hours, a considerable amount of activity (52.42%?±?1.86%) was externalized. In animal biodistribution studies, a receptor-specific uptake of radioactivity was observed in GRP-receptor-positive organs. After 4 hours, the uptake in mouse tumor and pancreas was 1.30%?±?0.18% ID/g (percentage of injected dose per gram of tissue) and 1.21%?±?0.13% ID/g, respectively. These data show that [(67)Ga]-DOTA-GABA-BBN (7-14) NH? is a specific radioligand for GRP receptor positive tumors and is a suitable candidate for clinical studies. 相似文献
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Subcellular localization of radiolabeled somatostatin analogues: implications for targeted radiotherapy of cancer 总被引:3,自引:0,他引:3
Wang M Caruano AL Lewis MR Meyer LA VanderWaal RP Anderson CJ 《Cancer research》2003,63(20):6864-6869
Copper-64 (T(1/2) = 12.7 h; beta(+), 17.4%; beta(-), 39%) has been used both in positron emission tomography imaging and in radiotherapy. Copper-64 radiopharmaceuticals have shown tumor growth inhibition with a relatively low radiation dose in animal models; however, the mechanism of cytotoxicity has not been fully elucidated. These studies incorporate the use of somatostatin receptor-positive AR42J rat pancreatic tumor cells in vitro to understand the cell killing mechanism of (64)Cu by focusing on subcellular distribution of the somatostatin analogues (64)Cu-labeled 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide ((64)Cu-TETA-OC) and (111)In-labeled diethylenetriaminepentaacetic acid-octreotide ((111)In-DTPA-OC). Cell uptake and organelle isolation studies were conducted on (64)Cu-TETA-OC and (111)In-DTPA-OC. Nuclear localization of (64)Cu and (111)In from (64)Cu-TETA-OC and (111)In-DTPA-OC, respectively, increased over time, with 19.5 +/- 1.4% and 6.0 +/- 1.0% in the cell nucleus at 24 h, respectively. In pulse-chase experiments, in which (64)Cu-TETA-OC was incubated with AR42J cells for 4 h, it was found that the nuclear localization of (64)Cu increased significantly over the next 20 h (from 9.8 +/- 1.0% to 26.3 +/- 5.4%). In a control pulse-chase experiment, levels of (64)Cu from [(64)Cu]cupric acetate decreased from 4 to 24 h postadministration (20.6 +/- 8.7 to 5.4 +/- 1.9), suggesting that the redistribution mechanism, or the kinetics of (64)Cu from (64)Cu-TETA-OC is different from that for (64)Cu from [(64)Cu]cupric acetate. The amount of (64)Cu from (64)Cu-TETA-OC also increased in the mitochondria over time, with 21.1 +/- 3.6% in the mitochondria at 24 h postadministration. These results suggest that localization of substantial quantities of (64)Cu to the cell nucleus and mitochondria may contribute to cell killing with (64)Cu radiopharmaceuticals. 相似文献
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Xu M Rettig MP Sudlow G Wang B Akers WJ Cao D Mutch DG DiPersio JF Achilefu S 《International journal of cancer. Journal international du cancer》2012,131(6):1351-1359
Cancer stem cells (CSCs) have been successfully isolated from solid tumors and are believed to be initiating cells of primary, metastatic and recurrent tumors. Imaging and therapeutic reagents targeted to CSCs have potential to detect subclinical tumors and completely eradicate the disease. Previously, we have demonstrated that Mab CC188 binds to colon cancer CD133- and CD133+ (CSCs) cells. In this study, we examined the reactivity of Mab CC188 to ovarian cancer cells including CD133+ cells and primary tumor tissues using immunofluorescence staining methods and tissue microarray technique. We also explored the feasibility of using NIR dye-labeled Mab CC188 probe to image ovarian tumors in vivo. Mab CC188 stains both CD133- and CD133+ cells of ovarian cancer. Tissue microarray analysis reveals that 75% (92/123) of ovarian cancer cases are positively stained with Mab CC188. Weak positive (±), positive (+), strong positive (++) and very strong positive (+++) stains are 14.8, 3.7, 11 and 24.4%, respectively. In contrast, Mab CC188 staining is low in normal cells and tissues. In vivo study show that significant amounts of the probe accumulates in the excretion organs in the early period postinjection. At 24 hr, the imaging probes have largely accumulates in the tumor, while the intensity of the imaging probe decreases in the liver. The tumor uptake was still evident at 120-hr postinjection. Our work suggests that Mab CC188-based imaging and therapeutic reagents are capable of detecting early stage ovarian tumors and effectively treating the tumor. 相似文献
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Novel imidazoacridinone derivatives, C1310 and C1311, have been evaluated for their potential to inhibit tumour cell growth in vitro and in vivo. A cell line panel, including seven human and murine colon carcinoma cell lines and three in vivo models, was used. The compounds were found to be potent inhibitors of tumour cell growth with IC50 values ranging between 10 nM and 2 microM in human colon cancer cell lines. Statistically significant tumour growth delay (P < 0.01) was observed after a single intraperitoneal (i.p.) dose of C1311 (100 mg kg-1 body weight) in MAC15A, MAC29 murine and HT29 human adenocarcinomas of the colon. Rapid accumulation of fluorescence of both C1310 and C1311 was seen in the nuclei of HT29 human colon tumour cells in culture. C1311 was also found to bind into calf thymus DNA as shown by spectrophotometric titration and thermal denaturation and to cause early inhibition of thymidine incorporation in HT29 cells in vitro. The results of this study suggest that C1311 should be considered as a candidate for clinical development. 相似文献
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Matthias Miederer Gjermund Henriksen Andrea Alke Ilona Mossbrugger Leticia Quintanilla-Martinez Reingard Senekowitsch-Schmidtke Markus Essler 《Clinical cancer research》2008,14(11):3555-3561
PURPOSE: Peptide receptor radionuclide therapy (PRRT) using somatostatin analogues labeled with beta-particle-emitting isotopes such as 90Y or 177Lu has been a promising treatment strategy for metastasized neuroendocrine tumors. Although remission can be accomplished in a high percentage of neuroendocrine tumors, some tumors do not respond to this treatment. alpha-Emitting isotopes-such as the 10-day half-life alpha-emitting generator nuclide Actinum-225 (225Ac)-are characterized by extremely high cytotoxic activity on the cellular level, and may be superior in the treatment of neuroendocrine tumors not responding to PRRT using beta-emitting isotopes. EXPERIMENTAL DESIGN: Radiolabeling of 225Ac 1,4,7,10-tetra-azacylododecane N,N',N',N'-J-tetraacetic acid-Tyr3-octreotide (DOTATOC) was done at pH 5 (60 minutes at 70 degrees C) without further purification. Biodistribution in nude mice bearing AR42J rat pancreas neuroendocrine tumor xenografts were measured for up to 24 hours. Toxicity was tested by weight changes, retention variables (blood urea nitrogen and creatine), and histopathology in mice 7 months after treatment with 10 to 130 kBq (n = 4-5). Therapeutic efficacy was assessed by tumor weighing in animals treated 4 days after xenotransplantation and compared with 177Lu-DOTATOC as a reference. RESULTS: Activities up to 20 kBq had no significant toxic effects in mice. In contrast, activities higher than 30 kBq induced tubular necrosis. Biodistribution studies revealed that 225Ac-DOTATOC effectively accumulated in neuroendocrine xenograft tumors. 225Ac-DOTATOC activities were shown to be nontoxic (12-20 kBq), reduced the growth of neuroendocrine tumors, and showed improved efficacy compared with 177Lu-DOTATOC. CONCLUSIONS: 225Ac might be suitable to improve PRRT in neuroendocrine tumors. 相似文献
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Payton M Bush TL Chung G Ziegler B Eden P McElroy P Ross S Cee VJ Deak HL Hodous BL Nguyen HN Olivieri PR Romero K Schenkel LB Bak A Stanton M Dussault I Patel VF Geuns-Meyer S Radinsky R Kendall RL 《Cancer research》2010,70(23):9846-9854
In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes. 相似文献
9.
Daniel K. Lee 《Cancer biology & therapy》2017,18(5):277-278
The standard treatments of localized prostate cancer include surgical resection and/or radiotherapy. Recently in 2016, Zhao et al. described a tool to predict which patients will most likely gain from postoperative radiotherapy. Such a method can personalize treatment plan by maximizing benefit but minimizing harm. 相似文献
10.
Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441 总被引:6,自引:0,他引:6
Zhao Y Thomas HD Batey MA Cowell IG Richardson CJ Griffin RJ Calvert AH Newell DR Smith GC Curtin NJ 《Cancer research》2006,66(10):5354-5362
DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by ionizing radiation and topoisomerase II poisons, such as etoposide and doxorubicin. A major pathway for the repair of DSB is nonhomologous end joining, which requires DNA-dependent protein kinase (DNA-PK) activity. We investigated the therapeutic use of a potent, specific DNA-PK inhibitor (NU7441) in models of human cancer. We measured chemosensitization by NU7441 of topoisomerase II poisons and radiosensitization in cells deficient and proficient in DNA-PK(CS) (V3 and V3-YAC) and p53 wild type (LoVo) and p53 mutant (SW620) human colon cancer cell lines by clonogenic survival assay. Effects of NU7441 on DSB repair and cell cycle arrest were measured by gammaH2AX foci and flow cytometry. Tissue distribution of NU7441 and potentiation of etoposide activity were determined in mice bearing SW620 tumors. NU7441 increased the cytotoxicity of ionizing radiation and etoposide in SW620, LoVo, and V3-YAC cells but not in V3 cells, confirming that potentiation was due to DNA-PK inhibition. NU7441 substantially retarded the repair of ionizing radiation-induced and etoposide-induced DSB. NU7441 appreciably increased G(2)-M accumulation induced by ionizing radiation, etoposide, and doxorubicin in both SW620 and LoVo cells. In mice bearing SW620 xenografts, NU7441 concentrations in the tumor necessary for chemopotentiation in vitro were maintained for at least 4 hours at nontoxic doses. NU7441 increased etoposide-induced tumor growth delay 2-fold without exacerbating etoposide toxicity to unacceptable levels. In conclusion, NU7441 shows sufficient proof of principle through in vitro and in vivo chemosensitization and radiosensitization to justify further development of DNA-PK inhibitors for clinical use. 相似文献
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Autret D Bitar A Ferrer L Lisbona A Bardiès M 《Cancer biotherapy & radiopharmaceuticals》2005,20(1):77-84
INTRODUCTION: Dosimetric studies for targeted radiotherapy require the quantification of activity from scintigraphic images. Quantitative imaging is difficult to achieve because of several effects that can lead to errors in activity estimates, some of which are more apparent when I-131 is considered as a source. An evaluation of these phenomena was performed by modeling the gamma camera and its behavior using Monte Carlo simulations. Two gamma cameras were modeled: DST-XLi and Millennium VG Hawk-Eye (GEMS), and two Monte Carlo codes were used: MCNP (LANL) and GATE (openGate collaboration). GATE is a dedicated single photon emission computed tomography/positron emission tomography (SPECT)/(PET) software based on Geant4 (CERN, Geneve). MATERIALS AND METHODS: Gamma-camera modeling was performed in 2 steps: first without a collimator, then with a high-energy, all-purpose (HEAP) collimator according to the specifications given by the manufacturer (the simulation took the hexagonal shape of collimator holes into account). Simulated and measured energy spectra from point sources in air were compared (with or without a collimator). Spatial resolution was obtained from line sources in air at various distances from the detector heads. The photons detected in the 20% energy window from a point source were analyzed in order to determine the amount of primary photons, scattered photons (in the collimator), and septal photons (i.e., photons that crossed the collimator septa without interacting). RESULTS: Both codes agree well with experimental measurements for the two gamma cameras considered in this study. This allowed us to validate gamma-camera modeling and also served as a benchmark of GATE (new code) versus MCNP (reference code). As shown previously by Dewaraja et al., septal penetration is an important source of image degradation when HEAP collimators are used for I-131 imaging. With the DST-XLi, and for a point source in air, our simulations have shown that 53% of scattered (30%) and septal penetration (23%) photons are detected in the 20% window. CONCLUSION: The modeling of two gamma cameras (DST-XLi and Millennium VG Hawk-Eye) has been performed with two Monte Carlo codes (MCNP and Gate). Results obtained with the two Monte Carlo codes agree well with experimental results. As already indicated by several authors, septal penetration and scattered photons in the collimator have a major impact on I-131 scintigraphic imaging. 相似文献
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Ganesan Vaidyanathan Henry S Friedman Donna J Affleck Margaret Schottelius Hans-Jürgen Wester Michael R Zalutsky 《Clinical cancer research》2003,9(5):1868-1876
PURPOSE: The objective of this study was to determine the feasibility of exploiting the overexpression of somatostatin subtype-2 receptors (sstr(2)) on human medulloblastoma cells to develop targeted radiodiagnostics and radiotherapeutics for this disease. EXPERIMENTAL DESIGN: The following radioiodinated peptides were prepared using chloramine-T and evaluated: [(131)I-Tyr(3)]octreotide ([(131)I]TOC), [(131)I-Tyr(3)]octreotate ([(131)I]TOCA), involving substitution of Thr(ol)(8) in TOC with Thr(8), and glucose-[(131)I-Tyr(3)]octreotide ([(131)I]Gluc-TOC) and glucose-[(131)I-Tyr(3)]octreotate ([(131)I]Gluc-TOCA), prepared by conjugation of glucose to the peptide NH(2) terminus. Specific internalization of the peptides by sstr(2)-expressing AR42J rat pancreatic carcinoma cells in vitro was evaluated in paired-label assays. The tissue distribution of i.v. administered [(131)I]TOC, [(131)I]TOCA, [(131)I]Gluc-TOC, and [(131)I]Gluc-TOCA was evaluated in athymic mice bearing s.c. D341 Med human medulloblastoma xenografts. RESULTS: Compared with [(125)I]TOC, internalized radioiodine levels were higher for the other three peptides. For example, internalized counts were 1.9 +/- 0.2, 2.0 +/- 0.3, and 5.7 +/- 1.9 times higher for [(131)I]Gluc-TOC, [(131)I]TOCA, and [(131)I]Gluc-TOCA after a 3-h incubation, respectively, demonstrating that carbohydration and COOH-terminus modification significantly improved the retention of radioiodine activity in sstr(2)-expressing tumor cells. COOH-terminus modification significantly increased (131)I localization in D341 Med medulloblastoma xenografts [[(131)I]TOCA, 8.1 +/- 2.2% of injected dose/g (% ID/g); [(131)I]TOC, 3.9 +/- 0.5% ID/g at 1 h], whereas carbohydration of the NH(2) terminus resulted in even higher gains in tumor accumulation ([(131)I]Gluc-TOC, 11.1 +/- 1.8% ID/g; [(131)I]Gluc-TOCA, 21.4 +/- 7.3% ID/g). In addition, the three modified peptides exhibited liver activity levels that were less than half those of [(131)I]TOC. Uptake of the two glucose-peptide conjugates in this human medulloblastoma xenograft was blocked by coinjection of 100 micro g of octreotide, demonstrating that it was receptor-specific. Tumor:normal tissue uptake ratios for [(131)I]Gluc-TOCA generally were higher that those for [(131)I]Gluc-TOC. At 1 h, tumor:normal tissue ratios for [(131)I]Gluc-TOCA were 29:1, 15:1, 8:1, 8:1, 240:1, and 82:1 for blood, liver, kidney, spleen, brain, and muscle, respectively. CONCLUSIONS: Our findings suggest that additional investigation of radiolabeled Gluc-TOCA analogues for the imaging and targeted radiotherapy of medulloblastoma is warranted. 相似文献
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Preclinical characterization of anlotinib,a highly potent and selective vascular endothelial growth factor receptor‐2 inhibitor
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Chengying Xie Xiaozhe Wan Haitian Quan Mingyue Zheng Li Fu Yun Li Liguang Lou 《Cancer science》2018,109(4):1207-1219
Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor‐2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase show unexpected adverse effects and limited anticancer efficacy. In the present study, we detailed the pharmacological properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP‐binding pocket of VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF‐induced signaling and cell proliferation in HUVEC with picomolar IC50 values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well‐known tyrosine kinase inhibitor sunitinib, once‐daily oral dose of anlotinib showed broader and stronger in vivo antitumor efficacy and, in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well‐tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies. 相似文献
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G Ramachandra Reddy Mahaveer S Bhojani Patrick McConville Jonathan Moody Bradford A Moffat Daniel E Hall Gwangseong Kim Yong-Eun L Koo Michael J Woolliscroft James V Sugai Timothy D Johnson Martin A Philbert Raoul Kopelman Alnawaz Rehemtulla Brian D Ross 《Clinical cancer research》2006,12(22):6677-6686
PURPOSE: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. EXPERIMENTAL DESIGN: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDT using Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDT and imaging agents. RESULTS: The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. CONCLUSIONS: This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer. 相似文献
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BACKGROUND AND PURPOSE: The technique known as the 'gamma evaluation method' incorporates pass-fail criteria for both distance-to-agreement and dose difference analysis of 3D dose distributions and provides a numerical index (gamma) as a measure of the agreement between two datasets. As the gamma evaluation index is being adopted in more centres as part of treatment plan verification procedures for 2D and 3D dose maps, the development of methods capable of encapsulating the information provided by this technique is recommended. PATIENTS AND METHODS: In this work the concept of gamma index was extended to create gamma histograms (GH) in order to provide a measure of the agreement between two datasets in two or three dimensions. Gamma area histogram (GAH) and gamma volume histogram (GVH) graphs were produced using one or more 2D gamma maps generated for each slice of the irradiated volume. GHs were calculated for IMRT plans, evaluating the 3D dose distribution from a commercial treatment planning system (TPS) compared to a Monte Carlo (MC) calculation used as reference dataset. RESULTS: The extent of local anatomical inhomogenities in the plans under consideration was strongly correlated with the level of difference between reference and evaluated calculations. GHs provided an immediate visual representation of the proportion of the treated volume that fulfilled the gamma criterion and offered a concise method for comparative numerical evaluation of dose distributions. CONCLUSIONS: We have introduced the concept of GHs and investigated its applications to the evaluation and verification of IMRT plans. The gamma histogram concept set out in this paper can provide a valuable technique for quantitative comparison of dose distributions and could be applied as a tool for the quality assurance of treatment planning systems. 相似文献
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