Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy

Purpose To evaluate the usefulness of 5 new¹⁰B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as¹⁰B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402 and a clinically used¹⁰B-carrier, sodium borocaptate-¹⁰B (BSH). Materials and Methods The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the¹⁰B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor¹⁰B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [=quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. Results ¹⁰B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of¹⁰B in tumors and maintaining a high enough¹⁰B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with γ-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. Conclusion A¹⁰B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep¹⁰B in tumors and sensitize tumor cells more markedly than conventional¹⁰B-carriers, such as TX-2100, is a promising candidate for use in BNCT. A part of this paper was presented at the 64th JRS annual meeting in Yokohama on April 8, 2005.     

辐射增强启动子调控的p53基因联合照射对肿瘤细胞的作用

目的 研究辐射增强启动子调控的野生型-p53抑癌基因系统联合照射对人肿瘤细胞系HeLa和A549细胞的特异性杀伤作用。方法 构建辐射增强启动子pE6（TATA）-p53,Western blot检测不同射线剂量诱导下人肺腺癌A549细胞系和人宫颈癌HeLa细胞系中P53蛋白的表达水平,筛选出最适的照射剂量;AnnexinV-FITC试剂盒检测肿瘤细胞系早期凋亡率;利用克隆形成实验检测此系统对肿瘤细胞放射敏感性的影响。结果 在HeLa和A549细胞中,P53蛋白表达均受放射线诱导增高,且在6 Gy时辐射诱导活性最高;实验组质粒的细胞早期凋亡率与转染对照组质粒的细胞早期凋亡率相比有明显提高（F=11.018、10.736,P<0.05）。HeLa细胞和A549细胞的放射增敏比（SER）分别为2.56和2.36。结论 辐射增强启动子调控的p53基因系统具有显著的诱导肿瘤细胞凋亡的作用,可以提高肿瘤细胞的辐射敏感性,对肿瘤的治疗提供了新思路。     

Measurement of pulmonary partial pressure of oxygen and oxygen depletion rate with hyperpolarized helium-3 MRI: a preliminary reproducibility study on pig model

RATIONAL AND OBJECTIVES: Pulmonary partial pressure of oxygen (pO(2)) and oxygen depletion rate (R) are two important parameters of lung function. The dependence of hyperpolarized (3)He (HP (3)He) T(1) on local oxygen concentration provides the basis for high-resolution mapping of the regional distributions of pO(2) and R in the lung. Although the oxygen-sensitive HP (3)He magnetic resonance imaging technique has been applied in human subjects and several animal species, reproducibility studies are rarely reported in the literature. This work presents a preliminary reproducibility study on a pig model. In this study, important scan parameters, such as measurement timing and flip angle, are optimized to minimize the noise-induced measurement uncertainty. MATERIALS AND METHODS: In the in vivo study, five normal pigs and one diseased pig with simulated pulmonary emboli were scanned with a small flip angle gradient echo sequence. The pulmonary oxygen measurement was repeated two to four times in each pig. In each measurement, a series of six images were acquired with optimal timing and flip angle. The parametric maps were generated using a bin-based data processing procedure that applied the multiple regression fitting method to extract the pO(2) and R. Variations of global mean, percentiles, and regions of interest were calculated from the maps to analyze reproducibility. RESULTS: The global statistical analyses show that average variation of global mean is 10.7% for pO(2) and 23.8% for R, and that the average variation of percentiles (10th, 25th, 50th, 75th, and 90th) and interquartile range is 14.8% for pO(2) and 30.4% for R. The region-of-interest analysis on the manually selected regions shows that the average variation of mean is 12.6% for pO(2) and 21.9% for R. CONCLUSION: In this work, a preliminary study on the reproducibility of measuring pO(2) and R with HP (3)He magnetic resonance imaging on a pig model is presented.     

Clinical significance of 18F-FDG uptake by primary sites in patients with diffuse large B cell lymphoma in the head and neck: a pilot study

Objective  This pilot study was launched to explore the utility of positron emission tomography scans, at the time of diagnosis, for clinical outcomes in patients with primary extranodal non-Hodgkin’s lymphoma (PENHL) in the head and neck, retrospectively. Methods  Twenty-two patients with a diffuse large B cell lymphoma (DLBCL) among those with a PENHL were included. We retrospectively evaluated the clinical outcomes of patients according to the maximum standardized ¹⁸F-fluoro-2-deoxy-glucose (¹⁸F-FDG) uptake value of the primary lesion (SUV_p). The SUV_p was initially analyzed as a continuous variable. The cut-offvalue of SUV_p was obtained from receiver-operating characteristic analysis to predict event-free survival. Using this value, patients were divided into those with a low and high SUV. Results  Seventeen patients (59%) were men and the median age was 50 years. Most primary sites were in Waldeyer’s ring (73%). The SUV_p ranged from 3.3 to 23.7. The international prognostic index (IPI < 2 vs. ≥ 2) was associated with the SUV_p (P = 0.014). Patients with low SUV_p showed favorable survival (P = 0.015). After IPI scores were stratified, the survival difference remained significant (P = 0.029). Conclusions  The results of this pilot investigation indicate that ¹⁸F-FDG uptake of the primary lesion may be related with survival outcomes in patients with extranodal DLBCL in the head and neck. Further studies are needed to confirm and extend these results. I.I. Na and G.J. Cheon contributed equally to this work.