Haematological studies on90Sr-90Y-toxicity: II. Femoral CFU-s kinetics and mitogen response of spleen cells

Summary Ferrokinetic perturbances in peripheral blood of mice treated with⁹⁰Sr-⁹⁰Y were demonstrated previously. This paper deals with the effects of⁹⁰Sr-⁹⁰Y treatment (2.5, 5, and 10 µCi/mouse), on the haemopoietic stem cell compartment and on the immune-status. The frequency and kinetics of haemopoietic stem cells in femoral marrow (determined as colony forming units in spleen, CFU-s) and their haemopoietic efficiency (as gauged by⁵⁹Fe-and¹²⁵IUdR-uptake) were estimated. The responsiveness of splenic lymphocytes of the same animals to mitogens (Con A, PHA, and LPS) were also measured. In all assays striking dose-dependent changes marked either by depressions or overshoots were observed during the first week post-incorporation. These are correlated with the pattern of deposition (primary and secondary) of the radionuclides⁹⁰Sr-⁹⁰Y. Towards the end of the period of observation and presumably thereafter, the dependence on dose disappeared and the values remained subnormal. An exception to this was the response of splenic lymphocytes to mitogens. Much higher reactivity was recorded up to the end. This higher reactivity is attributed to augmented cellular turnover, the newly recruited lymphocytes (in accord with their extreme radiosensitivity), being probably more reactive.     

Haematological studies on90Sr-90Y-toxicity

Summary Erythropoietic changes were observed, measured by⁵⁹Fe-uptake into red blood cells, and on radioiron turnover from blood plasma, at different time intervals (2–64 days) after treating adult female mice with varying activities of⁹⁰Sr-⁹⁰Y. Activities of 2.5 or 5.0 µCi radiostrontium per animal lead to a depression at time intervals of two and four days, at longer periods there was an overshoot. With activities of 0.5 or 1.0 µCi radiostrontium disturbances in the radioiron uptake are still observed, although these effects are not as pronounced as in experiments with higher burdens. In comparison with results obtained in experiments in which the plasma⁵⁹Fe-turnover was applied, even with an activity of 5 µCi radiostrontium per mouse, no deviation as against the untreated controls was detected.Dedicated to Prof. Dr. Hermann Muth, Homburg/Saar, on the occasion of his 65th birthday     

90Y-labeled monoclonal antibodies for cancer therapy

Monoclonal antibody 17-1A, which has specificity for colorectal carcinoma, was labeled with ⁹⁰Y (10–20% radiolabeling yield). Tissue distribution studies in tumor-bearing nude mice were carried out. ⁹⁰Y-labeled 17-1A showed good uptake in the SW 948 colon carcinoma cell line. However, ⁹⁰Y-labeled A5C3, a monoclonal antihepatitis virus antibody studied as a control, showed similar uptake in this tumor. Neither antibody was taken up well by a WM-9 melanoma. It is believed that the loss of specificity observed is due to the low specific activity of the ⁹⁰Y-labeled monoclonal antibody preparations used. This hypothesis is supported by radioimmunoassay data.     

Strukturveränderungen der Media der Kaninchenaorta nach lokaler Bestrahlung (90Sr-90Y)

Zusammenfassung Nach lokaler Bestrahlung von Kaninchenaorten mit einem ⁹⁰Sr-⁹⁰Y-Strahler von 3, 15 und 30 krad, wurde die Media in einem Zeitraum von 3 Tagen bis zu 8 Monaten nach der Bestrahlung untersucht. In der Aortenmedia kommt es zu einer Ablösung der elastischen Elemente von den glatten Muskelzellen, zu mottenfraßartigen Erscheinungen und schließlich zu einem vollständigen Untergang der elastischen Lamellen sowie zu einer Vakuolisierung der Muskelzellen mit nachfolgendem vakuolären Zerfall. Die Veränderungen der elastischen Fasern sind sowohl Folge einer direkten toxischen Schädigung als auch einer indirekten Schädigung durch den fehlenden Substanznachschub nach Untergang der Muskelzellen. Die in den Randpartien nach langer Zeit zu beobachtende Elasticahyperplasie geht mit einer Funktionszunahme der glatten Muskelzellen einher. Sie ist in gleicher Weise wie die Zunahme der kollagenen Fasern im Bestrahlungsgebiet als reaktives Ereignis anzusehen.     

Differentiation potential of rabbit CD90-positive cells sorted from adipose-derived stem cells in vitro

To investigate the differentiation potential of purified CD90⁺ cells sorted from adipose-derived stem cells (ADSCs), CD90⁺ cells were sorted from rabbit ADSCs using flow cytometry. Then, cell expansion of CD90⁺ cells and unsorted ADSCs was observed using an inverted microscope. Furthermore, cell surface markers including CD40, CD105, and CD90 on CD90⁺ cells and unsorted ADSCs were quantified using flow cytometry. Additionally, multi-lineage differentiation ability between CD90⁺ cells and unsorted ADSCs was compared, and expression of adipocyte-related genes PPAR-r and CEBPA as well as stem cell-related gene SOX2 in CD90⁺ cells and unsorted ADSCs was determined using real-time quantitative PCR. We found that CD90⁺ cells had a stronger cell proliferation ability than unsorted ADSCs. CD90⁺ cells showed a stronger ability of osteoblast and chondrocyte differentiation than unsorted ADSCs and CD90^? cells, whereas the adipose differentiation ability of CD90⁺ cells was similar to that of ADSCs and CD90^? cells. CD14, CD105, and CD90 on CD90⁺ cells were expressed more highly than those on ADSCs. Additionally, the mRNA expression level of SOX2 in CD90⁺ cells was significantly higher than that in ADSCs, whereas the expression of PPAR-r and CEBPA was markedly lower than that in ADSCs. These results suggested that the purified CD90⁺ cells sorted from ADSCs exhibit a stronger differentiation potential than the unsorted ADSCs.     

Anti-NSCLC activity in vitro of Hsp90N inhibitor KW-2478 and complex crystal structure determination of Hsp90N-KW-2478

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 ^N (Hsp90^N). Absence of complex crystal structure of Hsp90^N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90^N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, K_d, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90^N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC₅₀, 8.16 μM for A549; 14.29 μM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90^N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90^N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.     

Brassica napus hsp90 can autophosphorylate and phosphorylate other protein substrates

A Brassica napus cDNA encoding the 90 kDa heat shock protein, hsp90, was modified to add 6 histidines at the C-terminus and expressed in insect cells to prepare a recombinant histidine-tagged hsp90. The recombinant protein was purified over Ni²⁺-NTA agarose columns and its identity was confirmed by Western blotting, using a plant hsp90-specific antiserum. Incubation of purified hsp90 with [-³²P] ATP in the presence of Mn²⁺ resulted in its autophosphorylation on serine residues. The purified hsp90 could also phosphorylate other protein substrates such as histones and casein in the presence of Mn²⁺. Analysis of phosphorylated casein revealed that serine residues are phosphorylated by hsp90. This is the first demonstration that a cytosolic hsp90 homolog can phosphorylate other protein substrates.     

Optimisation of reconstruction,volumetry and dosimetry for 99mTc-SPECT and 90Y-PET images: Towards reliable dose-volume histograms for selective internal radiation therapy with 90Y-microspheres

PurposeIn Selective Internal Radiation Therapy (SIRT), ^99mTc-MAA SPECT images are commonly used to predict microspheres distribution but recent works used ⁹⁰Y-microspheres PET images. Nevertheless, evaluation of the predictive power of ^99mTc-MAA has been hampered by the lack of reliable comparisons between ^99mTc-SPECT and ⁹⁰Y-PET images. Our aim was to determine the “in situ” optimisation procedure in order to reliably compare ^99mTc-SPECT and ⁹⁰Y-PET images and achieve optimal personal dosimetry.MethodsWe acquired ^99mTc-SPECT/CT and ⁹⁰Y-PET/CT images of NEMA and Jaszczak phantoms. We found the best reconstruction parameters for quantification and for volume estimations. We determined adaptive threshold curves on the volumetric reconstruction. We copied the optimised volumes on the quantitative reconstruction, named here the “cross volumes” technique. Finally, we compared ^99mTc-SPECT and ⁹⁰Y-PET Dose Volume Histograms.ResultsOur “in situ” optimisation procedure decreased errors on volumes and quantification (from −44.2% and −15.8% to −3.4% and −3.28%, respectively, for the 26.5 mL PET phantom sphere). Moreover, ^99mTc-SPECT and ⁹⁰Y-PET DVHs were equivalent only after the optimisation procedure (difference in mean dose <5% for the three biggest spheres).ConclusionsThis work showed that a preliminary “in situ” phantom study was necessary to optimise volumes and quantification of ^99mTc-SPECT and ⁹⁰Y-PET images and allowed to achieve a reliable comparison between patient treatment planning and post implant dosimetry, notably by the use of the “cross volumes” technique. Methodology developed in this work will enable robust evaluations of the predictive power of ^99mTc-SPECT, as well as dose-response relationship and side effects in SIRT treatments.     

9OSr +90Y bremsstrahlung efficiency predicted for humans

Summary Bremsstrahlung x-rays are produced when energetic-particles are emitted and absorbed. Measurements of total-body bremsstrahlung efficiency (x-ray photon output per Ci⁹⁰Sr in the body, relative to that in water) have been made in the intact mouse, rat, rabbit, and dog sacrificed 2 weeks after the injection of⁹⁰Sr +⁸⁵Sr. Efficiencies were determined by a comparison of the bremsstrahlung output from⁹⁰Sr + its daughter⁹⁰Y and the gamma-ray emission of⁸⁵Sr. Results were checked by a-assay of the ashed animals. Bremsstrahlung efficiencies averaged 1.10 in a 0.04 kg mouse, 1.14 in a 0.13 kg rat, 1.23 in a 2.6 kg rabbit, and 1.32 in an 8.5 kg beagle. Extrapolating to a 70 kg human, a relative bremsstrahlung efficiency of about 1.4 is predicted. An estimate was made of the⁹⁰Sr body content in a former dial painter based on in vivo counting and a bremsstrahlung efficiency of 1.39 predicted for a 55 kg human female by these animal data. Our value of 1.42 ± 0.08 Ci⁹⁰Sr was in good agreement with corresponding results reported for this subject by 8 other laboratories.Supported by USERDA Contract E (11-1)-119     

Soil-to-grain transfer of fallout 90Sr for 28 winter wheat cultivars

In order to identify wheat cultivars with minimum soil-to-grain transfer of fallout ⁹⁰Sr, 28 winter wheat cultivars were investigated at three different sites with different soil types in Upper Bavaria. Each cultivar was grown on an area of 10 m² and harvested in August 1999. Mean soil-to-grain concentration ratios (C _r) were 0.151 ± 0.029, 0.205 ± 0.035 and 0.060 ± 0.012, respectively. The C _r values obtained varied by factors of up to 2.6 for the different cultivars at a given site, and by factors of up to 5.0 for the different sites and a given cultivar. Site-averaged normalized concentration ratios (SANC_r) ranged from 0.666 ± 0.062 to 1.503 ± 0.161. The cultivars Convent, Ludwig, and Semper, showed the lowest uptake of ⁹⁰Sr compared to the mean of all cultivars at each site. A cultivar that shows both minimum uptake of ⁹⁰Sr and ¹³⁷Cs could not be identified. The results suggest that ⁹⁰Sr rather than ¹³⁷Cs might be the limiting radionuclide concerning the use of contaminated land for wheat production. Thus, more efforts might be necessary identifying wheat cultivars with minimum ⁹⁰Sr uptake.     

Comparison of 90Y SIRT predicted and delivered absorbed doses using a PSF conversion method

PurposeThe aims of this study were to develop and apply a method to correct for the differences in partial volume effects of pre-therapy Technetium-99 m (^99mTc)-MAA SPECT and post-therapy Yttrium-90 (⁹⁰Y) bremsstrahlung SPECT imaging in selective internal radiation therapy, and to use this method to improve quantitative comparison of predicted and delivered ⁹⁰Y absorbed doses.MethodsThe spatial resolution of ^99mTc SPECT data was converted to that of ⁹⁰Y SPECT data using a function calculated from ^99mTc and ⁹⁰Y point spread functions. This resolution conversion method (RCM) was first applied to ^99mTc and ⁹⁰Y SPECT phantom data to validate the method, and then to clinical data to assess the power of ^99mTc SPECT imaging to predict the therapeutic absorbed dose.ResultsThe maximum difference between absorbed doses to phantom spheres was 178%. This was reduced to 27% after the RCM was applied.The clinical data demonstrated differences within 38% for mean absorbed doses delivered to the normal liver, which were reduced to 20% after application of the RCM. Analysis of clinical data showed that therapeutic absorbed doses delivered to tumours greater than 100 cm³ were predicted to within 52%, although there were differences of up to 210% for smaller tumours, even after the RCM was applied.ConclusionsThe RCM was successfully verified using phantom data. Analysis of the clinical data established that the ^99mTc pre-therapy imaging was predictive of the ⁹⁰Y absorbed dose to the normal liver to within 20%, but had poor predictability for tumours smaller than 100 cm³.     

Purification and characterization of porcine testis 90-kDa heat shock protein (HSP90) as a substrate for various protein kinases

We purified a large quantity of HSP90 from porcine testis by hydroxylapatite (HA-HSP90) and SDS-PAGE/electroelution (eluted-HSP90) to explore the molecular mechanism of HSP90 phosphorylation affecting its metabolism. The purified HSP90 was used as an antigen to raise polyclonal antibodies in rabbits. Immunoblot analysis revealed that most purified HSP90 was HSP90. Compared with the commercial anti-HSP90 antibody, the polyclonal antibody raised in this study could specifically detect the testis HSP90 and immunoprecipitate HSP90 from tissue homogenates or cell extracts. Incubation of the purified HSP90 or HSP90 immunoprecipitated from extracts of human A431 cells, Balb/c 3T3 fibroblasts, and porcine testis with [-³²P]ATP/Mg²⁺ resulted in phosphorylation of HSP90. However, the eluted-HSP90 lost its phosphorylation ability when incubated with [-³²P]ATP·Mg²⁺ alone but could be phosphorylated by various protein kinases, including PKA, CKII, kinase FA/GSK-3 , and AK. The order of phosphorylation of HSP90 by these kinases is PKA = CKII > AK >> kinase FA/GSK-3 .     

Comparison of the accumulation of 137Cs and 90Sr by six spring wheat varieties

The uptake of ¹³⁷Cs and ⁹⁰Sr by six varieties of spring wheat (Triticum aestivum) was compared in field trials on land contaminated by the Chernobyl accident. All the experimental varieties are officially adopted for agricultural use in Belarus and are used in large-scale production. Under identical conditions of nutrition, the productivity of the varieties varied significantly by a factor of 1.3. The extent of ¹³⁷Cs and ⁹⁰Sr accumulation by wheat grain, quantified as the concentration ratio, differed between the varieties by as much as a factor of 1.6, for both radionuclides. There was a significant linear positive correlation between the ⁹⁰Sr activity concentration in grain and straw, and the calcium concentration. The correlation between ¹³⁷Cs and potassium was not significant. The results suggest that certain varieties of spring wheat used in normal agricultural practice accumulate less ¹³⁷Cs and ⁹⁰Sr into grain than others. Some spring wheat varieties accumulated relatively less ¹³⁷Cs, but did not accumulate less ⁹⁰Sr. One variety, Quattro, had a significantly lower uptake of both ⁹⁰Sr (for grain) and ¹³⁷Cs (for both grain and straw) than that of the other varieties tested. The reduction efficiency achieved by the use of these varieties, however, is not as high as that achieved by soil amelioration techniques in the past. Nevertheless, since there are no additional costs or production losses associated with these varieties, their use in the contaminated areas is worth considering as a simple, practical, and effective contribution to reducing the uptake of both ⁹⁰Sr and ¹³⁷Cs and allowing farmers to produce food-grade grain.     

3D image-based dosimetry for Yttrium-90 radioembolization of hepatocellular carcinoma: Impact of imaging method on absorbed dose estimates

BackgroundTo improve therapy outcome of Yttrium-90 selective internal radiation therapy (⁹⁰Y SIRT), patient-specific post-therapeutic dosimetry is required. For this purpose, various dosimetric approaches based on different available imaging data have been reported. The aim of this work was to compare post-therapeutic 3D absorbed dose images using Technetium-99m (^99mTc) MAA SPECT/CT, Yttrium-90 (⁹⁰Y) bremsstrahlung (BRS) SPECT/CT, and ⁹⁰Y PET/CT.MethodsTen SIRTs of nine patients with unresectable hepatocellular carcinoma (HCC) were investigated. The ^99mTc SPECT/CT data, obtained from ^99mTc-MAA-based treatment simulation prior to ⁹⁰Y SIRT, were scaled with the administered ⁹⁰Y therapy activity. 3D absorbed dose images were generated by dose kernel convolution with scaled ^99mTc/⁹⁰Y SPECT/CT, ⁹⁰Y BRS SPECT/CT, and ⁹⁰Y PET/CT data of each patient. Absorbed dose estimates in tumor and healthy liver tissue obtained using the two SPECT/CT methods were compared against ⁹⁰Y PET/CT.ResultsThe percentage deviation of tumor absorbed dose estimates from ⁹⁰Y PET/CT values was on average −2 ± 18% for scaled ^99mTc/⁹⁰Y SPECT/CT, whereas estimates from ⁹⁰Y BRS SPECT/CT differed on average by −50 ± 13%. For healthy liver absorbed dose estimates, all three imaging methods revealed comparable values.ConclusionThe quantification capabilities of the imaging data influence ⁹⁰Y SIRT tumor dosimetry, while healthy liver absorbed dose values were comparable for all investigated imaging data. When no ⁹⁰Y PET/CT image data are available, the proposed scaled ^99mTc/⁹⁰Y SPECT/CT dosimetry method was found to be more appropriate for HCC tumor dosimetry than ⁹⁰Y BRS SPECT/CT based dosimetry.     

Concentration of Strontium-90 at Selected Hot Spots in Japan

This study is dedicated to the environmental monitoring of radionuclides released in the course of the Fukushima nuclear accident. The activity concentrations of β⁻ -emitting ⁹⁰Sr and β⁻/γ-emitting ¹³⁴Cs and ¹³⁷Cs from several hot spots in Japan were determined in soil and vegetation samples. The ⁹⁰Sr contamination levels of the samples were relatively low and did not exceed the Bq⋅g⁻¹ range. They were up four orders of magnitude lower than the respective ¹³⁷Cs levels. This study, therefore, experimentally confirms previous predictions indicating a low release of ⁹⁰Sr from the Fukushima reactors, due to its low volatility. The radiocesium contamination could be clearly attributed to the Fukushima nuclear accident via its activity ratio fingerprint (¹³⁴Cs/¹³⁷Cs). Although the correlation between ⁹⁰Sr and ¹³⁷Cs is relatively weak, the data set suggests an intrinsic coexistence of both radionuclides in the contaminations caused by the Fukushima nuclear accident. This observation is of great importance not only for remediation campaigns but also for the current food monitoring campaigns, which currently rely on the assumption that the activity concentrations of β⁻-emitting ⁹⁰Sr (which is relatively laborious to determine) is not higher than 10% of the level of γ-emitting ¹³⁷Cs (which can be measured quickly). This assumption could be confirmed for the samples investigated herein.     

Therapeutic Efficacy of C-Kit-Targeted Radioimmunotherapy Using 90Y-Labeled Anti-C-Kit Antibodies in a Mouse Model of Small Cell Lung Cancer

Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains poor. Therefore, the development of more effective therapy is needed. We previously reported that high levels of an anti-c-kit antibody (12A8) accumulated in SCLC xenografts. In the present study, we evaluated the efficacy of two antibodies (12A8 and 67A2) for radioimmunotherapy (RIT) of an SCLC mouse model by labeling with the ⁹⁰Y isotope.

Methods

¹¹¹In- or ¹²⁵I-labeled antibodies were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays in c-kit-expressing SY cells and in vivo by biodistribution in SY-bearing mice. Therapeutic efficacy of ⁹⁰Y-labeled antibodies was evaluated in SY-bearing mice upto day 28 and histological analysis was conducted at day 7.

Results

[¹¹¹In]12A8 and [¹¹¹In]67A2 specifically bound to SY cells with high affinity (8.0 and 1.9 nM, respectively). 67A2 was internalized similar to 12A8. High levels of [¹¹¹In]12A8 and [¹¹¹In]67A2 accumulated in tumors, but not in major organs. [¹¹¹In]67A2 uptake by the tumor was 1.7 times higher than for [¹¹¹In]12A8. [⁹⁰Y]12A8, but not [⁹⁰Y]67A2, suppressed tumor growth in a dose-dependent manner. Tumors treated with 3.7 MBq of [⁹⁰Y]12A8, and 1.85 and 3.7 MBq of [⁹⁰Y]67A2 (absorbed doses were 21.0, 18.0 and 35.9 Gy, respectively) almost completely disappeared approximately 2 weeks after injection, and regrowth was not observed except for in one mouse treated with 1.85 MBq [⁹⁰Y]67A2. The area of necrosis and fibrosis increased depending on the RIT effect. Apoptotic cell numbers increased with increased doses of [⁹⁰Y]12A8, whereas no dose-dependent increase was observed following [⁹⁰Y]67A2 treatment. Body weight was temporarily reduced but all mice tolerated the RIT experiments well.

Conclusion

Treatment with [⁹⁰Y]12A8 and [⁹⁰Y]67A2 achieved a complete therapeutic response when SY tumors received an absorbed dose greater than 18 Gy and thus are promising RIT agents for metastatic SCLC cells at distant sites.     

Biokinetics of <Superscript>90</Superscript>Sr after chronic ingestion in a juvenile and adult mouse model

The aim of our study was to define the biokinetics of ⁹⁰Sr after chronic contamination by ingestion using a juvenile and adult murine model. Animals ingested ⁹⁰Sr by drinking water containing 20 kBq l⁻¹ of ⁹⁰Sr. For the juvenile model, parents received ⁹⁰Sr before mating and their offspring were killed between birth and 20 weeks of ingestion. For the adult model, ⁹⁰Sr ingestion started at 9 weeks of age and they were killed after different ingestion periods up to 20 weeks. The body weight, food and water consumption of the animals were monitored on a weekly basis. Before killing and sampling of organs, animals were put in metabolic cages. ⁹⁰Sr in organs and excreta was determined by liquid scintillation β counting. Highest ⁹⁰Sr contents were found in bones and were generally higher in females than in males, and ⁹⁰Sr retention varied according to the skeletal sites. An accumulation of ⁹⁰Sr in the bones was observed over time for both models, with a plateau level at adult age for the juvenile model. The highest rate of ⁹⁰Sr accumulation in bones was observed in early life of offspring, i.e. before the age of 6 weeks. With the exception of the digestive tract, ⁹⁰Sr was below the detection limit in all other organs sampled. Overall, our results confirm that ⁹⁰Sr mainly accumulates in bones. Furthermore, our results indicate that there are gender- and age-dependent differences in the distribution of ⁹⁰Sr after low-dose chronic ingestion in the mouse model. These results provide the basis for future studies on possible non-cancerous effects during chronic, long-term exposure to ⁹⁰Sr through ingestion in a mouse model, especially on the immune and hematopoietic systems.     

FS36作为新型人源Hsp90抑制剂的发现

热休克蛋白90(Hsp90)通过对几百种蛋白质底物(客户蛋白质)进行合理的折叠、成熟其构象并且激活,在肿瘤细胞的生长和繁殖中发挥重要作用．因此,Hsp90成为非常有吸引力、有前途的抗肿瘤药物靶点,并且超过20种抑制剂已经进入临床实验阶段．我们在这里设计并合成了一个小分子抑制剂：FS36．收集了Hsp90^N-FS36复合物晶体结构的X射线衍射实验数据．高分辨率X射线晶体结构表明,FS36在ATP结合位点上与Hsp90^N相互作用,并且FS36可能替代核苷酸与Hsp90^N结合．FS36和Hsp90^N的复合物晶体结构和相互作用为后期设计和优化新型抗肿瘤药物奠定基础．     

Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

Purpose

Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (⁹⁰Y) and lutetium-177 (¹⁷⁷Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas ⁹⁰Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with ¹⁷⁷Lu. We therefore compared the therapeutic potential of targeting either ⁹⁰Y or ¹⁷⁷Lu to human B-cell lymphoma xenografts in mice.

Methods

Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an ⁹⁰Y- or ¹⁷⁷Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent.

Results

The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for ⁹⁰Y (1.3 Gy/MBq) as for ¹⁷⁷Lu (0.6 Gy/MBq). More importantly, therapy with ⁹⁰Y-DOTA-biotin was dramatically more effective than with ¹⁷⁷Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq ⁹⁰Y, whereas 0% were cured using identical amounts of ¹⁷⁷Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with ⁹⁰Y-PRIT and 0% cured with ¹⁷⁷Lu-PRIT. Toxicities were comparable with both isotopes.

Conclusion

⁹⁰Y was therapeutically superior to ¹⁷⁷Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models.     

Plutonium,241Am,90sr,and137cs concentrations in some antarctic matrices

A radioecological survey in Antarctica shows that the^239+240Pu,²³⁸Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs activities were detectable in nearly all the samples. The activity level of^239+240Pu,²⁴¹Am, and¹³⁷Cs in antarctic sediments was about 5–20 times lower than in the northern Adriatic Sea sediments, but the²³⁸Pu activities were relatively high. It was interesting to note that the⁹⁰Sr concentrations in all the sediments tended to be low, which could be the result of the easier exchangeable behavior of⁹⁰Sr in water. High concentrations were detected in mosses and lichens and their activity levels were comparable to those in central Italy. The radionuclide ratio analyses show that the major part of^239+240Pu,²⁴¹Am,⁹⁰Sr, and¹³⁷Cs was a result of nuclear weapon tests. The higher²⁴¹Am/^239+240Pu ratio was observed and it could perhaps be the result of fallout of nuclear weapon tests prior to 1962. The²³⁸Pu/^239+240Pu ratio in the antarctic matrices was about seven times higher than in the Northern hemisphere and it could be inferred that the major part of²³⁸Pu was originating from the SNAP-9A satellite accident.