Selection of radiolabeled gastrin analogs for peptide receptor-targeted radionuclide therapy.

The gastrin/cholecystokinin-2 (CCK-2) receptor has been identified as a possible target for peptide receptor radionuclide imaging and therapy. Several radiolabeled peptides binding to this receptor have been explored in animal models and clinical trials but either low tumor uptake or high renal retention has been found. The aim of this study was to identify a peptide with improved tumor-to-kidney pharmacodynamics when compared with current candidates. METHODS: A small peptide-chelator library of 34 compounds based on the C-terminal sequences of CCK-8 or minigastrin was constructed. The peptides were radiolabeled with (111)In with high labeling efficiency (>90%), as determined by high-performance liquid chromatographic analysis. The labeled peptides were screened by assessing tumor and kidney uptake in pancreatic xenograft nude mouse models, including AR42J. An extensive biodistribution analysis was performed on the lead candidate from the library. RESULTS: Minigastrin analogs containing a pentaglutamate sequence showed the highest tumor uptake but very high renal retention. CCK analogs showed the lowest tumor and renal uptake. Deletion of the pentaglutamate sequence in the gastrin analogs lowered the tumor uptake by a factor of 3 but decreased the kidney uptake by a factor of 20. Insertion of histidine residues in the sequence reduced kidney uptake by a further factor of almost 2-fold. In AR42J tumor-bearing mice, the peptide with the sequence DOTA-HHEAYGWMDF-NH(2) (DOTA is tetraazacyclododecane tetraacetic acid) showed the highest tumor-to-kidney ratio of all peptides studied, with saturable uptake in target organs and low uptake by nontarget tissues other than the kidney. CONCLUSION: This peptide is a worthwhile candidate for clinical studies to determine whether it is suitable for use in peptide receptor-targeted radionuclide therapy.     

Preclinical and initial clinical evaluation of 111In-labeled nonsulfated CCK8 analog: a peptide for CCK-B receptor-targeted scintigraphy and radionuclide therapy.

The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types. METHODS: The aim of this study was to evaluate in vitro and in vivo whether 111In-labeled CCK-B receptor-specific CCK8 analog [D-Asp26,Nle28,31]CCK26-33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA0]CCK8 and tetraazacyclododecanetetraacetic acid [DOTA0]CCK8 analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range. RESULTS: In vitro, [111In-DOTA0]CCK8 showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [111In-DOTA0]CCK8 and (125I)I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [111In-DOTA0]CCK8, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [111In-DOTA0]CCK8 with the radioiodinated nonsulfated CCK10 analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [111In-DOTA0]CCK8 than for 125I-CCK10, analogous to the findings with radioiodinated and 111In-labeled octreotide. The study in humans with [111In-DTPA0]CCK8 showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection. CONCLUSION: [111In-DOTA0]CCK8 is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.     

钠碘转运体基因介导的肿瘤放射性核素治疗研究

钠碘转运体(NKS)是一种跨膜糖蛋白,介导碘的主动摄取,使得放射性碘用于治疗不摄碘的肿瘤成为可能。目前NIS基因已被成功转入多种肿瘤并表达出有功能的NIS蛋白,但治疗的效果并不令人满意。为此,研究者们应用不同的方法进行了改进,并收到较好的效果。     

Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy.

The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors. METHODS: [DTPA-Pro(1),Tyr(4)]BN (A), [DOTA-Pro(1),Tyr(4)]BN (B), [DTPA-epsilon-Lys(3),Tyr(4)]BN (C), and [DOTA-epsilon-Lys(3),Tyr(4)]BN (D) (where DOTA is dodecanetetraacetic acid) were synthesized and studied for competition with binding of [(125)I-Tyr(4)]BN to the GRP receptor. The (111)In-labeled BN analogs were studied in vitro for binding and internalization by GRP receptor-expressing CA20948 and AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats. Specific tissue binding was tested by coinjection of 0.1 mg [Tyr(4)]BN. RESULTS: All BN analogs competitively inhibited the binding of [(125)I-Tyr(4)]BN to the GRP receptor with 50% inhibitory concentration values in the range of 2-9 nmol/L. All (111)In-labeled analogs showed high and specific time- and temperature-dependent binding and internalization by CA20948 and AR42J cells. In in vivo studies, high and specific binding was found in GRP receptor-positive tissues such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for A-D, respectively). In a rat model, the AR42J tumor could clearly be visualized by scintigraphy using [(111)In-DTPA-Pro(1),Tyr(4)]BN as the radioligand. Although [(111)In-DOTA-Pro(1),Tyr(4)]BN showed the highest uptake of radioactivity in GRP receptor-positive tissues as well as higher target-to-blood ratios, [(111)In-DTPA-Pro(1),Tyr(4)]BN was easier to handle and is more practical to use. Therefore, we decided to start phase I studies with this DTPA-conjugated radioligand. CONCLUSION: [(111)In-DTPA-Pro(1),Tyr(4)]BN is a promising radioligand for scintigraphy of GRP receptor-expressing tumors. We are currently performing a phase I study on patients with invasive prostate carcinoma.     

Optimizing MIBG therapy of neuroendocrine tumors: preclinical evidence of dose maximization and synergy

[(131)I]meta-Iodobenzylguanidine ([(131)I]MIBG) has been used for the therapy of tumors of neuroectodermal origin since the 1980s. Its role in the management of these malignancies remains controversial because of the large variation in response rates. Appreciation of the mode of conveyance of [(131)I]MIBG via the noradrenaline transporter into malignant cells and of factors that influence the activity of the uptake mechanism has indicated various ways in which the effectiveness of this type of targeted radiotherapy may be improved. Experimental observations indicate that radiolabeling of MIBG to high specific activity reduced the amount of cold competitor, thereby increasing tumor dose and minimizing pressor effects. We observed supra-additive tumor cell kill and inhibition of tumor growth following combined topotecan and [(131)I]MIBG treatment. The improved efficacy is related to topotecan's increased disruption of DNA repair. Radiation damage to targeted tumors may also be enhanced by the use of the alpha-particle emitter [(211)At]astatine rather than (131)I as radiolabel. Furthermore, recent experimental findings indicate that [(123)I]MIBG may have therapeutic potential over and above its utility as an imaging agent. It has recently been demonstrated that potent cytotoxic bystander effects were induced by the intracellular concentration of [(131)I]MIBG, [(123)I]MIBG or meta-[(211)At]astatobenzylguanidine. Identification of the nature of bystander factors could be exploited to maximize the specificity and potency of MIBG-targeted radiotherapy. By employing a range of strategies, there are good prospects for the improvement of the [(131)I]MIBG therapy of neuroectodermal tumors.     

胃肠道间质瘤的临床及影像学表现

目的：提高对胃肠道间质瘤(GISTs)的认识和影像学诊断水平。方法：回顾性分析31例GISTs的临床及影像学资料。结果：病灶分布于胃22例，小肠7例，胃肠道外2例；肿瘤平均直径6．5cm。病理分型：良性6例，交界性7例，恶性18例。临床表现多为腹部不适(18／28)、消化道出血(13／28)、腹痛(11／28)和消瘦(5／28)。主要影像学表现为粘膜下富血供肿块，境界清晰光整，外生性为主，内部出血、坏死、囊变明显，局部淋巴结无转移。结论：GISTs是一类潜在恶性的肿瘤，应手术完整切除。其影像学表现具有一定特征，但不能定性，确诊需依赖免疫组化和电镜检查。     

Use of the rat pancreatic CA20948 cell line for the comparison of radiolabelled peptides for receptor-targeted scintigraphy and radionuclide therapy

We have evaluated the usefulness of the rat pancreatic CA20948 tumour as an in vitro cell culture model and as an in vivo model in Lewis rats comparing different radiolabelled peptides for receptor-targeted scintigraphy. In vitro the receptor-specific uptake and internalization of different radiolabelled analogues of somatostatin, bombesin, substance P and cholecystokinin were demonstrated. Analogues were selected based on high-affinity binding to their respective receptors. Their uptake and internalization in CA20948 cells were compared to these processes in AR42J cells, a well-known rat pancreatic tumour cell line used for peptide-receptor studies. Receptor-specific internalization, which was blocked by excess unlabelled peptide analogue, was found in both the CA20948 and AR42J cells for all the peptide analogues tested. This indicates specific receptor expression for all the different peptides, making these cells highly suitable for peptide studies. Internalization of the different peptides was as follows, in increasing order: [111In-DOTA0]CCK < [111In-DTPA0,Arg1]substance P < [111In-DTPA0]octreotide < [111In-DTPA0,Pro1,Tyr4]bombesin. Internalization appeared to be time and temperature dependent. In accordance with the in vitro experiments, receptor-specific uptake of all the peptide analogues was also found in vivo in the solid CA20948 tumour. The in vivo tumour uptake of [111n-DTPA0]octreotide was the highest amongst the peptides tested, the order of tumour uptake being [111In-DTPA0]octreotide >[111In-DTPA0,Pro1,Tyr4]bombesin >[111In-DTPA0,Arg1]substance P > [111In-DOTA0]CCK, which is different from the in vitro findings and points to either different receptor numbers on the tumour cells for the different peptide receptors in vitro and in vivo or to differences between the peptides with regard to metabolic stability. It can be concluded that the CA20948 tumour, both in cell culture and as a solid tumour in rats, is a very useful model for peptide receptor scintigraphy and radionuclide therapy studies.     

Preliminary evaluation of <Superscript>177</Superscript>Lu-labeled knottin peptides for integrin receptor-targeted radionuclide therapy

Purpose  

Cystine knot peptides (knottins) 2.5D and 2.5F were recently engineered to bind integrin receptors with high affinity and specificity. These receptors are overexpressed on the surface of a variety of malignant human tumor cells and tumor neovasculature. In this study, 2.5D and 2.5F were labeled with a therapeutic radionuclide, ¹⁷⁷Lu, and the resulting radiopeptides were then evaluated as potential radiotherapeutic agents in a murine model of human glioma xenografts.     

Imaging of carcinoid tumors: spectrum of findings with pathologic and clinical correlation

Carcinoid tumors are primary malignant neoplasms that arise from neuroendocrine cells. These cells are located throughout the body, resulting in many possible locations for the development of carcinoid tumor. The most common primary location is the gastrointestinal tract, followed by respiratory and thymic carcinoids. The presentations of these tumors are variable depending on their location, aggressiveness, production of functional peptides, and tendency to invade or metastasize. Carcinoid tumors can be imaged by various modalities including gastrointestinal studies, ultrasound, computed tomography, and magnetic resonance imaging as well as nuclear medicine studies (radioactive octreotide). In this review, we illustrate the spectrum of imaging features of carcinoid tumors in various locations of the human body.     

Late results after resection of benign hepatic tumors: clinical and radiological findings

The purpose of our work was to provide data on the recurrence of resected benign hepatic lesions and to evaluate the value of follow-up examinations in this group of patients. From August to October 1993, 75 patients who had been admitted for liver surgery for benign tumors between 1975 and 1993 were controlled by physical examinations, serological tests, US, and, in the case of equivocal US findings, by CT. The histological diagnoses of the operative specimen included hydatidosis in 43 patients, focal nodular hyperplasia (FNH) in 12 patients, liver cell adenoma in 8 patients, cavernous hemangioma in 8 patients, and congenital cyst in 4 patients. Hepatic scars were observed in 36 of the 75 patients. Four cases of intrahepatic recurrence and 1 case of intraperitoneal spread were observed in the 42 patients with recent hydatosis. Long-term postoperative controls (specific serological tests, US) are necessary in the management of patients with hydatid disease. Follow-up examinations are not indicated in asymptomatic patients who have been operated on for FNH, hemangioma, or congenital cysts. Received 8 November 1995; Revision received 27 March 1996; Accepted 2 July 1996     

177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

Purpose

We evaluated the activity and safety profile of ¹⁷⁷Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced, well-differentiated (G1-G2) gastrointestinal neuroendocrine tumors (GI-NETs).

Methods

Forty-three patients with radiological tumor progression at baseline and a positive Octreoscan® completed the treatment with Lu-PRRT, resulting in the cumulative activity of 18.5 or 27.8 GBq in five cycles. Total activity was scheduled on the basis of kidney function or bone marrow reserve.

Results

Twenty-five (58 %) patients were treated with a “standard” Lu-PRRT full dosage (FD) of 25.7 GBq (range 22.2-27.8), while the remaining 18 patients (42 %) who, at enrolment, showed a higher probability of developing kidney or bone marrow toxicity received a reduced dosage (RD) of 18.4 GBq (range 14.4-20.4). According to SWOG criteria, the overall response was complete response (CR) in (7 %) cases and stable disease (SD) in 33 (77 %), with a disease control rate (DCR) of 84 %. Median response duration was 25 months (range 7-50). Median progression-free survival (PFS) was 36 months (95 % CI 24-nr), and median overall survival (OS) has not yet been reached. Remarkably, none of the patients, including those at a higher risk of toxicity, showed side-effects after either dosage of Lu-PRRT.

Conclusion

Lu-PRRT was shown to be an effective therapeutic option in our patients with advanced progressive GI-NETs, showing an 84 % DCR (95 % CI 73-95) that lasted for 25 months and a PFS of 36 months. Both activities of 27.8 GBq and 18.5 GBq proved safe and effective in all patients, including those with a higher probability of developing kidney or bone marrow toxicity.     

Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy.

Therapeutic options in patients with advanced-stage gastroenteropancreatic (GEP) neuroendocrine tumors are limited. We compared the efficacy of radionuclide therapy with 111In-pentetreotide and 131I-metaiodobenzylguanidine (MIBG) in 20 patients (group A) with the outcome of similar patients who could not be treated for nonmedical reasons (group B, n = 12). The intent was to treat all patients because of uncontrolled tumor disease (n = 21), contraindication to chemotherapy or surgery (n = 7), or uncontrolled and badly tolerated clinical symptoms (n = 4). METHODS: Group A patients received 3 monthly administrations of 3.7-7.4 GBq of 131I-MIBG (n = 5) or 7 GBq of 111In-pentetreotide (n = 15), according to the best tracer uptake. Clinical evaluation, biologic tests, and conventional imaging were performed at 3, 6, 12, 18, and 24 mo. Therapy was considered beneficial if clinical status improved, laboratory tests for secreting tumors improved by >20%, tumor progression was halted, the size of the most significant localization had decreased by >25%, and the dosage of analgesic and cold somatostatin therapy could be lowered. Pejorative events were defined as side effects due to therapy, relapse in clinical symptoms, tumor progression, tumor laboratory marker increase, and death. RESULTS: The overall survival rate at 3 mo was significantly higher in group A (P = 0.05). Radionuclide therapy was beneficial in 14 patients (73% of group A), with only 1 significant side effect. The average time before relapse was 16.1 +/- 7.8 mo. The overall Kaplan-Meier survival rate and cumulative progression-free and cumulative event-free survival rates during the first 15 mo were significantly higher in patients receiving radionuclide therapy (P = 0.019, P = 0.024, and P = 0.019, respectively). CONCLUSION: Radionuclide therapy is feasible and safe and significantly defers the occurrence of fatal and nonfatal events in patients clinically uncontrolled by conventional therapy.     

乳腺叶状肿瘤的MRI表现及临床病理学分析

目的:分析乳腺叶状肿瘤(phyllodes tumors,PTs)的MRI表现,以提高MRI的诊断价值。方法:回顾性分析8例PTs患者的临床及影像资料,包括肿瘤在T1WI、STIR序列上的信号强度,肿瘤大小、形状、边缘、内部强化方式、早期强化率、时间-信号强度曲线(time-signal intensity curve,TIC)类型及ADC值;比较PTs与正常腺体ADC值的差异。结果:8例乳腺PTs中,3例良性,4例交界性,1例恶性。MRI平扫T1WI呈等及较低信号,STIR呈高信号,3例肿瘤内见低信号未强化分隔,6例见裂隙状高信号;最大径线2.4~7.5cm;2例呈圆形、类圆形,6例呈分叶状;8例边缘均较清晰;增强扫描病灶均呈不均匀强化;7例PTs早期强化率大于100%,1例50%且100%;TIC类型1例为流入型,5例为平台型,2例为廓清型。DWI病灶均呈高信号,且ADC值低于正常腺体,PTs平均ADC值为(1.30±0.25)×10-3 mm2/s,正常腺体ADC值为(1.64±0.12)×10-3 mm2/s,二者差异有统计学意义(t=3.375,P0.05)。结论:乳腺PTs的MRI征象具有一定的特征性,结合其临床特点综合分析,可提高其术前诊断准确率。     

术中125I粒子植入治疗肿瘤的临床应用

目的 探讨在手术中永久性植入125I粒子治疗脑瘤、肝癌、胆管癌、肺癌、直肠癌、前列腺癌及恶性畸胎瘤临床应用的安全性及疗效.方法 回顾性分析38例经穿刺活检、组织学或细胞学检查确诊的肿瘤患者,采用治疗计划系统(TPS)重建肿瘤的三维图像,计算出粒子植入的数量和剂量分布曲线,125I粒子治疗肿瘤处方剂量为60～120 Gy,每例植入粒子6～40颗,中位粒子数为23颗.结果 随访12个月,肿瘤完全缓解9例,部分缓解24例,无变化5例.12个月总有效率为86.8%.结论 术中植入125I粒子治疗肿瘤是一种安全、有效的方法.