177Lu-DOTA(0),Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy

Receptor-targeted scintigraphy using radiolabeled somatostatin analogs such as octreotate is being used with great success to demonstrate the in vivo presence of somatostatin receptors on various tumors. A new and promising application for these analogs is radionuclide therapy. Radionuclides suitable for this application include the Auger electron-emitter (111)In and the beta-emitters (90)Y (high energy) and (177)Lu (low energy). We investigated [DOTA(0),Tyr(3)]octreotate, labeled with the lanthanide (177)Lu, in biodistribution and radionuclide therapy experiments using male Lewis rats bearing the somatostatin receptor-positive rat CA20948 pancreatic tumor. Biodistribution studies in Lewis rats showed the highest uptake in the rat pancreatic CA20948 tumor and sst(2)-positive organs, which include the adrenals, pituitary and pancreas, of [(177)Lu-DOTA(0),Tyr(3)]octreotate in comparison with (88)Y- and (111)In-labeled analogs. Kidney uptake of [(177)Lu-DOTA(0),Tyr(3)]octreotate could be reduced by approximately 40% by co-injection of 400 mg/kg D-lysine. In radionuclide therapy studies, a 100% cure rate was achieved in the groups of rats bearing small (< or =1 cm(2)) CA20948 tumors after 2 doses of 277.5 MBq or after a single dose of 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate. A cure rate of 75% was achieved after a single administration of 277.5 MBq. In rats bearing larger (> or =1 cm(2)) tumors, 40% and 50% cure rates were achieved in the groups that received 1 or 2 277.5 MBq injections of [(177)Lu-DOTA(0),Tyr(3)]octreotate, respectively. After therapy with [(177)Lu-DOTA(0),Tyr(3)]octreotide in rats bearing small tumors, these data were 40% cure after 1 injection with 277.5 MBq and 60% cure after 2 repeated injections. In conclusion, [(177)Lu-DOTA(0),Tyr(3)]octreotate has demonstrated excellent results in radionuclide therapy studies in rats, especially in animals bearing smaller tumors. This candidate molecule shows great promise for radionuclide therapy in patients with sst(2)-expressing tumors.     

Tyr3-octreotide and Tyr3-octreotate radiolabeled with 177Lu or 90Y: peptide receptor radionuclide therapy results in vitro

Somatostatin analogs promising for peptide receptor scintigraphy (PRS) and peptide receptor radionuclide therapy (PRRT) are D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol) (Tyr 3-octreotide) and D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (tyr3-octreotate). For radiotherapeutic applications these peptides are being labeled with the beta(-) particle emitters 177Lu or 90Y. We evaluated the therapeutic effects of these analogs chelated with tetra-azacyclododecatatro-acetic acid (DOTA) and labeled with 90Y or 177Lu in an in vitro colony-forming assay using the rat pancreatic tumor cell line CA20948. Furthermore, we investigated the effects of incubation time, radiation dose, and specific activity of [177Lu-DOTA]-D-Phe1-c (Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr (177Lu-octreotate). 177Lu-octreotate could reduce tumor growth to 100% cell kill and effects were dependent on radiation dose, incubation time, and specific activity used. Similar concentrations of 177Lu-DOTA, which is not bound to the cells, had a less pronounced effect on the tumor cell survival. Both tyr3-octreotide and tyr3-octreotate labeled with either 177Lu or 90Y, using DOTA as chelator, were able to control tumor growth in a dose-dependent manner. In all concentrations used radiolabeled tyr3-octreotate had a higher tumor kill compared to radiolabeled tyr3-octreotide, labeled with 177Lu or 90Y. This is in accordance with the higher affinity of tyr3-octreotate for the subtype 2 (sst2)-receptor compared to tyr3-octreotide, leading to a higher amount of cell-associated radioactivity, resulting in a significantly higher tumor radiation dose. In conclusion, tyr3-octreotate labeled with 177Lu or 90Y is the most promising analog for PRRT.     

TRAIL receptor-targeted therapy

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines. Based on its ability to induce apoptosis selectively in a wide variety of cancer cell lines and human tumor xenografts, TRAIL has been in drug development as a potential biological agent for cancer therapy. A variety of chemotherapy agents have been shown to enhance the cytotoxic effects of TRAIL. The potential benefits of TRAIL as an anticancer therapy have been further indicated by its ability to enhance the efficacy of radiotherapy. Preclinical studies have shown the potential use of agonistic monoclonal antibodies that selectively bind TRAIL death receptors for cancer therapy. This review provides an overview of TRAIL receptor-mediated apoptosis of tumor cells, with TRAIL or agonistic monoclonal antibodies only or with chemotherapy drugs. Treatment of tumor xenografts with these ligands, alone or in combination with chemotherapy or radiation, are discussed along with preliminary information about early clinical trials. Additional clinical trials with TRAIL receptor ligands in combination treatment regimens are required to determine their potential for targeted therapy of cancer.     

Epidermal growth factor receptor-targeted therapy for pancreatic cancer

Clinical and experimental work supports the view that the epidermal growth factor receptor (EGFR) is a relevant target for cancer therapy. Expression of EGFR is exaggerated in pancreatic adenocarcinoma and activation of EGFR appears to have an important role in the growth and differentiation of this and other types of cancers. EGFR-targeted therapeutic approaches have shown clinical activity in advanced human cancers for which chemotherapy over the last 30 years has sustained a mere palliative role at best. Therefore, the need remains for novel anti-cancer therapies that effectively and specifically target epithelial tumor cells while minimizing the toxic side-effects commonly associated with cytotoxic conventional therapies. Agents capable of inhibiting EGFR activity with resultant inhibition of cell proliferation and angiogenesis have significant potential as chemotherapeutic agents for the treatment of pancreatic adenocarcinomas as well as multiple other malignancies.     

Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers for somatostatin receptor-targeted scintigraphy and radionuclide therapy

We have evaluated the potential usefulness of radiolabelled [DTPA⁰,Tyr³]octreotide and [DOTA⁰,Tyr³]octreotide as radiopharmaceuticals for somatostatin receptor–targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [¹¹¹In-DTPA⁰] octreotide. Comparing different peptide–chelator constructs, [DTPA⁰,Tyr³]octreotide and [DOTA⁰, Tyr³]octreotide were found to have a higher affinity than [DTPA⁰]octreotide for subtype 2 somatostatin receptors (sst₂) in mouse AtT20 pituitary tumour cell membranes (all IC₅₀ values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor-bearing Lewis rats revealed a significantly higher uptake of both ¹¹¹In-labelled [DOTA⁰,Tyr³]octreotide and [DTPA⁰,Tyr³]octreotide in sst₂-expressing tissues than after injection of [¹¹¹In-DTPA⁰]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of ¹¹¹In-labelled [DTPA⁰]octreotide, [DTPA⁰,Tyr³]octreotide and [DOTA⁰,Tyr³]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre-treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst₂. Comparing different radionuclides, [⁹⁰Y-DOTA⁰,Tyr³]octreotide had the highest uptake in sst₂-positive organs, followed by the [¹¹¹In-DOTA⁰,Tyr³]octreotide, whereas [DOTA⁰, ¹²⁵I-Try³]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of ¹¹¹In-labelled [DTPA⁰]octreotide, [DTPA⁰, Tyr³]octreotide and [DOTA⁰,Tyr³]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg d-lysine, whereas radioactivity in blood, pancreas and adrenals was not affected. Int. J. Cancer 75:406–411, 1998. © 1998 Wiley-Liss, Inc.     

Peptide receptor radionuclide therapy for metastatic paragangliomas

There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with ¹⁷⁷Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16–47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0–78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.     

Radiolabeled immunoglobulin therapy in patients with Hodgkin's disease

Translational research supports the use of radiolabeled antiferritin for recurrent Hodgkin's disease. A 60% tumor response rate is obtained after treatment of out-patients with polyclonal radiolabeled antiferritin. Hodgkin's disease masses shrink after radiolabeled antiferritin treatment due to the radiation delivered by the radioimmunoconjugate. Unlabeled antiferritin does not cause tumor shrinkage. Hodgkin's disease provides unique opportunities for the development and optimization of radiolabeled immunoglobulin therapy for other malignancies as well. Radiolabeled Immunoglobulin Therapy is a useful addition to the cancer treatment armamentarium due to its high therapeutic ratio: high tumor response rates with side effects limited to hematopoetic tissues.     

Treatment planning for molecular targeted radionuclide therapy

Molecular targeted radionuclide therapy promises to expand the usefulness of radiation to successfully treat widespread cancer. The unique properties of radioactive tags make it possible to plan treatments by predicting the radiation absorbed dose to both tumors and normal organs, using a pre-treatment test dose of radiopharmaceutical. This requires a combination of quantitative, high-resolution, radiation-detection hardware and computerized dose-estimation software, and would ideally include biological dose-response data in order to translate radiation absorbed dose into biological effects. Data derived from conventional (external beam) radiation therapy suggests that accurate assessment of the radiation absorbed dose in dose-limiting normal organs could substantially improve the observed clinical response for current agents used in a myeloablative regimen, enabling higher levels of tumor control at lower tumor-to-normal tissue therapeutic indices. Treatment planning based on current radiation detection and simulations technology is sufficient to impact on clinical response. The incorporation of new imaging methods, combined with patient-specific radiation transport simulations, promises to provide unprecedented levels of resolution and quantitative accuracy, which are likely to increase the impact of treatment planning in targeted radionuclide therapy.     

Folate receptor-targeted liposomes as possible delivery vehicles for boron neutron capture therapy

BACKGROUND: The folate receptor is amplified in a variety of human tumors including over 90% of ovarian carcinoma. FR-targeted liposomes have previously been used by us to selectively deliver entrapped boron-containing compounds to tumor cells for neutron capture therapy (NCT). In the present study we have evaluated the delivery of Na3(B20H17NH3), which has been loaded into FR-targeted liposomes, in mice bearing xenograft implants of FR (+) KB subcutaneous tumor. MATERIALS AND METHODS: Na3(B20H17NH3) was passively entrapped into FR-targeted liposomes, which were administered intravenously into nude mice bearing s.c. implants of the FR(+) human oral carcinoma KB cell line. Normal and tumor boron content was measured by direct current plasma-atomic emission spectroscopy. RESULTS: Mice that received FR-targeted liposomes containing boron showed the highest tumor boron levels at 24 hours (6.1 micrograms/g) and tumor/blood boron ratios continued to rise for up to 120 hours. CONCLUSION: Boron delivery via FR-targeted liposomes is feasible and potentially can improve tumor uptake compared to non-targeted liposomes, and may improve cellular and subcellular localization.     

自杀基因靶向核素治疗肿瘤研究进展

肿瘤的基因治疗是近年来的研究热点。而基因治疗与放射性核素结合产生的基因靶向性放射性核素治疗，是在自杀基因疗法等基础上建立起来的一种新的肿瘤基因治疗方法。它形成了自杀基因和放射性核素对肿瘤的双重杀伤作用，为肿瘤的基因治疗开拓了新的研究方向。     

肽受体放射性核素治疗胃肠胰神经内分泌肿瘤

胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)是最常见的神经内分泌肿瘤,其起病隐匿,常因出现压迫症状和/或所分泌激素引起的相关症状时方被发现.因此,大多数确诊时已经出现局部扩散和/或远处转移,失去了可能根治的手术机会.GEP-NENs常能高表达生长抑素受体(SSTR2),从而为肽受体放射性核素治疗(peptide receptor radionuclide therapy,PRRT)提供了靶点.本文通过查阅近五年来关于PRRT治疗GEP-NENs的国内外文献,综述了PRRT在GEP-NENs治疗中的临床应用经验,以期为PRRT在GEP-NENs治疗中的合理应用提供指导.     

Radiolabeled immunoglobulin therapy: old barriers and new opportunities

The development of cancer-selective therapies, in particular radiolabeled immunoglobulin therapy (RIT), has stalled. RIT limitations/opportunities are identified in translational research in nude mice, beagles and rhesus monkeys, and in patients with Hodgkin’s disease, neurological paraneoplastic syndromes or small vessel vasculitis. Intravenous RIT is most successful in patients with hematological malignancies due to high tumor uptake and long tumor retention of radiolabeled immunoglobulins. Patients with solid tumors are only expected to benefit from RIT by the administration of radiolabeled immunoglobulins directly into the tumor. Tumor-reactive IgG is the best vehicle for iv. RIT. Tumor-reactive IgM is the best vehicle for intratumoral RIT. The authors do not intend to review the whole clinical RIT experience, but instead analyze the current limitations to success and how they can be circumvented. When the scientific community can reach a consensus on the development and use of these promising and economical radiopharmaceuticals, increasing numbers of patients with recurrent cancer will start to benefit from RIT.     

Radiolabeled immunoglobulin therapy: old barriers and new opportunities

The development of cancer-selective therapies, in particular radiolabeled immunoglobulin therapy (RIT), has stalled. RIT limitations/opportunities are identified in translational research in nude mice, beagles and rhesus monkeys, and in patients with Hodgkin's disease, neurological paraneoplastic syndromes or small vessel vasculitis. Intravenous RIT is most successful in patients with hematological malignancies due to high tumor uptake and long tumor retention of radiolabeled immunoglobulins. Patients with solid tumors are only expected to benefit from RIT by the administration of radiolabeled immunoglobulins directly into the tumor. Tumor-reactive IgG is the best vehicle for i.v. RIT. Tumor-reactive IgM is the best vehicle for intratumoral RIT. The authors do not intend to review the whole clinical RIT experience, but instead analyze the current limitations to success and how they can be circumvented. When the scientific community can reach a consensus on the development and use of these promising and economical radiopharmaceuticals, increasing numbers of patients with recurrent cancer will start to benefit from RIT.     

Multicellular dosimetry in voxel geometry for targeted radionuclide therapy

A software package to investigate absorbed doses and dose-rates at the cellular and multicellular scale has been developed that considers two- and three-dimensional activity distributions and makes use of analytical representations of the point-dose kernels for (131)I, (32)P, and (90)Y. This software allows cell assemblies to be simulated by definition of the number, size, and geometry of cells and their nuclei, and radionuclide uptake can be specified to occur within the nucleus, the cytoplasm, at the membrane, or within the extracellular space. The software has been validated at a cellular scale by comparison with results obtained using spherical geometry, as found in the literature. At a multicellular scale, comparisons were made with a Monte Carlo simulation in voxel geometry. The software has been designed to work within a user-defined voxel geometry. This geometry is useful not only to simulate complex cell assemblies and realistic heterogeneous radionuclide distributions, but will also allow the use of histological and autoradiographic data. Absorbed dose distributions for a single cell calculated using this code varied significantly with activity localization within the cell, and to a lesser extent, with the cellular geometry. At a multicellular level, a two-dimensional heterogeneous activity distribution inferred from a two-dimensional image of a slice throughout a spheroid was used to calculate a dose-rate distribution. This resulted in a heterogeneous dose-rate delivery even for longer-range radionuclides such as (90)Y and (32)P.     

Whole-body dosimetry for targeted radionuclide therapy using spectral analysis

The whole-body dose (WBD) is routinely calculated for targeted radionuclide therapy (TRT). The aim of this work was to investigate the feasibility of using spectral analysis (SA) for the automatic delineation of decay phases, and consequently, the calculation of the WBD given a whole-body (WB) time-activity curve (TAC). SA characterizes the TAC as an arbitrary sum of exponential functions determined by fitting the data with a non-negative least-squares (NNLS) algorithm. The cumulated activity (CA) is calculated analytically as the integral of the fitted curve while the number of phases describing the kinetics of the radiopharmaceutical and the half-lives of the phases can be determined from the spectrum. The uncertainty associated with the estimation of the WBD can be obtained using bootstrap techniques. SA was applied to WB TACs from (186)Re-HEDP and (131)I-mIBG therapies. The results were compared to results obtained using a semiempirical method and showed good agreement in the calculated WBDs. Bootstrapping with resampling on a subset of patients from the two therapies showed much larger coefficient-ofvariation (CV) for the (186)Re-HEDP TACs than for the (131)I-mIBG therapies. We concluded that SA provides a fast, accurate, and reproducible method to obtain WBDs and accurate estimates of the parameters describing the radiotracer kinetics. The method could be extended to other dosimetric applications.