Radioimmunotherapy with alpha-emitting nuclides

McDevitt, Michael R.; Sgouros, George; Finn, Ronald D.; Humm, John L.; Jurcic, Joseph G.; Larson, Steven M.; Scheinberg, David A.

doi:10.1007/s002590050306

Cited by 360 publications

(226 citation statements)

References 22 publications

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“…Several studies have shown the successful use of alpha particle-emitting nuclides, such as 211 At, 213 Bi and 227 Th for radionuclide therapy due to their higher liner energy transfer and shorter path length as compared to beta particle-emitting nuclides. [19][20][21] However, one possible issue is the control of the radiation to normal tissues (kidney or bone marrow etc.) due to its high cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

Yoshimoto

Ogawa

Washiyama

et al. 2008

Intl Journal of Cancer

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The a v b 3 integrin plays a pivotal role in angiogenesis and tumor metastasis. Angiogenic blood vessels overexpress a v b 3 integrin, as in tumor neovascularization, and a v b 3 integrin expression in other microvascular beds and organs is limited. Therefore, a v b 3 integrin is a suitable receptor for tumor-targeting imaging and therapy. Recently, tetrameric and dimeric RGD peptides have been developed to enhance specificity to a v b 3 integrin. In comparison to the corresponding monomeric peptide, however, these peptides show high levels of accumulation in kidney and liver. The purpose of this study is to evaluate tumor-targeting properties and the therapeutic potential of 111 In-and 90 Y-labeled monomeric RGD peptides in BALB/c nude mice with SKOV-3 human ovarian carcinoma tumors. DOTA-c(RGDfK) was labeled with 111 In or 90 Y and purified by HPLC. A biodistribution study and scintigraphic images revealed the specific uptake to a v b 3 integrin and the rapid clearance from normal tissues. These peptides were renally excreted. At 10 min after injection of tracers, 111 In-DOTA-c(RGDfK) and 90 Y-DOTA-c(RGDfK) showed high uptake in tumors (7.3 6 0.6% ID/g and 4.6 6 0.8% ID/g, respectively) and gradually decreased over time (2.3 6 0.4% ID/g and 1.5 6 0.5% ID/g at 24 hr, respectively). High tumor-to-blood and -muscle ratios were obtained from these peptides. In radionuclide therapeutic study, multipledose administration of 90 Y-DOTA-c(RGDfK) (3 3 11.1 MBq) suppressed tumor growth in comparison to the control group and a single-dose administration ( The a v b 3 integrin recognizes the amino acid sequence of arginine-glycine-aspartic acid (RGD peptide). On the basis of the RGD peptide, many peptidomimetic compounds and peptides have been designed to antagonize the a v b 3 integrin. 4 These compounds and anti-a v b 3 integrin monoclonal antibodies have been reported to inhibit angiogenesis without affecting preexisting vessels. 2,5,6 Because of its restricted expression, the a v b 3 integrin is an attractive targeting molecule for tumor imaging and therapy, leading to decreased side effects compared to conventional chemotherapy.The expression of the a v b 3 integrin has been reported to be associated with metastatic potential in melanoma, breast cancer, and colon cancer. 7-9 The development of radiopharmaceuticals for targeting the a v b 3 integrin would be clinically beneficial, not only for screening and for treating patients with a v b 3 integrin-positive tumors but also for monitoring therapeutic efficacy.Many RGD peptides labeled with gamma-emitting and positron-emitting nuclides ( 18 F, 64 Cu, 99m Tc, 125 I, etc.) have been reported as angiogenesis-imaging agents. 10 A recent trend in the development of RGD peptides is the multimerization of RGD peptides to improve the high tumor accumulation and retention of RGD peptides. 11 However, this also leads to the enhancement of radioactive accumulation in nontargeted organs such as kidney and liver. 12 Compared with antibody or multimeric RGD peptides, monomeric RGD ...

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Section: Discussionmentioning

confidence: 99%

α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

Yoshimoto

Ogawa

Washiyama

et al. 2008

Intl Journal of Cancer

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“…Targeted therapy, first discussed over 100 years ago, is based on the idea that a drug will attack its target without damaging other tissue (Raso, 1990). Targeted alpha therapy (TAT) uses an a-emitting radionuclide as a lethal medicament via an effective targeting carrier to kill cancer cells (McDevitt et al, 1998;Allen, 1999b). We are investigating a novel targeting approach that exploits the involvement of cell-surface receptor bound urokinase plasminogen activator (uPA) in the metastatic spread of breast cancer cells (Kruithof et al, 1995).…”

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confidence: 99%

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

et al. 2003

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The control of micrometastatic breast cancer remains problematic. To this end, we are developing a new adjuvant therapy based on 213 Bi-PAI2, in which an a-emitting nuclide ( 213 Bi) is chelated to the plasminogen activator inhibitor-2 (PAI2). PAI2 targets the cellsurface receptor bound urokinase plasminogen activator (uPA), which is involved with the metastatic spread of cancer cells. We have successfully labelled and tested recombinant human PAI2 with the a radioisotope 213 Bi to produce 213 Bi-PAI2, which is highly cytotoxic towards breast cancer cell lines. In this study, the 2-day postinoculation model, using MDA-MB-231 breast cancer cells, was shown to be representative of micrometastatic disease. Our in vivo efficacy experiments show that a single local injection of 213 Bi-PAI2 can completely inhibit the growth of tumour at 2 days postcell inoculation, and a single systemic (i.p.) administration at 2 days causes tumour growth inhibition in a dose-dependent manner. The specific role of uPA as the target for 213 Bi-PAI2 therapy was determined by PAI2 pretreatment blocking studies. In vivo toxicity studies in nude mice indicate that up to 100 mCi of 213 Bi-PAI2 is well tolerated. Thus, 213 Bi-PAI2 is successful in targeting isolated breast cancer cells and preangiogenic cell clusters. These results indicate the promising potential of 213 Bi-PAI2 as a novel therapeutic agent for micrometastatic breast cancer.

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“…In radionuclide therapy, many available α-emitting nuclides undergo successive α-and β-cascade disintegrations [22]. Whether these successive radiations could deliver high-dose irradiation to tumor foci is dependent on retention of daughter nuclides produced in vivo.…”

Section: Discussionmentioning

confidence: 99%

227Th-EDTMP: A potential therapeutic agent for bone metastasis

Washiyama

Amano

Sasaki

et al. 2004

Nuclear Medicine and Biology

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The biodistribution of 227 Th-EDTMP and retention of its daughter nuclide 223 Ra were examined. 227 Th-EDTMP was found to show high uptake and long-term retention in bone. The clearance of 227 Th-EDTMP from blood and soft tissues was rapid and the femur-to-tissue uptake ratios reached more than 100 within 30 min for all tissues except the kidney. Seven and 14 days after injection of 227 Th-EDTMP, the retention index of 223 Ra in bone showed high values, and the differences between these time points were not significant. Therefore, 227 Th-EDTMP is a potential radiotherapeutic agent for bone metastasis.

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Radioimmunotherapy with alpha-emitting nuclides

Cited by 360 publications

References 22 publications

α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

227Th-EDTMP: A potential therapeutic agent for bone metastasis

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Radioimmunotherapy with alpha-emitting nuclides

Cited by 360 publications

References 22 publications

αvβ3 Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

αvβ3 Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2

227Th-EDTMP: A potential therapeutic agent for bone metastasis

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α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide

α_vβ₃ Integrin‐targeting radionuclide therapy and imaging with monomeric RGD peptide