astatine and Adenocarcinoma

Astatine (

Topics: Adenocarcinoma; Animals; Astatine; Humans; Iodine Radioisotopes; Mice; Thyroid Neoplasms; Transplantation, Heterologous

Radioactive iodine has long been used clinically for patients with differentiated thyroid cancer. Radioiodine(131I) is used for the ablation of thyroid remnants or treatment of metastatic thyroid cancer. However, some patients with multiple metastases are refractory to repetitive 131I treatment, despite the targeted regions showing sufficient iodine uptake. In such patients, β- particle therapy using 131I is inadequate and another strategy is needed using more effective radionuclide targeting the sodium/iodide symporter(NIS). Astatine(211At)is receiving increasing attention as an α-emitter for targeted radionuclide therapy. 211At is a halogen element with similar chemical properties to iodine. α particles emitted from 211At has higher linear energy transfer as compared to β particles from 131I and exert a better therapeutic effect by inducing DNA double strand breaks and free radical formation. We showed that increase of the radiochemical purity of astatide of 211At solution by addition of ascorbic acid was associated with significantly enhanced uptake of 211At by both normal thyroid tissue and differentiated thyroid cancer cells. The treatment effect of 211At solution in the K1-NIS xenograft model was dose-dependent and was associated with prolonged survival, suggesting the potential applicability of targeted α therapy for the treatment of advanced differentiated thyroid cancer. Thus, targeted α therapy using 211At is highly promising for the treatment of advanced differentiated thyroid cancer. We have already started the clinical trial of 211At-NaAt in Osaka University Hospital since November 2021 after getting the approval by IRB and PMDA investigation. We would like to get the proof of concept that astatine can be used safely and effectively in patients, aiming at the drug approval as a targeted α therapeutic from Japan.

Topics: Adenocarcinoma; Astatine; Clinical Trials as Topic; Humans; Iodine Radioisotopes; Thyroid Neoplasms

Significant improvement of in vivo stability of 211At-labeled radioimmunoconjugates achieved upon employment of a recently reported new linker, succinimidyl N-2-(4-[211At]astatophenethyl)succinamate (SAPS), prompted additional studies of its chemistry. The 211At radiolabeling of succinimidyl N-2-(4-tributylstannylphenethyl)succinamate (1) was noted to decline after storage at -15 degrees C for greater than 6 months. Compound 1 was found to degrade via a ring closure reaction with the formation of N-2-(4-tributylstannylphenethyl)succinimide (3), and a modified procedure for the preparation of 1 was developed. The N-methyl structural analog of 1, succinimidyl N-2-(4-tributylstannylphenethyl)-N-methyl succinamate (SPEMS), was synthesized to investigate the possibility of improving the stability of reagent-protein linkage chemistry. Radiolabeling of SPEMS with 211At generates succinimidyl N-2-(4-[211At]astatophenethyl)-N-methyl succinamate (Methyl-SAPS), with yields being consistent for greater than 1 year. Radiolabelings of 1 and SPEMS with 125I generated succinimidyl N-2-(4-[125I]iodophenethyl)succinamate (SIPS) and succinimidyl N-2-(4-[125I]iodophenethyl)-N-methyl succinamate (Methyl-SIPS), respectively, and showed no decline in yields. Methyl-SAPS, SAPS, Methyl-SIPS and SIPS were conjugated to Herceptin for a comparative assessment in LS-174T xenograft-bearing mice. The conjugates of Herceptin with Methyl-SAPS or Methyl-SIPS demonstrated immunoreactivity equivalent to if not superior to the SAPS and SIPS paired analogs. The in vivo studies also revealed that the N-methyl modification resulted in a superior statinated product.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Astatine; Cell Line, Tumor; Colonic Neoplasms; Cross-Linking Reagents; Drug Stability; Excipients; Humans; Isotope Labeling; Isotopes; Metabolic Clearance Rate; Mice; Mice, Nude; Organ Specificity; Protein Binding; Radiopharmaceuticals; Tissue Distribution

The syntheses, radiolabeling, antibody conjugation and in vivo evaluation of new linkers for (211)At labeling of monoclonal antibodies are described. Syntheses of the N-succinimidyl esters and labeling with (211)At to form succinimidyl 4-methoxymethyl-3-[(211)At]astatobenzoate (9) and succinimidyl 4-methylthiomethyl-3-[(211)At]astatobenzoate (11) from the corresponding bromo-aryl esters is reported. Previously reported succinimidyl N-{4-[(211)At]astatophenethyl}succinamate (SAPS) is employed as a standard of in vivo stability. Each agent is conjugated with Herceptin in parallel with their respective (125)I analogue, succinimidyl 4-methoxymethyl-3-[(125)I]iodobenzoate (10), succinimidyl 4-methylthiomethyl-3-[(125)I]iodobenzoate (12) and succinimidyl N-{4-[(125)I]iodophenethyl}succinamate (SIPS), respectively, for comparative assessment in LS-174T xenograft-bearing mice. With 9 and 11, inclusion of an electron pair donor in the ortho position does not appear to provide in vivo stability comparable to SAPS. Variables in radiolabeling chemistry of these three agents with (211)At are notable. Sequential elimination of acetic acid and oxidizing agent, N-chlorosuccinimide (NCS), from the (211)At radiolabeling protocol for forming SAPS improves yield, product purity and consistency. NCS appears to be critical for the radiolabeling of 6 with (211)At. Formation of 11, however, is found to require the absence of NCS. Elimination of acetic acid is found to have no effect on radiolabeling efficiency or yield for either of these reactions.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Astatine; Cell Line, Tumor; Colonic Neoplasms; Cross-Linking Reagents; Female; Humans; Isotope Labeling; Mice; Mice, Nude; Organ Specificity; Radioimmunotherapy; Radiopharmaceuticals; Tissue Distribution; Trastuzumab; Treatment Outcome

The sodium/iodide symporter (NIS) has been recognized as an attractive target for radioiodine-mediated cancer gene therapy. In this study we investigated the role of human NIS for cellular uptake of the high LET alpha-emitter astatine-211 ((211)At) in comparison with radioiodine as a potential radionuclide for future applications. A mammalian NIS expression vector was constructed and used to generate six stable NIS-expressing cancer cell lines (three derived from thyroid carcinoma, two from colon carcinoma, one from glioblastoma). Compared with the respective control cell lines, steady state radionuclide uptake of NIS-expressing cell lines increased up to 350-fold for iodine-123 ((123)I), 340-fold for technetium-99m pertechnetate ((99m)TcO(4)(-)) and 60-fold for (211)At. Cellular (211)At accumulation was found to be dependent on extracellular Na(+) ions and displayed a similar sensitivity towards sodium perchlorate inhibition as radioiodide and (99m)TcO(4)(-) uptake. Heterologous competition with unlabelled NaI decreased NIS-mediated (211)At uptake to levels of NIS-negative control cells. Following uptake both radioiodide and (211)At were rapidly (apparent t(1/2) 3-15 min) released by the cells as determined by wash-out experiments. Data of scintigraphic tumour imaging in a xenograft nude mice model of transplanted NIS-modified thyroid cells indicated that radionuclide uptake in NIS-expressing tumours was up to 70 times ((123)I), 25 times ((99m)TcO(4)(-)) and 10 times ((211)At) higher than in control tumours or normal tissues except stomach (3-5 times) and thyroid gland (5-10 times). Thirty-four percent and 14% of the administered activity of (123)I and (211)At, respectively, was found in NIS tumours by region of interest analysis ( n=2). Compared with cell culture experiments, the effective half-life in vivo was greatly prolonged (6.5 h for (123)I, 5.2 h for (211)At) and preliminary dosimetric calculations indicate high tumour absorbed doses (3.5 Gy/MBq(tumour) for (131)I and 50.3 Gy/MBq(tumour) for (211)At). In conclusion, NIS-expressing tumour cell lines of different origin displayed specific radionuclide uptake in vitro and in vivo. We provide first direct evidence that the high-energy alpha-emitter (211)At is efficiently transported by NIS. Application of (211)At may direct higher radiation doses to experimental tumours than those calculated for (131)I. Thus, (211)At may represent a promising alternative radionuclide for future NIS-based tumour thera

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Animals; Astatine; Biomarkers, Tumor; Colonic Neoplasms; Gene Expression; Glioblastoma; Humans; Iodine Radioisotopes; Mice; Mice, Nude; Neoplasm Transplantation; Radionuclide Imaging; Radiopharmaceuticals; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Sodium Pertechnetate Tc 99m; Symporters; Thyroid Neoplasms; Tissue Distribution; Tumor Cells, Cultured

6-[211At]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an onco-APase isoenzyme expressed by certain epithelial and germ cell tumors. The therapeutic efficacy and acute toxicity of its endogenous alpha-particle emissions have been studied in a murine tumor model.. 211At was produced by the 207Bi(alpha,2n)211 At cyclotron-based nuclear reaction. High specific activity 6-[211At]-astato-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isotopic exchange. The therapeutic potential of 6-[211At]-astato-MNDP and 211At- was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity.. Significant therapeutic effects due to targeted alpha-particle emissions have been confirmed for the activity dose range, 10-750 kBq 6-[211At]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of approximately 45-65% were achieved following administration of 55-300 kBq 6-[211At]-astato-MNDP. Estimated tumor absorbed radiation doses were not inconsistent with clinical response. Irreversible hematoxicity or stigmata of acute radiation damage in other critical normal tissues were not encountered. Nonspecifically internalized 211At- exerted no therapeutic effect.. Therapeutic results for 6-[211At]-astato-MNDP have confirmed the profound in vivo cytotoxicity of its targeted alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[211At]-astato-MNDP endoradiotherapy is discussed, and its putative role in the possible individualized management of certain human tumors has been proposed.

Topics: Adenocarcinoma; Animals; Astatine; Brachytherapy; Energy Transfer; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Rectal Neoplasms; Vitamin K; Vitamin K 3

Topics: Adenocarcinoma; Alpha Particles; Animals; Astatine; Humans; Injections, Intravenous; Male; Mice; Mice, Nude; Neoplasm Transplantation; Thyroid Neoplasms; Tissue Distribution; Transplantation, Heterologous

For the purposes of evaluation of the therapeutic potential of the radiohalogenated thymidine analogue 125IUdR, estimation of the radiation dose to the tumour cells and normal tissues is important. To determine the dose to any tissue from the radionuclide 125I is not simple, since the major emissions are very short-range Auger electrons. The cytotoxicity of 125I is strongly dependent on the position of the decay relative to the DNA, the principal target for cell sterilization. Estimates of the cytotoxicity of 125I based on the traditional MIRD recommended formulation (ICRU Report 32, 1979) may produce gross underestimates if it is incorporated into the DNA via the thymidine precursor 125IUdR. In this work, tissue count and autoradiography (ARG) data from studies by Bagshawe et al were used to estimate tissue doses following the administration of 125IUdR to LS174/T (a colorectal carcinoma) and CC3 (a choriocarcinoma) tumour-bearing animals, after a hydroxyurea block of the normal tissue turnover. The tumour cell toxicity is estimated from ARG data on the degree of 125I incorporation into the cell nucleus. Major drawbacks with 125I for this type of therapy are the long 60-day half-life, leading to radiological and waste disposal problems and the extreme short range of the radiotoxic effects. Possible alternative radiohalogens, 13I, 77Br, 131I and 211At, are suggested in place of 125I in the thymidine analog iododeoxyuridine. Dose calculations are performed and cytotoxicities estimated on the assumption that their biological retention characteristics are the same as for 125IUdR.

Topics: Adenocarcinoma; Animals; Astatine; Bromine Radioisotopes; Cell Nucleus; Cell Survival; Choriocarcinoma; Colonic Neoplasms; Drug Resistance; Female; Half-Life; Idoxuridine; Iodine Radioisotopes; Mice; Radiation Dosage; Radiotherapy Dosage; Uterine Neoplasms

The concentrations of 211At and 125I were measured in various tissues in nude mice bearing xenografts of human thyroid tissue (fetal and malignant). The relative concentration of the two halogens was obtained at 4 and 24 h after injection. Samples were taken of the host blood, muscle and thyroid gland and the grafted tissues. The mouse thyroid concentrated 125I more efficiently than 211At but the human grafts concentrated both halogens about equally.

Topics: Adenocarcinoma; Animals; Astatine; Autoradiography; Carcinoma; Fetus; Humans; Injections, Intraperitoneal; Iodine Radioisotopes; Male; Mice; Mice, Nude; Thyroid Gland; Thyroid Neoplasms

6-[211At]astato-MNDP is currently being investigated as a potential high LET endoradiotherapeutic drug. Biodistribution and whole-body radiation retention studies have been carried out with 6-[211At]astato-MNDP and 211At- in a murine rectal tumour model; results indicate that the 211At-C bond in the compound is metabolically stable for at least 6 h. The Mean Biological Concentration of 6-[211At]astato-MNDP in tumour tissue ranged from 170-253% over an initial 12 h period; this was higher than that observed for the [211At]astatide anion. Conversely, the uptake of compound into radiobiologically critical organs was significantly lower.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Astatine; Female; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Rectal Neoplasms; Tissue Distribution; Vitamin K; Vitamin K 3

A potential endoradiotherapeutic drug, 6-211At-astato-2-methyl-1,4-naphthoquinol bis (diphosphate salt), incorporating the alpha-emitting radio-halogen astatine-211 of half-life 7.2 h, is shown to be valuable for localization studies by means of alpha-particle track autoradiography in malignant and normal cells and tissues in the mouse with transplanted adenocarcinoma of the rectum.

Topics: Adenocarcinoma; Alpha Particles; Animals; Antineoplastic Agents; Astatine; Autoradiography; Colon; Lung; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Rectal Neoplasms; Spleen; Subcellular Fractions; Vitamin K; Vitamin K 3