PubMed · 1837045
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S Eto. 1991-09-10. [Hypercalcemia in malignancy].. https://doi.org/10.2169/naika.80.1534
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The effects of hydroxyl radical attack on a peptidic drug were studied in vitro. Different chemico-physical techniques were used to investigate structural damage induced by oxidative stress conditions in salmon calcitonin (sCT), a peptide hormone used in treating osteoporosis. Reversed-phase liquid chromatography (RP-HPLC), circular dichroism (CD) and transmission electron microscopy (TEM) were applied to measure formation of oxidation/degradation products and to reveal the conformational and ultrastructural modifications in the presence of OH. free radicals. Hydroxyl radicals were obtained from ferrous sulfate and ascorbic acid mixtures. The RP-HPLC results revealed the formation of new chromatographic peaks indicating a number of degradation/oxidation products formed in the presence of OH. free radicals. CD spectra showed slight protein conformational modifications as well as aggregation. TEM confirmed sCT aggregation and suggested the formation of fibrillar aggregates.
Labeling of proteins with metallic radionuclides for use in radiopharmaceuticals involves covalently attaching a bifunctional chelator. In principle, use of smaller peptides allows this chelator to be incorporated during solid-phase peptide synthesis (SPPS) with total site specificity. To realize the advantages of this approach, a lysine-hynic conjugate Fmoc-N-epsilon-(Hynic-Boc)-Lys was synthesized for incorporating the well-known technetium-99m-binding hydrazinonicotinamide ligand into peptides during SPPS. It was used to synthesize a technetium-99m-labeled salmon calcitonin with the hynic-linked amino acid in place of lysine-18. A trifluoroacetate group protected the hynic during alkaline oxidation to the cyclic disulfide and was readily removed by mild acid treatment. The peptide was efficiently labeled (91-98% radiochemical yield) with Tc-99m in the presence of tricine and SnCl(2) with high specific activity (>100 MBq/microg). The product showed good serum stability and specific affinity for human calcitonin receptors. Fmoc-N-epsilon-(Hynic-Boc)-Lys is a highly versatile technetium-binding amino acid for incorporation into peptides during SPPS. This allows total flexibility and control in the site of attachment and is suitable for a combinatorial approach to peptide radiopharmaceuticals.
In the situation of persistent hypercalcaemia after cervicotomy for medullary carcinoma of the thyroid (CMT), the concerns are radically different depending on whether the initial operation has been adequate or not. If it has been inadequate, it is necessary to reoperate via cervicotomy and facilitate, in all cases, a total thyroidectomy and a bilateral and central neck dissection. If the cervicotomy has been adequate, it is necessary to have a high index of suspicion for a locoregional recurrence and systemic disease, but the indications for reintervention must be respected. The essential problem is the difficulty in staging residual or recurrent disease. In this situation all the imagery available should be utilised, including laparoscopy to rule out the possibility of miliary metastatic liver disease. There is no hope of cure in the setting of systemic disease, but it is necessary to recall that an extremely elevated calcitonin can be well tolerated and compatible with a survival for several decades. The overall prognosis lies not in the level of elevation of the tumoral marker but the extent of local invasion and systemic disease. There is no hope of cure when the calcitonin level is superior to 1000 pg/ml. There is also no chance of localising recurrent disease when the calcitonin level is inferior to 50 pg/ml. Therefore, one should only utilise the various available localisation techniques when the level of calcitonin is between 50 and 1000 pg/ml. A mediastinal dissection via sternotomy is only indicated in the absence of distal metastases and in the setting of nodal involvement just caudal to the initial cervicotomy, and only after a laparoscopy to exclude hepatic metastases. The future hopes lie with radio-immunoguided surgery in cases of local invasive disease and radiolabelled immunochemotherapy for systemic disease.