Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.
PurposeRadiolabelled peptides used for peptide receptor radionuclide therapy are excreted mainly via the kidneys and are partly reabsorbed and retained in the proximal tubular cells. The resulting high renal radiation dose can cause nephrotoxicity, limiting the maximum activity dose and the effectiveness of peptide receptor radionuclide therapy. The mechanisms of kidney reabsorption of these peptides are incompletely understood, but the scavenger receptor megalin has been shown to play a role in the reabsorption of 111In-octreotide. In this study, the role of megalin in the renal reabsorption of various relevant radiolabelled peptides was investigated.MethodsGroups of kidney-specific megalin-deficient mice and wild-type mice were injected with 111In-labelled somatostatin, exendin, neurotensin or minigastrin analogues. Single photon emission computed tomographic (SPECT) images of the kidneys were acquired and analysed quantitatively, or the animals were killed 3 h after injection and the activity concentration in the kidneys was measured.ResultsMegalin-deficient mice showed significantly lower uptake of all studied radiolabelled peptides in the kidneys, ranging from 22% (111In-octreotide) to 65% (111In-exendin) of uptake in wild-type kidneys. Quantitative analysis of renal uptake by SPECT and ex vivo measurements showed a very good correlation.ConclusionMegalin is involved in the renal reabsorption of radiolabelled octreotide, octreotate, exendin, neurotensin and minigastrin. This knowledge may help in the design of strategies to reduce this reabsorption and the resulting nephrotoxicity in peptide receptor radionuclide therapy, enabling more effective therapy. Small-animal SPECT is an accurate tool, allowing in vivo quantification of renal uptake and serial measurements in individual mice.
Seven hybridoma cell lines secreting monoclonal antibodies (mAb) to nonlymphoid cells of the mouse thymus have been prepared. These mAb clearly demonstrate the heterogeneity of the thymic stroma. Based on their anatomical distribution patterns observed with the immunoperoxidase technique on frozen tissue sections, they were subdivided into four groups. The first group of mAb, ER-TR1, 2 and 3, detects antigens encoded for by the I region of the major histocompatibility complex. These antigens are expressed on both stromal and lymphoid cells in lymphoid organs. mAb of the second category, ER-TR4, react with epithelial cells in the thymic cortex. mAb of the third group detect stromal cells of the thymic medulla. One antibody of this group, ER-TR5, exclusively reacts with medullary epithelial cells. ER-TR6, the other antibody of this group, reacts with medullary interdigitating cells and macrophages. The fourth type of antibodies, ER-TR7, detects the reticular fibroblasts of the thymus. The possible role of the thymic cell types detected by the present antibodies in T cell differentiation is discussed.
We have produced a panel of monodonal antibodies directed against nonlymphoid cells in central and peripheral lymphoid organs. In this paper we present the reactivity of one of these antibodies, ER-TR7. This antibody detects reticular fibroblasts, which constitute the cellular framework oflymphoid and nonlymphoid organs and their products. In frozen sections of the spleen incubated with this antibody, the red pulp and white pulp are clearly delineated. Furthermore, the major white pulp compartments the follides and peniarteriolar lymphoid sheath as well as the marginal zoneare recognized by their characteristic labeling patterns. In lymph nodes, the capsule, sinuses, follides,
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