ABSTRACT
OBJECTIVES: Scintigraphy is generally not the first choice treatment for prostate cancer, although successful studies using bombesin analog radiopeptides have been performed. Recently, a novel peptide obtained using a phage display library demonstrated an affinity for prostate tumor cells. The aim of this study was to compare the use of a bombesin analog to that of a phage display library peptide (DUP-1) radiolabeled with technetium-99m for the treatment of prostate carcinoma. The peptides were first conjugated to S-acetyl-MAG3 with a 6-carbon spacer, namely aminohexanoic acid. METHODS: The technetium-99m labeling required a sodium tartrate buffer. Radiochemical evaluation was performed using ITLC and was confirmed by high-performance liquid chromatography. The coefficient partition was determined, and in vitro studies were performed using human prostate tumor cells. Biodistribution was evaluated in healthy animals at various time points and also in mice bearing tumors. RESULTS: The radiochemical purity of both radiotracers was greater than 95 percent. The DUP-1 tracer was more hydrophilic (log P = -2.41) than the bombesin tracer (log P = -0.39). The biodistribution evaluation confirmed this hydrophilicity by revealing the greater kidney uptake of DUP-1. The bombesin concentration in the pancreas was greater than that of DUP-1 due to specific gastrin-releasing peptide receptors. Bombesin internalization occurred for 78.32 percent of the total binding in tumor cells. The DUP-1 tracer showed very low binding to tumor cells during the in vitro evaluation, although tumor uptake for both tracers was similar. The tumors were primarily blocked by DUP1 and the bombesin radiotracer primarily targeted the pancreas. CONCLUSION: Further studies with the radiolabeled DUP-1 peptide are recommended. With further structural changes, this molecule could become an efficient alternative tracer for prostate tumor diagnosis.
Subject(s)
Animals , Humans , Male , Mice , Aminocaproates/chemistry , Bombesin , Oligopeptides/chemistry , Peptides , Prostatic Neoplasms , Radiopharmaceuticals , Technetium , Aminocaproates/pharmacokinetics , Bombesin/analogs & derivatives , Culture Media , Disease Models, Animal , Isotope Labeling/methods , Mice, Nude , Oligopeptides/pharmacokinetics , Pancreas , Random Allocation , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Receptors, Bombesin/analysis , Receptors, Bombesin/metabolism , Biomarkers, Tumor/metabolismABSTRACT
El péptido bombesina (BN), de 14 amino ácidos, se aisló de la piel de los batracios y forma parte de un amplio grupo de neuropéptidos con diversas funciones biológicas. El homólogo equivalente en los mamíferos es el péptido liberador de la gastrina (GRP) y sus receptores (GRP-r) se expresan abundantemente en la membrana de las células tumorales, estimulando su crecimiento. La unión BN-GRP-r es una fuerte unión altamente específica por lo cual la BN marcada con radionucleidos se ha utilizado en medicina nuclear para la localización de tumores malignos de cáncer de mama y próstata principalmente. Las modificaciones en la cadena peptídica y el marcado se llevan a cabo en la región de extremo-N inicial, quedando el extremo C-terminal con su especificidad y acción biológica intactas. Se presentan varios análogos de BN radiactivos y la estructura de uno nuevo formado por un conjugado EDDA/HYNIC-BBN que fácilmente se une al 99mTc. Las expectativas para utilizar radiofármacos de BN marcados con emisores beta-negativos en radiopéptidoterapia son grandes y prometedoras.
Subject(s)
Humans , Bombesin/analogs & derivatives , Bombesin/pharmacology , Gastrin-Releasing Peptide/analogs & derivatives , Gastrin-Releasing Peptide/pharmacology , Receptors, Bombesin/metabolism , Bombesin , Bombesin/therapeutic use , Molecular Sequence Data , Neoplasms/diagnosis , Neoplasms/radiotherapy , Gastrin-Releasing Peptide , Gastrin-Releasing Peptide/therapeutic use , Radiopharmaceuticals , Radiopharmaceuticals/therapeutic use , Structure-Activity RelationshipABSTRACT
The effect of substance P (SP) on thyrotropin (TSH) secretion is controversial. In this study we evaluated the effect of SP on TSH secretion by hemipituitaries of 3-month-old Wistar rats in vitro and its interaction with gastrin-releasing peptide (GRP) at equimolar concentrations (1 µM and 10 µM). TSH release was measured under basal conditions and 30 min after incubation in the absence or presence of SP, GRP or both peptides. Pituitary TSH content was also measured in the pituitary homogenate after incubation. SP at both concentrations caused a significant (P<0.05) increase in TSH secretion compared with all other groups, which was approximately 60 percent (1 µM) and 85 percent (10 µM) higher than that of the control group (23.3 + or - 3.0 ng/ml). GRP at the lower concentration did not produce a statistically significant change in TSH secretion, whereas at the concentration of 10 µM it produced a 50 percent reduction in TSH. GRP co-incubated with substance P completely blocked the stimulatory effect of SP at both concentrations. Pituitary TSH content decreased in the SP-treated group compared to controls (0.75 + or - 0.03 µg/hemipituitary) at the same proportion as the increase in TSH secretion, and this effect was also blocked when GRP and SP were co-incubated. In conclusion, in an in vitro system, SP increased TSH secretion acting directly at the pituitary level and this effect was blocked by GRP, suggesting that GRP is more potent than SP on TSH secretion, and that this inhibitory effect could be the predominant effect in vivo