ABSTRACT
Radioligand therapy (RLT) using 177Lu labelled inhibitors of the prostate-specific membrane antigen (177Lu-PSMA) is performed in patients with metastatic castration-resistant prostate cancer (mCRPC) after exhaustion of other options. German University Clinics offer RLT since 2013 on a compassionate use basis. The present consensus document includes recommendations for RLT with 177Lu-PSMA-617. These consensus statements were developed by an expert panel formed by the German Society of Nuclear Medicine (DGN) in December 2015. Statements include recommendations for indication, baseline tests, therapy protocol, concomitant therapy, dosimetry, and follow-up. Consensus recommendations aim to inform the attending medical staff, standardize 177Lu-PSMA-617 RLT, and improve quality of individual patient care.
Subject(s)
Dipeptides/therapeutic use , Heterocyclic Compounds, 1-Ring/therapeutic use , Nuclear Medicine/standards , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Prostatic Neoplasms, Castration-Resistant/secondary , Radiation Dosage , Radiometry/standards , Dipeptides/standards , Follow-Up Studies , Germany , Heterocyclic Compounds, 1-Ring/standards , Humans , Lutetium , Male , Practice Guidelines as Topic , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/diagnosis , Radiopharmaceuticals/standards , Radiopharmaceuticals/therapeutic use , Treatment OutcomeABSTRACT
Nick translation is a commonly used method for labeling DNA to make DNA hybridization probes. In this approach, the use of DNase I to generate nicks in double-stranded DNA presents an inherent drawback, because the enzyme's high rate of reaction causes significant fragmentation and shortening of the hybridization probes. Based on our recent findings regarding the nucleolytic activity of the dipeptide seryl-histidine (Ser-His) and generation of free 3' hydroxyl and 5' phosphate groups at the cleavage sites of the substrate DNA by Ser-His, it was hypothesized that this disadvantage may be overcome by using Ser-His in place of DNase I as an alternative DNA nicking agent. In this study we demonstrate that like DNase I, Ser-His randomly nicks DNA, but the dipeptide has a much lower rate of reaction that enables more complete labeling of the DNA probes with less fragmentation. DNA probes labeled through nick translation using Ser-His as the DNA nicking agent were consistently larger in size and exhibited significantly higher specific activities, and enhanced hybridization signals in Southern blot analyses compared to control DNA probes that were made using DNase I as the nicking agent. Furthermore, the degree of nicking and consequently the quality of the probes could be easily controlled by adjusting the temperature and time of the Ser-His nicking reaction. These results affirm our hypothesis that Ser-His can serve as an alternative DNA nicking agent in nick translation to yield superior DNA probes and hybridization results and suggest the possible general utility of Ser-His for wide range of biological and biomedical applications that require more moderated nicking of nucleic acids. Based upon these and computer modeling results of Ser-His, a mechanism of action is proposed to explain how Ser-His may nick DNA.
Subject(s)
DNA Probes/biosynthesis , Dipeptides/metabolism , In Situ Nick-End Labeling/methods , Nucleic Acid Hybridization/methods , Binding Sites , Blotting, Southern , Computer Simulation , DNA/analysis , DNA/metabolism , DNA Fragmentation , DNA Probes/analysis , DNA Probes/standards , Deoxyribonuclease I/metabolism , Deoxyribonuclease I/standards , Dipeptides/standards , In Situ Nick-End Labeling/standards , Molecular WeightABSTRACT
A general approach to the solution phase, parallel synthesis of chemical libraries, which allows the preparation of multi-milligram quantities of each individual member, is exemplified with both a universal and dipeptide mimetic template. In each step of the sequence, the reactants, unreacted starting material, reagents and their byproducts are removed by simple liquid/ liquid or liquid/solid extractions providing the desired intermediates and final compounds in high purities (> or = 90-100%) independent of the reaction yields and without deliberate reaction optimization.
Subject(s)
Dipeptides/chemical synthesis , Dipeptides/standards , Drug Design , Solutions/chemistry , Templates, GeneticABSTRACT
En los últimos años se han estudiado a fondo los efectos de los péptidos intravenosos. Las soluciones de dipéptidos son un medio para suministrar determinados aminoácidos que podrían ser inidispensables en ciertas condiciones clínicas. En particular, podría ser díficil administrar aminoácidos tales como la cistina, la glutamina y la tirosina en su forma libre, mientras que su disponiblidad aumenta considerablemente cuando se suministran en forma de dipéptidos. Losestudios en animales y en seres humanos han demostrado que los dipéptidos parentales son eliminados rápidamente del plasma e influyen favorablemente sobre el balance del nitrógeno tanto en individuos sanos como en pacientes catábolicos.(RESUMEN TRUNCADO A 2.500 CARACTERES)
