[90Y]DOTA-DPhe1-Tyr3-octreotide ([90Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [86Y]DOTA-DPhe1-Tyr3-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [86Y]DOTA-DPhe1-Tyr3-octreotide was administered at two different peptide concentrations, namely 2 and 100 microg peptide per m2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [86Y]DOTA-DPhe1-Tyr3-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [90Y]DOTA-DPhe1-Tyr3-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide injected. For the 100 microg/m2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide, respectively. The average effective dose equivalent amounted to 0. 23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [90Y]DOTA-DPhe1-Tyr3-octreotide in patients with somatostatin receptor-expressing tumours.
Non-specific generation of intracellular free radicals in excess of normal levels, e.g. by the acute radiation absorption event in cells, has led to a delayed and temporary inhibition of thymidine kinase. The enzyme activity reaches a minimum at 4 h even after a low-level exposure with full recovery soon thereafter. This process appears to represent a biochemical response to an initial physical event, but must be distinguished from the response of the DNA repair enzyme system. A reduction of cellular thymidine kinase activity is expected to cause a temporary reduction of DNA synthesis and may be of advantage to the cell. Such a response may be regarded as an instance of radiation hormesis in the sense that such a compensatory response to the stimulus of irradiation may confer protection against a repeated increase in free radical concentration whether by renewed radiation exposure or by metabolism in general. An improvement of the efficiency of repair or an increased level of free radical detoxification should be of benefit to both the individual cell and to the organism as a whole.
Low-dose whole-body exposure of mice to less than 0.01 Gy gamma-rays causes inhibition of incorporation of thymidine or 5-iodo-2-deoxyuridine into DNA of bone-marrow cells in vitro; the effect is maximal in cells at 4 hours after exposure and then subsides within about 10 hours. This is due to the inhibition of cellular thymidine kinase, which gradually develops to a maximum at 4 hours after exposure and again subsides within the next 10 hours. This inhibition involves only 35 per cent of the entire cellular enzyme activity and, analogous to the depression of thymidine incorporation into the cells, is only seen when the cells are collected into medium that is buffered to 7.2-7.4 and contains about 1350 mg NaHCO3 per litre. Addition of NaHCO3 to the cell homogenate or to the high speed supernatant containing the enzyme, but not to intact cells, failed to produce enzyme inhibition. There is also no depression of 5-iodo-2-deoxyuridine uptake into the intact cells in vitro when the mice are irradiated either shortly before or after i.v. injection of 0.02 mg of procain chloride. The reversibility of the effect in vivo and in vitro suggests a particular enzyme control mechanism that may be non-specifically triggered by intracellular charges, such as peroxides, and may enhance repair.
Low-dose irradiation is usually considered to be rather ineffective in producing biologically relevant effects. Yet, individual radiation absorption events within cell nuclei or whole cells interact stochastically with subcellular structures due to the multiple ionizations along primary or secondary particle tracks, depending on ionization density. Whereas radiation effects are usually seen in the context of structure and function of DNA, other cellular effects, perhaps influencing DNA by secondary biochemical mechanisms, also warrant attention. Thus, previous work from this laboratory with bone marrow that was obtained from whole-body exposed mice, has shown that single or few instantaneous radiation absorption events per cell from gamma-rays produce an acute and temporary partial inhibition of the enzyme thymidine kinase; the effect appears within about 1 h after the event, reaches its maximum at approximately 4 h and disappears completely within another 6 h. This pattern of enzyme inhibition is fully concordant with the pattern of inhibition of uptake of tritiated thymidine or 125I-labelled deoxyuridine into the DNA; also concordant is a temporary increase in the concentration of free thymidine in the blood serum of the exposed mice. The particular response of thymidine kinase was considered to relate to some, thus far unknown, repair systems and/or to a defence mechanism of the hit cells. In order to further elucidate the role of the acute and temporary partial inhibition of thymidine kinase in cellular metabolism, experiments were carried out in which mice were acutely exposed to 0.01 or 0.1 Gy and again exposed to the same dose at different times up to 12 h after the first exposure. At regular time intervals after the second exposure bone marrow cells were obtained and thymidine kinase activity was studied by various assays. The results indicate that the first acute irradiation conditioned the cells in such a way that the second acute irradiation produced either an enhanced inhibition and recovery of thymidine kinase activity, or no effect at all was seen, when the second irradiation was given between about 3 and 8 h after the first irradiation. From 8 to 12 h after the first irradiation the cells apparently resumed their original state, so that the second irradiation produced effects quite similar to those seen after a single irradiation in unconditioned cells.(ABSTRACT TRUNCATED AT 400 WORDS)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.