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Biomedical subjects

S Nishimoto

Publications and source records attributed to S Nishimoto.

At least 55 records · Page 3Linked to original sources
PubMed1992

Fluorine modification of nitroazole radiosensitizers for the enhancement of sensitizing activity with lowering toxicity: a pharmacokinetic characterization.

Pharmacokinetic characterization of various nitroazole radiosensitizers was carried out to clarify the effect of fluorine modification of the side-chain groups on the sensitizing activity and the acute toxicity. The in vivo tumor/plasma partition coefficient (PTP) of sensitizers increased with increase in the octanol/water partition coefficient (Pow) up to approximately 0.3 and was almost unity (maximum) for sensitizers with their Pow values larger than approximately 0.3. This relationship was observed commonly for all types of sensitizers independent of the fluorine modification. The in vivo brain/plasma partition coefficient (PBP) of sensitizers increased with increase in the Pow, attaining a constant value of almost unity at Pow greater than 0.5 for non-fluorine sensitizers or at Pow greater than 1.5 for fluorine-modified sensitizers. The maximum brain-affinity factor ((FB,t)max = (CB,t)max/Ds, where (CB,t)max and Ds are the maximum intrabrain concentration and the administered dose of sensitizer, respectively) was proportional to the maximum tumor-affinity factor ((FT,t)max = (CT,t)max/Ds, where (CT,t)max is the maximum intratumor concentration of sensitizer), depending on the side-chain structure of the sensitizer. A series of non-fluorine and fluorine-modified nitroazole derivatives, including N-(2'-hydroxyethyl)-2,2-difluoro-3-(3''-nitro-1'-triazolyl)propionamide (KU-2285), gave a smaller brain to tumor ratio of approximately 1/7. The toxicity index defined by 1/LD50/7 was parallel to the sensitizing activity measured by 1/DS,1.5 (DS,1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo). The therapeutic risk index defined by Ds,1.5/LD50/7 depended on the side-chain structures of sensitizers. The DB,1-5LD50-/7 values of KU-2285 and ethanidazole (SR-2508) were 1/3 that of misonidazole (MISO). The sensitizers were smaller Ds,1.5/LD50/7 values showed higher sensitizing activities as their tumor affinities increased, without an increase in serious toxicity.

Animals↗
PubMed1992

Pharmacokinetics of fluorinated 2-nitroimidazole hypoxic cell radiosensitizers in murine peripheral nervous tissue.

We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH2-CF2CONH(CH2)nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of etanidazole (a 2-nitroimidazole with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF2 group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH2 groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.

Animals↗
PubMed1992

Nitrotriazoles bearing sulfur-substituted side chains: preparation and characterization as hypoxic cell radiosensitizers.

A series of 3-nitro-1,2,4-triazole (NTA) derivatives with -(CH2)mC(= Y)NH(CH2)nZCH3(Y, Z = O or S; m = 1 or 2; n = 2 or 3) group in the side chain at the N-1 position of NTA and their fluorinated analogs were synthesized. Their physicochemical properties and radiosensitizing activities in vitro and in vivo were investigated with respect, particularly, to the effects of sulfur substitution on the side chain of triazoles. The sulfur substitution of the oxygen atom in the side chain of NTA derivatives increased the partition coefficient (P value), but had little effect on the one-electron reduction potential. The derivatives bearing a thioether group in the side chain were more effective in vitro on hypoxic EMT6/KU cells, but were less effective in vivo on SCCVII tumor than their oxygen analogs. The thioamide compounds showed almost the same or slightly higher sensitizing activities in vitro compared with their oxygen analogs.

Animals↗
PubMed1991

A fluorinated 2-nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.

To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-nitroimidazole. Of the resulting compounds, KU-2285 (a 2-nitroimidazole with an N1-substituent of CH2CF2CONHCH2-CH2OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in vivo radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were -0.96 V and -1.05 V vs Ag/Ag+ in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vivo radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in vivo-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H/He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD50/7 in 8-week-old female C3H/HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole.

Animals↗
PubMed1991

In vivo radiosensitizing activity of a new fluorinated hypoxic cell radiosensitizer, KU-2285, in combination with radiation dose fractionation.

Since most clinical radiotherapy is given as multiple small irradiation fractions, the present study was undertaken to test the in vivo radiosensitizing activity of a new hypoxic cell radiosensitizer, KU-2285, in combination with radiation dose fractionation. Radiosensitizing activity was measured by a growth delay assay using a transplanted mammary tumor in C3H/He mice, and by an in vivo-in vitro assay using the SCC VII tumor. KU-2285 was injected intraperitoneally 30 min before irradiation in all experiments. The in vivo-in vitro assay using SCC VII tumors showed that 12.5 micrograms/g of KU-2285 sensitized the tumors to irradiation (5 Gy/fr x 5 fr/48 hr or 6 Gy/fr x 3 fr/48 hr). KU-2285 also sensitized the transplanted mammary tumors to fractionated irradiation. We concluded that KU-2285 was able to sensitize two different murine tumors when given in combination with radiation dose fractionation.

Animals↗
PubMed1990

Pharmacokinetics of 2-nitroimidazole hypoxic cell radiosensitizers in rodent peripheral nervous tissue.

The concentrations of seven 2-nitroimidazoles--including misonidazole, etanidazole (SR-2508), pimonidazole (Ro 03-8799), desmethylmisonidazole (Ro 05-9963), RK28, RP170, and KU2285--were measured in the sciatic nerves of C3H/He mice using reverse-phase high-performance liquid chromatography. Drug exposure to the peripheral nervous system was highest for misonidazole, followed by desmethylmisonidazole, etanidazole, pimonidazole and RK28. The lower drug exposure of pimonidazole and RK28 seemed to be related to their lower hydrophilicity. The apparent biological half-lives of the compounds in the peripheral nerves were correlated to their hydrophilicity: the more hydrophilic the compound, the longer the apparent biological half-life in the peripheral nervous tissue of the mice. Measurement of drug exposure in the rodent peripheral nervous system, rather than in the brain, was a better indicator for estimating the occurrence of clinical peripheral neuropathy by 2-nitroimidazoles.

Animals↗
PubMed1989

Age- and diabetes-accelerated glycation in the human aorta.

The extent of glycation in pieces of human aorta was estimated by determining the content of furosine, which is derived from fructose-lysine through acid hydrolysis. Glycation of human aorta was found to increase with advancing age. A significant positive correlation was found between the degree of atherosclerosis and the furosine level in the aorta in subjects over 60 years of age. Furthermore, the furosine level in the aortae of diabetic patients was significantly higher than that in normal subjects of the same age. These results suggest not only that glycation in the aorta may increase with aging and with the development of arteriosclerosis, but also that diabetes may be related as well to premature aging as to arteriosclerosis.

Adult↗
PubMed1989

Importance of tumor affinity of nitroazoles in hypoxic radiosensitization.

In vitro and in vivo sensitizing activities of a variety of nitroazole derivatives including misonidazole (MISO), SR-2508, and RSU-1069 were correlated by the aid of pharmacokinetic measurements of the drug uptake in animal solid tumors. The sensitizer enhancement ratio in vivo (SERvivo) on solid tumors increased linearly with the square root of administrated dose (Ds). The specific activity (A) in vivo of nitroazoles was evaluated from the square-root empirical relationship, SERvivo = 1.00 + A D1/2S. The intratumor concentration of nitroazoles at a given time t after administration was in proportion to the DS, in which the proportional constant was defined as the tumor-affinity factor FT,t. The absolute molar activity alpha M defined by A(M/FT,t)1/2, where M is the molecular weight of nitroazoles, showed a linear relationship with the SER in vitro (SERvitro) at 1 mM of sensitizers. The sensitizer dose required to achieve an SERvivo of 1.5 (DS,1.5) decreased and thus the overall sensitizing efficiency on animal solid tumors increased as the FT,t became greater.

Animals↗
PubMed1989

Characteristics of fluorinated nitroazoles as hypoxic cell radiosensitizers.

Types of 2-nitroimidazoles and 3-nitro-1,2,4-triazoles bearing one or two fluorine atoms on their side chains were synthesized to evaluate their physicochemical properties, radiosensitizing effects, and toxicity. The reduction potential of the compounds containing one fluorine was similar to that of misonidazole (MISO), whereas that of the difluorinated compounds was slightly higher. Both mono- and difluorinated compounds had an in vitro sensitizing activity comparable to or slightly higher than that of MISO. The fluorinated 3-nitrotriazoles were almost as efficient as the 2-nitroimidazoles with the same substituent. In vivo, some of the compounds were up to twice more efficient than MISO, whereas others were as efficient as MISO. Toxicity in terms of LD50/7 in mice was quite variable depending on the side-chain structure; the amide derivatives were less toxic than MISO, whereas the alcohol and ether derivatives were more toxic. In view of the radiosensitizing effect and toxicity in vivo, at least one compound, KU-2285 (a 2-nitroimidazole with an N1-substituent of: CH2CF2CONHCH2CH2OH) has been found to be as useful a hypoxic cell sensitizer as SR-2508.

Animals↗
PubMed1989

Alterations of life span in the nematode Caenorhabditis elegans under monoxenic culture conditions.

The nematode Caenorhabditis elegans was cultured monoxenically with E. coli as a food source and the influence of the bacterial growth conditions on the life span was studied. When bacterial growth was restricted by reducing the concentration of bactopeptone, which was supplied as the energy source in nematode growth medium (NGM), the nematode's life span tended to be prolonged without a marked effect on postembryonic development. The effect of bactopeptone on the life span was clearly observed during the postreproductive period (that is, after the egg-laying stage of the wild-type C. elegans) rather than during the larval to young adult stage. Evidence is presented that this alteration of the life span was not brought about by any factor in the bactopeptone but by the concentration of bacteria.

Animals↗
PubMed1989

A new, potent 2-nitroimidazole nucleoside hypoxic cell radiosensitizer, RP170.

The radiosensitizing activity, acute toxicity and pharmacokinetics of RP170, a new hypoxic cell radiosensitizer, were compared with those of misonidazole (MISO) and SR2508. RP170 belongs to the group of 2-nitroimidazole nucleosides, which are designed to be selectively excluded from the neural tissue. The reduction potential of RP170 was similar to that of MISO and SR2508. The partition coefficients in octanol/water of RP170, MISO, and SR2508 were 0.094, 0.35, and 0.021, respectively. The radiosensitizing activity of RP170 was similar to that of MISO and SR2508 in vitro and in vivo. There was no significant difference in the radiosensitizing activity of RP170 in vivo between intravenous and intraperitoneal administration. The acute toxicity of RP170 was the same as that of SR2508. Pharmacokinetic evaluation showed that the concentration of RP170 in the brain was as low as that of SR2508. RP170 is expected to have the same radiosensitizing effects as MISO and SR2508, and to be less neurotoxic than MISO.

Animals↗
PubMed1989

Radiosensitizing hypoxic cells with new 3-nitro-1,2,4-triazole derivatives in vitro and in vivo.

The new regioisomer derivatives 4a-f and 5a-f of 3-nitro-1,2,4-triazole (3-NTR) were synthesized for the development of new radiosensitizers of hypoxic cancer cells for radiotherapy. N(2)-Substituted 3-NTR derivatives 5a-f were stronger radiosensitizers of hypoxic cells in vitro (Chinese hamster V79 cells) than N(1)-substituted 3-NTR derivatives 4a-f, but in vivo they were weaker (SCCVII carcinoma cells inoculated into C3H/He mouse).

Animals↗
PubMed1989

The effect of fructose on collagen glycation.

The effect of fructose on the formation of advanced Maillard reaction products which have fluorescence and cross-links was investigated. Type I collagen was added to various concentrations of glucose and fructose which were then incubated at 37 C for 4 weeks. Both the level of furosine and the fluorescence intensity increased in direct proportion to glucose and fructose levels and to the duration of incubation. Incubation with fructose produced less furosine but more intense fluorescence than incubation with glucose. These results suggest that fructose in the polyol pathway plays an important role in the formation of advanced Maillard products.

Animals↗