PubMed Health⌕ Search

Biomedical subjects

R Haubner

Publications and source records attributed to R Haubner.

22 records · Page 2Linked to original sources
PubMed1999

Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting.

UNLABELLED: The alpha(v)beta3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective alpha(v)beta3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [1251]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized alphaIIbeta3 and alpha(v)beta3 integrins. Expression of the alphaVbeta3 receptor on the different tumors was validated by immunohistochemical methods using alpha(v) and alpha(v)beta3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. RESULTS: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for alpha(v)beta3. Immunohistochemical staining clearly indicates the presence of the alpha(v)beta3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 +/- 0.32 %ID/g for the melanoma M21 and 3.50 +/- 0.49 %ID/g for the osteosarcoma and decreases to 1.30 +/- 0.13 %ID/g and 2.03 +/- 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 +/- 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [1251]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. CONCLUSION: [125I]P2 exhibits high affinity and selectivity for the alpha(v)beta3 integrin in vitro and in vivo and, thus, represents the first radiolabeled alpha(v)beta3 antagonist for the investigation of angiogenesis and metastasis in vivo.

Animals↗
PubMed1988

The occurrence of tobacco-specific nitrosamines in oral tobacco products and their potential formation under simulated gastric conditions.

The levels of the tobacco-specific nitrosamines: N-nitrosoanabasine, N-nitrosoanatabine, N-nitrosonornicotine and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone in a variety of chewing tobaccos, oral snuffs, masheri and zarda samples were determined. The potential endogenous formation of tobacco-specific nitrosamines was estimated by incubation of tobacco samples at pH 2.0 for 1 hr at 37 degrees C and over the pH range 1.0 to 5.5 under conditions simulating the normal fasting stomach, with a constant nitrite concentration of 25 microM. Under the simulated gastric conditions, N-nitrosoanabasine, N-nitrosoanatabine and N-nitrosonornicotine were formed, and maximum formation of these tobacco-specific nitrosamines occurred at pH 2.5. Nicotine, the major alkaloid present in tobacco and precursor to N-nitrosonornicotine and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone, was not nitrosated. The formation of N-nitrosonornicotine resulted from nitrosation of nornicotine, another alkaloid also present in tobacco. Under the acidic simulated gastric conditions, slight decomposition of 4-(N-nitrosomethyl-amino)-1-(3-pyridyl)-1-butanone via transnitrosation was observed.

Carcinogens↗
PubMed1983

Metabolism of carcinogenic and non-carcinogenic N-nitroso-N-methylaminopyridines. II. Investigations in vivo.

A comparative study of in vivo metabolism of isomeric N-nitroso-N-methylaminopyridines (NMPY) by analysis of urinary metabolites showed remarkable qualitative and quantitative differences in metabolic pathways. After oral application of the carcinogenic and mutagenic 2-NMPY to BD VI rats only 2-hydroxypyridine and 2-aminopyridine were excreted in urine. 2-Hydroxypyridine most probably is formed after activation of the parent compound by alpha-C-hydroxylation, demethylation and hydrolysis of the putative pyridine-2-diazonium intermediate. Evidence is presented that 2-amino-pyridine is generated by the same pathway after reductive cleavage of pyridine-azobonds formed by coupling of the diazonium intermediate to various nucleophiles. No metabolites derived from deactivating pathways and no unchanged 2-NMPY were detected in urine. After oral application of non-carcinogenic 4-NMPY, only the parent compound, its N-oxide and a ring hydroxylated metabolite with intact N-nitroso structure were found, together with 4-aminopyridine. Formation of the latter is thought to result from demethylation of the denitrosation product 4-methylaminopyridine. In contrast to metabolism of carcinogenic 2-NMPY, no 4-hydroxypyridine, indicative for activation of 4-NMPY to a diazonium intermediate, was detectable in urine.

Administration, Intranasal↗