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Biomedical subjects

A M Treston

Publications and source records attributed to A M Treston.

46 records · Page 3Linked to original sources
PubMed1989

In vivo diagnosis and therapy of human tumors with monoclonal antibodies: selection of antibodies and preliminary clinical studies in small cell carcinoma of the lung.

Initial monoclonal antibody therapy trials include an attempt to control malignant proliferation of small cell lung cancer by blocking the autocrine stimulation of gastrin releasing peptide. A critical issue is the adequacy of antibody penetration into the tumor bed to effect immunologic blockade of the mitogenic peptide. The use of an indium-111 antibody chelate which is coadministered with the first therapeutic antibody administration facilitates analysis of the pharmacokinetic dynamics for this trial. If this approach is successful with gastrin releasing peptide, other peptide hormones with autocrine effects could also be targeted. A combination of anti growth factor therapies could lead to successful therapeutic control of this lethal disease.

Antibodies, Monoclonal↗
PubMed1988

Insulin-like growth factor-I can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro.

The effect of insulin-like growth factor I (IGF-I) on growth of small cell lung cancer (SCLC) cell lines was studied. Western blot analysis of whole cell lysates of cell lines NCI-H345 and NCI-N417 demonstrated the presence of a 16-kD band consistent with an IGF-I precursor molecule. Scatchard plot analysis of cell line NCI-H345 using 125I-labeled IGF-I demonstrated two high affinity specific binding sites (Kd 1.3 and 4.0 nM with maximal rate (Bmax) 200 and 500 fmol/mg protein, respectively). The exogenous addition of IGF-I, IGF-II, or insulin resulted in marked proliferation of human SCLC cells as evaluated using an in vitro growth assay. These peptides stimulated the growth of SCLC cell lines NCI-H82, NCI-H209, NCI-H345, and NCI-N417. The concentration of IGF-I producing maximal SCLC cell growth was 10-100-fold less than that of insulin or IGF-II, whereas the maximal growth stimulated by the optimal concentration of these peptides were similar. An MAb that specifically binds to the IGF-I receptor (but not to the insulin receptor) mediates a dose-dependent inhibition of cell growth in basal media as well as IGF-I, IGF-II, or insulin-supplemented media. The IGF-I receptor thus appears to be the common pathway for the mitogenic activity by IGF-I, IGF-II, and insulin for human SCLC cell lines. The demonstration of an IGF-I precursor molecule, specific IGF-I receptor binding, IGF-I-mediated growth stimulation, and inhibition of basal cell growth by an MAb to the IGF-I receptor suggests that an IGF-I-like molecule can function in vitro as an autocrine growth factor for human SCLC cell lines.

Animals↗
PubMed1987

Identification and synthesis of O-methylcatechol metabolites of phenobarbital and some N-alkyl derivatives.

5-Ethyl-5-(4-hydroxy-3-methoxyphenyl) barbituric acid was identified as a new, minor metabolite of phenobarbital in man. The identity of this O-methylcatechol metabolite was confirmed by an unequivocal chemical synthesis, and by GC-MS studies. Mephobarbital and the 1,3-dimethyl, 1-ethyl, and 1,3-diethyl analogues of phenobarbital yielded the corresponding N-alkylated O-methylcatechol metabolites, all of which were confirmed by synthesis. The N-alkyl barbiturates each gave additionally at least one O-methylcatechol metabolite in which N-dealkylation had occurred. These metabolites accounted for approximately 1-5% of the orally administered dose in man.

Catechols↗
PubMed1987

The metabolism of 2,5-diphenyloxazole (PPO) in human lymphocytes and rat liver microsomes.

The oxidative metabolism of 2,5-diphenyloxazole (PPO) is associated with 3-methylcholanthrene inducible cytochrome P-450. The major metabolite formed has m/z of 237, corresponding to hydroxylated PPO. All the possible hydroxylated metabolites of PPO were synthesized and characterized, enabling the assignment of a structure for the major metabolite and two minor metabolites. The metabolites are easily extracted and their fluorescence is quantifiable in alkaline medium with a sample fluorescence to blank fluorescence ratio of 400:1. A sensitive HPLC assay of PPO metabolism was also developed. PPO metabolism is readily catalyzed by 3-methylcholanthrene-induced rat liver microsomes and strongly inhibited by alpha-naphthoflavone, but poorly inhibited by metyrapone or SKF 525A, indicating the involvement of cytochrome P-448 or P1-450 in the metabolism of PPO. With human lymphocytes the method has proven to be a good indicator of "aryl hydrocarbon hydroxylase" (AHH) activity, correlating well with AHH assays using benzo(alpha)pyrene (BP) as a substrate. Both the induced BP and PPO metabolism by human lymphocytes is inhibited by alpha-naphthoflavone, but not by metyrapone.

Animals↗
PubMed1985

N-Alkyl barbiturates. A series of compounds for the study of metabolic structure-activity relationships.

Many therapeutic agents are metabolised along multiple pathways, but up to now there have been few investigations addressing the question of which chemical features of drugs govern the participation in, and quantitative significance of, different biotransformation pathways. To assess the influence of variations of the chemical structure upon metabolism, a series of novel barbiturate analogues has been synthesized. The N1-monoalkylated and N1,N2-dialkylated phenobarbitones and 2-desoxyphenobarbitones have been synthesized via condensation of ethylphenylmalonic acid derivatives with different N-alkylated ureas or thioureas, and/or by base-catalyzed N-alkylation of different barbituric acids.

Animals↗
PubMed1984

The regulatory roles of liver and kidney in cobalamin (vitamin B12) metabolism in the rat: the uptake and intracellular binding of cobalamin and the activity of the cobalamin-dependent enzymes in response to varying cobalamin supply.

To examine possible regulatory roles of liver and kidney in cobalamin metabolism, specific activities of the two cobalamin-dependent enzymes, uptake in vivo of cyano [57Co]cobalamin [( 57Co]CNCbl) and the binding of [57Co]Cbl to intracellular proteins were measured in normal, cobalamin-loaded and cobalamin-deficient rats. Cobalamin deficiency and cobalamin loading produced greater changes in cobalamin concentration in the kidney than in the liver. Although cobalamin deficiency resulted in a decrease in total methylmalonyl-coenzyme A mutase (methylmalonyl-CoA mutase) in both organs, cobalamin loading had no effect. Neither deficiency nor loading altered total methyltransferase activity. The holoenzyme activities of both enzymes correlated with changes in tissue cobalamin levels. Uptake of [57Co]Cbl indicated that the kidney, in contrast to the liver, increased its uptake during loading and reduced it during deficiency, suggesting a possible regulatory role for this organ. In the normal rat, 24 h after injection of [57Co]CNCbl, 0.3% of the administered [57Co]Cbl was present in the liver as free cobalamin. By contrast, in the kidney, over 13% of the [57Co]Cbl was present in the free form. During deficiency free renal [57Co]Cbl was reduced to 0.6% of the administered [57Co]Cbl whereas in cobalamin-loaded rats it was increased to more than 27%. It is concluded that alterations in tissue cobalamin levels resulting from differences in cobalamin supply are due to changes in the large pool of free cobalamin present in the kidney and not to changes in the intracellular binding.

Animals↗
PubMedDate not supplied

Identification of p-hydroxyprimidone as a minor metabolite of primidone in rat and man.

Urine specimens from rats and humans who received single doses of primidone (PRM) have been investigated by GC/MS procedures. In addition to the previously documented metabolites of PRM, a small chromatographic peak was encountered which had a mass spectrum suggesting a hydroxy-PRM derivative. Synthesis of p-hydroxy-PRM from PRM was effected; the para isomer was separated from unwanted isomers by preparative HPLC. The PMR spectrum of the synthetic compound proved the position of the hydroxy substituent to be para. This compound had identical GC retention time and an almost identical mass spectrum with that obtained in the urinary extracts. Para-hydroxy-PRM was therefore confirmed as a new, minor metabolite of PRM in rat and man.

Adult↗