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Biomedical subjects

A Begleiter

Publications and source records attributed to A Begleiter.

At least 73 records · Page 4Linked to original sources
PubMed1983

Uptake and decomposition of chlorambucil by L5178Y lymphoblasts in vitro.

The uptake of [14C]chlorambucil by L5178Y lymphoblasts was studied using thin-layer chromatography to identify the various radioactive components that enter or leave cells. Theoretical calculations predicted that entry of chlorambucil into cells by simple diffusion would be rapid and essentially complete in 45 sec or less. Uptake of intact chlorambucil was rapid, reaching a cell/medium ratio of approximately 1.5 in less than 15 sec at both 37 degrees and 4 degrees, consistent with a simple diffusion mechanism. In cells treated with [14C]chlorambucil for 60 min, the intracellular level of intact drug decreased with time, and this decay was attributed to hydrolysis and alkylation. The level of intact drug in the medium decreased at a similar rate resulting in a nearly constant cell/medium distribution ratio. Intact chlorambucil in the cells was found to be entirely ethanol- and trichloroacetic acid-soluble. Efflux of intact chlorambucil was very rapid and temperature-insensitive. These findings suggest that chlorambucil efflux, as well as influx, is by a simple diffusion mechanism. A derivative of chlorambucil was found in ethanol solutions of the drug. This derivative, which may be the ethyl ester of the drug, is highly concentrated in cells and may interfere with pharmacological investigations of chlorambucil.

Alkylation↗
PubMed1983

Cytocidal action of the quinone group and its relationship to antitumor activity.

Many clinically useful antitumor agents have a quinone group in their structure. A series of model compounds has been studied to determine if the quinone group is involved in the cytotoxic activity of these agents and to investigate the mechanism of this action. Hydrolyzed benzoquinone mustard, which contains a quinone group, produced significant cell kill of L5178Y lymphoblasts, whereas hydrolyzed aniline mustard, which has a similar chemical structure but contains no active functional groups, showed little activity against this cell line. Benzoquinone mustard, which possesses both a quinone moiety and an active alkylating group, was approximately 30,000 times more active against L5178Y cells than was hydrolyzed benzoquinone mustard. It was approximately 600 times more active than aniline mustard, a compound which has the same alkylating group but no quinone function, and 200 times more active than an equimolar combination of aniline mustard and hydrolyzed benzoquinone mustard. The cytotoxic activity of hydrolyzed benzoquinone mustard was inhibited by either superoxide dismutase or catalase, while catalase but not superoxide dismutase inhibited the activity of benzoquinone mustard. Neither enzyme had any effect on the cytocidal action of aniline mustard. These studies suggest that the presence of a quinone group in the chemical structure of a compound can result in significant cell kill by a mechanism that appears to involve free radicals and active oxygen species. In addition, if the compound contains an alkylating group which can bind to DNA, as well as a quinone moiety, the cytocidal activity of the agent appears to be enhanced and is greater than that resulting from an additive effect of the two groups.

Animals↗
PubMed1982

Mechanism of efflux of melphalan from L5178Y lymphoblasts in vitro.

The mechanism of efflux of melphalan from L5178Y lymphoblasts in vitro was investigated. Evidence was obtained that drug efflux occurs by a process different from the influx mechanism. A time course of efflux followed a first-order process for at least 5 min, with a rate constant K of 0.13 +/- 0.05 (S.D.) min-1, and approximately 80% of drug taken up by the cells was exchangeable. From a kinetic analysis of melphalan efflux, it was not possible to determine if the mechanism of drug efflux was simple diffusion or a technically nonsaturable carrier-mediated process. The Q10 for drug efflux varied from 1.2 to 1.8, values intermediate between those expected for simple diffusion and a carrier-mediated process. Furthermore, drug efflux was sodium independent and was not inhibited by the presence of amino acids on the same side of the membrane, findings which support the concept that efflux was by simple diffusion. The presence of a wide variety of amino acids in the extracellular medium was found to stimulate melphalan efflux. An evaluation of the structure-activity relationship disclosed that amino acids containing hydroxyl, acidic, or amide side chains were most active; however, a distinct pattern between amino acid structure and stimulation of efflux was not established. The stimulation process was concentration dependent and was not restricted to either L5178Y cells or to melphalan as transport substrate.

Amino Acids↗
PubMed1980

A comparison of melphalan transport in human breast cancer cells and lymphocytes in vitro.

Evidence is presented that melphalan uptake by MCF-7 human breast cancer cells and peripheral blood lymphocytes from normal human subjects is an active process involving 2 amino acid carriers. Quantitative differences were observed in drug transport between the 2 cell types. Cell/medium distribution ratios of melphalan at equilibrium conditions were approx. 4-fold higher in breast cancer cells than in lymphocytes. The transport capacity, Vmax, for both carrier systems was at least 50-fold greater in MCF-7 cells than in lymphocytes, whereas the Michaelis constants were similar. These findings, in part, provide a rational basis for the use of melphalan in the chemotherapy of breast cancer.

Amino Acids↗
PubMed1980

Metastatic renal cell carcinoma in the gingiva mimicking a hyperplastic lesion. Case report.

An unusual case of metastatic cell carcinoma in the gingiva, without roentgenographic evidence of underlying bone involvement, is described. The tumor had the clinical appearance of a pyogenic granuloma and peripheral giant cell granuloma. Histologic sections and the pertinent history revealed the tumor to be a metastatic renal cell carcinoma. Review of the literature reveals that metastatic lesions to the gingiva are rare, but when they occur they tend to mimic clinically the common localized hyperplastic lesions of the gingiva.

Adenocarcinoma↗
PubMed1979

Active carrier-mediated transport of melphalan by two separate amino acid transport systems in LPC-1 plasmacytoma cells in vitro.

Previous studies have shown that uptake of several alkylating agents occurs by independent transport mechanisms. Uptake of one of these agents, the phenylalanine derivative of nitrogen mustard (melphalan), has been investigated in LPC-1 plasmacytoma cells in vitro. Evidence suggesting that melphalan uptake is an active process is that uptake of free intact melphalan proceeds "uphill" against a concentration gradient, is temperature- and sodium-dependent, and is inhibited by several metabolic antagonists. Other findings supporting the concept that melphalan uptake is carrier-mediated is that uptake follows biphasic Michaelis-Menten kinetics, is chemically specific, and is mediated by at least two separate amino acid transport systems. Uptake by one system was sensitive to DL-beta-2-aminobicyclo[2,2,1]-heptane-2-carboxylic acid, was sodium-independent, and appeared to be mediated by system L. The second unassigned system was characterized by sodium dependence, insensitivity to 2-aminoisobutyric acid and 2-(methylamino)isobutyric acid, and was inhibited by alanine, serine, cysteine, and other amino acids.

Amino Acids↗