tretinoin and Leukemia-L5178

The effects of simultaneous administration of some dyadic combinations of antioxidants or vitamins and related agents on cellular proliferation of mouse leukaemia L5178Y cells in-vitro have been examined experimentally. The data were analysed on the basis of the concept of independence for evaluation of interactions between biologically active agents. An approach for evaluation of the synergism or antagonism of the action of two agents is proposed in which the types and extents of interactions are described by response-surface diagrams. The combinations phytol with trans-retinol, abscisic acid with trans-retinol, and menadione with sodium L-ascorbate were synergistic, whereas menadione with trans-retinol, and plumbagin with trans-retinol were antagonistic in the dose-range tested. These results reveal that the interactions between two agents depend not only on the combinations of agents but also on the dose ranges or the ratios of agents under the experimental domain studied.

Topics: Abscisic Acid; Animals; Antineoplastic Agents; Antioxidants; Cell Division; Drug Screening Assays, Antitumor; Drug Synergism; Leukemia L5178; Mice; Tretinoin; Tumor Cells, Cultured; Vitamin K

The importance of cell membrane components as target sites for the action of 2,3,5-tris(ethyleneimino)-benzoquinone (Trenimon), mechlorethamine hydrochloride (HN2) and tris(2-chloroethyl) amine hydrochloride (HN3) was investigated. Uptake of 2-aminoisobutyric acid (AIBA) was studied under nonsaturating conditions where the transport system was rate-limiting for the uptake. Uptake of AIBA into L5178Y leukaemic cells was either inhibited or stimulated, depending on the type of the drug, the drug concentration and the length of incubation. Treatment of human erythrocytes with 10(-3) M HN3 produced new high-molecular-weight protein bands on SDS-polyacrylamide gel electrophoresis. Conversely, HN3 had no effect on L5178Y cell membrane proteins. Neither HN2 nor Trenimon produced any detectable changes in membrane proteins of L5178Y cells or human erythrocytes. None of the three drugs at concentrations and incubation conditions which inhibited cell replication changed the stoichiometry or dissociation constant of concanavalin A (Con A) binding sites on L5178Y cells. Trenimon at highly toxic concentrations had no effect on the fluidity of phospholipid membranes or of membranes of Ehrlich ascites tumour cells as analysed by ESR spin-label methods. The results presented here do not support the hypothesis that cell membranes are the primary target sites for alkylating drugs.

Topics: Alkylating Agents; Aminoisobutyric Acids; Animals; Carcinoma, Ehrlich Tumor; Cell Membrane; Electron Spin Resonance Spectroscopy; Erythrocyte Membrane; Humans; Leukemia L5178; Mechlorethamine; Mice; Nitrogen Mustard Compounds; Tretinoin

As part of the preclinical drug safety evaluation of the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide (HPR) in vitro and in vivo tests were conducted to assess its genotoxic activity. Negative findings from HPR testing were demonstrated in the Ames Salmonella/microsomal activation test, the L5178Y mouse lymphoma assay, and a rat bone marrow cytogenetics study. These data imply that HPR lacks the ability to induce point mutations or chromosomal aberrations, and is therefore not genotoxic. Limited testing of retinyl acetate in the Ames test, the L5178Y mouse lymphoma assay, and the primary rat hepatocyte/DNA repair assay yielded consistently negative results. These findings and previously published results concerning retinoid genotoxicity are discussed.

Topics: Animals; Antineoplastic Agents; Bone Marrow Cells; Chromosome Aberrations; Cricetinae; Cytogenetics; Diterpenes; Fenretinide; Leukemia L5178; Male; Mesocricetus; Mice; Mitosis; Mutagenicity Tests; Rats; Retinoids; Retinyl Esters; Salmonella typhimurium; Tretinoin; Vitamin A

Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver microsomal metabolizing system (S-9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S-9 reduced cellular toxicity. For N-(4-hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S-9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S-9. HPR was metabolized by the S-9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S-9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S-9 or lymphoma cells. The reduced toxicity of this drug in the presence of S-9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biotransformation; Cell Division; Cell Line; Cells, Cultured; Epoxy Compounds; Ethers, Cyclic; Fenretinide; Leukemia L5178; Leukemia, Experimental; Male; Mice; Microsomes, Liver; Mutagenicity Tests; Mutagens; Piperidines; Propionates; Rats; Tretinoin