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Biomedical subjects

T S Lin

Publications and source records attributed to T S Lin.

At least 163 records · Page 9Linked to original sources
PubMed1980

The effect of the nitrosourea analog of thymidine, 3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine, on Escherichia coli thymidine kinase.

Escherichia coli thymidine kinase (ATP:thymidine 5'-phosphotransferase, EC 2.7.1.21) is irreversibly inactivated by incubation with 3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine (3'-CTNU). The inactivation of the enzyme followed first-order kinetics even after loss of 96% of the original activity. This indicates that the inactivation process is a one-kill phenomenon and not a generation of less active enzyme. The addition of a preincubated aqueous solution of 3'-CTNU to the enzyme reaction mixture did not inactivate the enzyme. ATP . Mg2+ but not thymidine protects the enzyme from inactivation by 3'-CTNU. The allosteric regulators, dTTP, dCTP and dCDP also afforded complete protection of the enzyme from inactivation by 3'-CTNU. These data indicate that the dimer form of the enzyme is completely resistant to inactivation by 3'-CTNU, but the monomer form of the enzyme is sensitive. The specificity of the protection is supported by the finding that neither ATP . Mg2+ nor thymidine protect yeast alcohol dehydrogenase from inactivation by this nitrosourea analog of thymidine.

Adenosine Triphosphate↗
PubMed1980

Synthesis and antineoplastic activity of a novel series of phosphoramide mustard analogues of pyrimidine deoxyribonucleosides.

A novel series of cyclophosphamide derivatives of pyrimidine deoxyribonucleosides (6-9) has been synthesized from the corresponding amino nucleosides. Our preliminary findings have shown that three of these cyclophosphamide nucleoside analogues, 6, 7, and 9, have potent inhibitory effects on the replication of L1210 cells in vitro (ED50 = 1.2-1.5 x 10(-5) M). Since cyclophosphamide (cytoxan) has no cytotoxicity under these conditions, our findings indicate that these novel phosphamide derivatives have unusual biological properties which may include a unique mode of activation.

Animals↗
PubMed1980

2-Methylanthraquinone derivatives as potential bioreductive alkylating agents.

Hypoxic cells of solid tumors are an obstacle to effective cancer therapy. Since hypoxic cells remote from the tumor blood supply may have a greater capacity for reductive reactions than well-oxygenated cells, we have prepared a series of anthraquinone prodrugs which may be capable of generating a reactive quinonemethide species following enzymatic reduction to the hydroquinone and loss of the substituent on the methylene group in the 2 position. The synthesized 2-methyl-substituted anthraquinone derivatives have first half-wave reduction potentials of -0.52 to -0.56 V at pH 7.0, which are the lowest oxidation-reduction potentials of quinone bioreductive alkylating agents synthesized by this laboratory to date. Tests of the cytotoxicity of these agents to oxygenated and chronically hypoxic EMT6 tumor cells in culture demonstrated that 2-(hydroxymethyl)anthraquinone, 2-[(N-methylcarbamyl)-methyl]anthraquinone, 2-[[(p-toluenesulfonyl)oxy]methyl]anthraquinone, and 2-(methoxymethyl)anthraquinone were significantly more toxic to hypoxic cells than to their normally aerated counterparts. The findings demonstrate differences between various leaving groups in the 2 position for the expression of differential cytotoxicity.

Alkylating Agents↗
PubMed1980

Synthesis and biological activities of chloroethylurea, methylurea, and nitrosourea analogues of N-deacetylmethylthiocolchicine.

A series of urea and nitrosourea analogues of N-deacetylmethylthiocolchicine (1) has been synthesized, and their antineoplastic and antiviral activities were evaluated. The objective for combination of two active moieties, such as thiocolchicine and nitrosourea, into one molecule was the generation of compounds with potential improved biological and pharmacological properties. The ED50 for 2, 3, 4, and 5 was 1.6, 1.2, 3.3, and 1.8 X 10(-8) M for L1210 cells and 3.0, 2.7, 2.9, and 2.6 X 10(-8) M for S-180 cells, respectively. The synthesis and cytotoxic and antiviral properties of these compounds are discussed.

Animals↗
PubMed1980

Topical therapeutic efficacy of 9-(2-hydroxyethoxymethyl)guanine and 5-iodo-5'-amino-2',5'-dideoxyuridine on oral infection with herpes simplex virus in mice.

The therapeutic efficacy of two new antiviral agents, 5-iodo-5'-amino-2', 5'-dideoxyuridine (AIdUrd) and 9-(2-hydroxyethoxymethyl)guanine (ACV), in the model of mouse lip inoculated with herpes simplex virus type 2 is reported. The effects on development of clinical lesions, viral replication in the inoculated lips, and establishment of latent viral infection in the trigeminal ganglia were observed. The earlier the treatment with AIdUrd and ACV was initiated after inoculation, the better was the chemotherapeutic effect. AIdUrd and ACV treatment, when initiated 48 and 72 hr after inoculation, respectively, showed no chemotherapeutic efficacy. Establishment of viral latent infection in sensory ganglia was significantly prevented only when ACV treatment was initiated very early (1 or 3 hr) after inoculation. The results indicate that both drugs have significant antiviral activity, in part dependent on the time of initiation of therapy, and that ACV is superior to AIdUrd as a topical agent for therapy of herpes simplex virus type 2 infections.

Acyclovir↗
PubMed1980

Structural studies on cutinase, a glycoprotein containing novel amino acids and glucuronic acid amide at the N terminus.

Cutinase I and cutinase II, two extracellular enzymes produced by Fusarium solani pisi, were shown to be glycoproteins containing 4.3% and 5.1% carbohydrates, respectively. Upon treatment with alkali both enzymes generated chromophores which absorbed at 241 nm. Treatment of both proteins with alkaline NaB3H4 gave labeled protein and labeled monosaccharides. Hydrolysis of the labeled protein followed by chromatographic and enzymatic analyses of the products showed that alanine, 2-aminobutyrate, phenylalanine, tyrosine and L-gulonic acid accounted for nearly all of the 3H contained in the protein. The four labeled amino acids were shown to be 1:1 mixture of D and L isomers and 3H was nearly equally distributed between alpha and beta positions in each amino acid. The N-terminal amino group of cutinase I did not react with either phenylisothiocyanate of dansyl chloride. This amino group was suggested to be in amide linkage with glucuronic acid because upon treatment of the protein with neutral NaB3H4, gulonic acid attached to the protein became labeled and only gulonic acid was labeled when the protein was deglycosylated with HF prior to alkaline NaB3H4 treatment. Furthermore, N-gulonyglycine was isolated from the pronase digest of the labeled protein. Chromatographic identification and quantification of the labeled carbohydrates released from cutinase I by alkaline NaB3H4 showed that one mole of cutinase I has one mole each of mannose, arabinose, N-acetylglucosamine, and glucuronic acid O-glycosidically linked to serine, threonine, beta-hydroxyphenylalanine, and beta-hydroxytyrosine. In addition, the N-terminal glycine is in amide linkage with glucuronic acid. Since almost identical experimental results were obtained with cutinase II this protein is also suggested to have the same structural features as those suggested above for cutinase I.

Amino Acids↗
PubMed1980

Comparative analysis of the immunosuppressive properties of two antiviral, iodinated thymidine analogs, 5-iodo-2'-deoxyuridine and 5-iodo-5'-amino-2',5'-dideoxyuridine.

5-Iodo-5'-amino-2',5'-dideoxyuridine (AldUrd), given as five single i.p. injections on Days 0 to 4 after antigenic challenge with sheep erythrocytes, had no demonstrable effect on serum hemagglutinin titers in doses as high as 2000 mg/kg/day. This was the maximum feasible single dose, but no 10% lethal dose was determinable. Similarly, 5-iodo-2'-deoxyuridine (IdUrd), 50 mg/kg/day (10% lethal dose), on Days 0 to 4 did not significantly affect this humoral response. However, with a more sensitive assay, immunocytoadherence, reductions in the number of hemagglutinin-forming cells in the spleen were found at several levels of AldUrd and IdUrd, but the same level of inhibition was attained by a course of AldUrd, 2000 mg/kg, or IdUrd, 50 mg/kg. Spleen cell-mediated immunity against lethally irradiated L1210 was measured by 4-hr 51Cr release and 48-hr growth inhibition assays. Both drugs showed dose-related immunosuppression. With AldUrd, 2000 mg/kg/day, and IdUrd, 100 mg/kg/day, on Days 0 to 4, cytotoxicity was inhibited by 35 to 68% and 73 to 90%, respectively. In comparison, a similar course of 1-beta-D arabinofuranosylcytosine, 40 mg/kg/day, completely abrogated both humoral and cell-mediated immunity. When AldUrd and IdUrd were administered on Days -5 to -1, little effect on either type of immunity was found, while pretreatment with the alkylating agent, cyclophosphamide, abolished all T-cell-mediated killing as measured on Day 7. Thus, AldUrd appears to be a very mild and IdUrd a moderate to strong cell cycle-dependent immunosuppressive.

Animals↗
PubMed1979

Effect of 5-iodo-5'-amino-2',5'-dideoxyuridine on varicella-zoster virus in vitro.

The antiviral effect of the nucleoside analog 5-iodo-5'-amino-2',5'-dideoxyuridine (AIU) was tested with three isolates of varicella-zoster virus (VZV). AIU concentrations of 10 to 800 muM (3.5 to 288 mug/ml) reduced the number of plaques produced by VZV-infected cells and cell-free VZV from approximately 30 to 95%. Smaller plaque size was also observed in the presence of AIU. AIU was less effective than arabinofuranosylthymine in reducing VZV-induced plaques since as little as 5 mug of arabinofuranosylthymine per ml completely blocked plaque formation by cell-free VZV. Toxicity assays with human diploid embryo fibroblast cells were also carried out. Drug concentrations as high as 800 muM were not toxic to human diploid embryo fibroblast cells as determined by radiolabeling of cell deoxyribonucleic acid, ribonucleic acid, and protein.

Arabinonucleosides↗
PubMed1978

A novel synthesis and biological activity of several 5-halo-5'-amino analogues of deoxyribopyrimidine nucleosides.

A novel synthetic procedure has been developed for the large-scale synthesis of 5-chloro-, 5-bromo-, and 5-iodo-5'-amino-2',5'-dideoxyuridine (4c-e) as well as of two new analogues, 5-iodo-5'-amino-2',5'-dideoxycytidine and 5-fluoro-5'-amino-2',5'-dideoxyuridine (4a and 4b), in good yield. The starting materials, 5-halo-2'-deoxyuridine and 5-halo-2'-deoxycytidine, are readily available and the method is straightforward. This report describes the synthesis and the biologial activities of these compounds.

Animals↗
PubMed1978

Antineoplastic agents. 1. Synthesis and antineoplastic activities of chloroethyl- and methylnitrosourea analogues of thymidine.

A new class of chloroethyl- and methylnitrosourea analogues of thymidine, 5a,b, 6, 10, and 11, has been synthesized from the corresponding amino nucleosides, 2 and 7. The 3'-chloroethyl and 3'-methyl derivatives, 10 and 11, inhibited L1210 cell growth in culture (ED50 = 1.5 and 1.0 micrometer, respectively) more effectively than 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (ED50 = 4 micrometer) and the 5'-nitrosourea analogues. Neither the alkylating nor the carbamoylating activities of these compounds correlated with their biological activity.

Alkylating Agents↗
PubMed1978

Induction of a biopolyester hydrolase (cutinase) by low levels of cutin monomers in Fusarium solani f.sp. pisi.

Cutin hydrolysate induced the production of an extracellular cutinase by glucose-grown Fusarium solani f. sp. pisi. The rate of production depended on the amount of cutin hydrolysate added up to 80 mug/ml, and saturation was attained at this level. Glucose was found to be a repressor of cutinase production. A radial immunodiffusion assay for cutinase was developed, and the induction of cutinase by cutin hydrolysate was confirmed by this direct assay. When cutinase was induced by cutin hydrolysate, exogenous labeled phenylalanine was incorporated into cutinase, which was shown to be the major (>70%) protein in the extracellular fluid. Induction of cutinase by cutin hydrolysate was not inhibited by actinomycin D and was stimulated ( approximately 100%) by cordycepin. Addition of cycloheximide with the inducer, or up to 12 h after the addition of the inducer, resulted in a nearly immediate cessation of cutinase production. Deoxyglucose, an inhibitor of proten glycosylation, inhibited the induction of cutinase by cutin hydrolysate. omega-Hydroxy fatty acids were more effective in inducing cutinase than any of the other more polar acids of cutin. Experiments with derivatives and analogues of omega-hydroxy C(16) acid indicated that a free hydroxyl group at the omega-position was the most important factor determining the cutinase-inducing activity. n-Aliphatic primary alcohols with 14 or more carbon atoms induced cutinase, and n-C(16) was the most effective inducer. These results strongly suggest that the monomers function as the chemical signal which induces the extracellular hydrolase.

Carboxylic Ester Hydrolases↗