Biomedical subjects

T C Chou

Publications and source records attributed to T C Chou.

At least 145 records · Page 8Linked to original sources

PubMed1990

Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.

Antiviral Agents↗

PubMed1990

Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A.

Optimal management of human immunodeficiency virus type 1 (HIV-1) infections may require combinations of agents that attack different targets in the viral replicative cycle. Zidovudine (AZT), recombinant soluble CD4 (rsCD4), and recombinant interferon-alpha A (rIFN-alpha A) were evaluated in 2- and 3-drug regimens against HIV-1 replication in vitro. Peripheral blood mononuclear cells and a CD4+ T cell line (H9) were studied using multiple HIV-1 replicative end points. Drug interactions were evaluated by the median-effect principle and the isobologram technique. AZT, rsCD4, and rIFN-alpha A inhibited HIV-1 synergistically in 2- and 3-drug combinations. The 3-drug regimen provided more complete virus suppression than the 2-drug regimens. In H9 cells, single-drug regimens lost effectiveness at 10-14 days and 2-drug regimens lost effectiveness at 14-18 days. In contrast, the 3-drug regimen showed nearly complete suppression over 28 days in culture without toxicity. Clinical trials of these 3 drugs in combination should be considered.

CD4 Antigens↗

PubMed1990

Analysis of the interactions of immunosuppressive drugs with cyclosporine in inhibiting DNA proliferation.

Though the high immunosuppressive efficacy of cyclosporine has revolutionized clinical transplantation, renal, hepatic, and neural toxicities limit its therapeutic potential. One approach to this problem is to combine CsA therapy with immunosuppressive agents that act synergistically with it, thereby permitting lower doses and mitigating drug-induced toxicity. The present study examines the in vitro interactions of various immunosuppressive agents--namely, 6-mercaptopurine (6MP), dexamethasone (Dexa), FK506, and Enisoprost (EP)--with CsA. These investigations dissect the impact of the drug combinations in inhibiting 3H-thymidine incorporation into DNA by normal human peripheral blood lymphocytes activated by mitogens or by alloantigens in mixed lymphocyte culture responses. The median-effect equation was used to analyze the dose-effect relationships of immunosuppressive drugs either alone or in combination. The interactions were quantified by calculation of combination indices (CI). CI values less than 1, greater than 1, and equal to 1 represent synergistic, antagonistic, and additive interactions, respectively. In combination with CsA, 6MP showed modest and Dexa profound synergism, while EP displayed modest and FK506 marked antagonism. These findings confirm the clinical impression of in vivo synergism between CsA and Dexa. They suggest that in vitro analysis of drug interactions may distinguish synergistic drug combinations potentially applicable to clinical practice.

Alprostadil↗

PubMed1990

In vitro inhibition of the infectivity and replication of human immunodeficiency virus type 1 by combination of antiretroviral 2',3'-dideoxynucleosides and virus-binding inhibitors.

We tested the in vitro inhibitory activities of three 2',3'-dideoxynucleosides and two inhibitors of viral binding in combinations against the infectivity and cytopathic effect of human immunodeficiency virus type 1. 3'-Azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine, combined with recombinant soluble CD4 (sCD4), brought about synergistic antiretroviral activity without toxicity at clinically achievable concentrations. Combinations of 2',3'-dideoxynucleosides plus dextran sulfate exerted similar synergistic antiviral effects without concomitant increases in toxicities. When sCD4 and dextran sulfate were combined, apparent antagonism was observed. We confirmed that no combination of sCD4 plus 3'-azido-2',3'-dideoxythymidine, 2',3'-dideoxyinosine, or 2',3'-dideoxycytidine significantly increased the inhibitory effect on colony formation of human myeloid-monocytic bone marrow cells in vitro at the concentrations used in this study. These data might have clinical relevance for the treatment of patients infected with human immunodeficiency virus.

Antiviral Agents↗

PubMed1990

Interferon-alpha and 3'-azido-3'-deoxythymidine are highly synergistic in mice and prevent viremia after acute retrovirus exposure.

This study was undertaken to calculate the in vivo drug interactions between recombinant human interferon-alpha A/D (rHuIFN-alpha A/D) and 3'-azido-3'-deoxythymidine (AZT) in a quantitative model for retroviral viremia. When given as single agents, both AZT and rHuIFN-alpha A/D suppressed virus-induced splenomegaly in a dose-dependent fashion in mice inoculated with Rauscher murine leukemia virus (RLV). However, suppressive doses of single-agent AZT caused anemia after 20 days of therapy. Combining rHuIFN-alpha A/D with AZT allowed drastic dose reductions for each agent while maintaining greater than or equal to 93% inhibition of splenomegaly. No clinically significant toxicity was seen. Computer analysis with the isobologram technique and combination index method showed that these combination regimens were highly synergistic. A 20-day course of AZT + rHuIFN-alpha A/D started 4 h after virus exposure was protective against RLV viremia and disease. After cessation of therapy, the animals were resistant to rechallenge with fully infectious RLV. We conclude that prompt initiation of effective combination therapy after retroviral exposure prevented viremia and disease and led to protective immunity.

Animals↗

PubMed1990

Inhibitory effects of isoquinoline-type alkaloids on leukemic cell growth and macromolecule biosynthesis.

A number of benzylisoquinoline alkaloids of plants indigenous to Taiwan were isolated and purified and their chemical structures were determined. These compounds, namely benzyltetrahydroisoquinolines or their N-oxides, aporphines, oxoaporphines and 1-N, N-dimethylaminoethylphenanthrenes or their N-oxides, were studied for their potency in inhibiting precursor incorporation into DNA, RNA and protein. Inhibition of murine leukemic L1210 and human leukemic CCRF-CEM and HL-60 cell growth was also examined. Of the compounds evaluated for cell growth inhibition, (+-)-N-methylcoclaurine(3), (-)-norannuradhapurine HBr(19), oxoglaucine (23), dicentrine methine (27) and 1-(N-methyl-N-hydroxyaminoethyl)-3, 4-methylenedioxy-7-methoxyphenanthrene (28) showed an IC50 less than 10 microM.

Alkaloids↗

PubMed1989

Enhancement of trimetrexate cytotoxicity in vitro and in vivo by carboxypeptidase G2.

Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia cell line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. The cytotoxic effect in vitro was detected using a colorimetric assay with a tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Dose-effect relationships of drugs alone and in combination were analyzed by the median effect principle and by the combination indices for quantitation of synergy or antagonism with the aid of a computer program. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure. The concentration of CPG2 required to decrease the cell count to 50% control for these cell lines was 3.5, 2.6, 26.6, and 7.9 x 10(-5) units/ml for CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively. A synergistic cytotoxic effect of trimetrexate after simultaneous continuous exposure with CPG2 was observed with CCRF-CEM cells and with the three resistant cell lines. This drug combination given to BALB/c x DBA/2 F1 mice bearing L1210 cells also produced synergy over a narrow range of drug doses. The activity of this combination in both methotrexate sensitive and methotrexate resistant cell lines indicates that clinical trials of this combination should be undertaken.

Animals↗

PubMed1989

The enhancement of the activity of 10-propargyl-5,8-dideazafolate and 5,10-dideazatetrahydrofolate by inhibitors of dihydrofolate reductase.

Treatment of H35 hepatoma cells with the lipid soluble dihydrofolate reductase inhibitors metoprine and trimetrexate cause a nearly 10-fold increase in the toxicity of the antipyrimidine folate analogue PDDF and the antipurine folate analogue DDATHF. Evaluation of these interactions by the combination index developed by Chou (17-20) yields results conforming to synergistic interactions. The capacity of PDDF to inhibit thymidylate synthase in intact cells as measured by tritium release from [5-3H]deoxyuridine was increased by approximately the same amount by preincubation with the dihydrofolate reductase inhibitors. The primary effect of the reductase inhibitors in causing greater activity may be a reduction in cellular folates which can cause 5,10-CH2H4PteGlun to decrease and cellular PDDF (polyglutamates) to increase. These conditions would favor inhibition of thymidylate synthase by PDDF by promoting formation of the stable, inhibited PDDF (polyglutamates)-thymidylate synthase-dUMP complex (12).

Animals↗

PubMed1989

Carboxypeptidase G2 enhances trimetrexate cytotoxicity in CCRF-CEM cell lines sensitive and resistant to methotrexate.

Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, degrades folates as well as methotrexate and other folic acid analogs such as aminopterin and dichloromethotrexate, but not the "non-classical" folate antagonist trimetrexate (TMTX). The possibility of enhancing TMTX cytotoxicity of CPG2 induced depletion of intracellular folates was investigated in human leukemic CCRF-CEM cells and in three methotrexate resistant sublines of these cells with different mechanisms of resistance, CCRF-CEM/E, a subline with increased DHFR; CCRF-CEM/P, a subline defective in polyglutamylation and CCRF-CEM/T, a subline with impaired MTX uptake. The cytotoxic effect was detected using a colorimetric assay with MTT. Dose-effect relationships of single drugs alone and in combination were analyzed by the median effect principle and by the combination indices for the quantitation of synergism or antagonism with the aid of a microcomputer. TMTX alone was very effective on the parent and all the resistant cell lines (CCRF-CEM/E, CCRF-CEM/P, CCRF-CEM/T) with ED50 values in the nanomolar range (1.4, 1.6, 1.5 and 0.7 nM, respectively) following 5 days of exposure. The ED50s of CPG2 for these cell lines were 3.5, 2.6, 26.6 and 7.9 X 10(-5) U/ml, respectively. A synergistic cytotoxic effect of TMTX after simultaneous continuous exposure was observed with CPG2 on CCRF-CEM cells and on the three resistant cell lines.

Antineoplastic Agents↗

PubMed1989

Combined effects of interferon and steroid hormones on 2',5'-oligoadenylate synthetase activity in chronic lymphocytic leukemia cells.

2',5'-oligoadenylate synthetase (OAS) has been implicated in the effects of interferons (INF) and steroid hormones on cell growth and differentiation. We studied the combined effects in vitro of hormones and INF on OAS activity in cells from 10 patients with chronic lymphocytic leukemia. IFN enhanced OAS activity in all cells studied and also induced morphologic transformation. Diethylstilbestrol was also found to induce OAS activity, but not morphologic transformation. Progesterone, tamoxifen and dihydrotestosterone had no effect on enzyme activity nor on morphology. In five samples, all with estrogen receptor activity, DES and INF were synergistic in inducing OAS activity. TAM-INF synergism was observed in one sample. DES and TAM did not, however, significantly enhance IFN-induced morphologic transformations. Hydrocortisone reduced OAS activity, and antagonized INF-induced enzyme activity and morphologic transformations. We conclude that hormones can modulate OAS activity in CLL cells. These findings may be of importance in the design of INF-based therapies of CLL.

2',5'-Oligoadenylate Synthetase↗

PubMed1989

An in vivo evaluation of alpha adrenergic receptors in canine prostate.

The role of alpha 2 adrenergic receptors in the prostate in vivo is unknown. A model was developed to measure canine prostatic urethral pressure in vivo, and to assess the ability of various alpha adrenergic blocking agents to affect prostatic pressure. In this model, an esophogeal pressure catheter is inserted into the prostatic urethra to record prostatic urethral pressure. We investigated the effects of alpha adrenergic agonists and antagonists on prostatic pressure using this model. Dose-response curves were generated for epinephrine, and were then repeated in the presence of either prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) or SK&F-86466 (alpha 2 antagonist). Prazosin was the most potent of the three drugs in competitively blocking epinephrine-induced contraction of the prostate, with an inhibition constant of 0.24 micrograms./kg. calculated from the double reciprocal plot. Clonidine, an alpha 2 adrenergic agonist, caused contraction of the prostate, which was also blocked by prazosin. Furthermore, the specific alpha 2 agonist BHT-920 was totally inactive in our system. These results demonstrate that the increase in urethral pressure caused by alpha-adrenergic agonists can be blocked by alpha adrenergic antagonists. However, the specific alpha 1 antagonist, prazosin, is more potent than alpha 2 antagonists, and is also effective against an alpha 2 agonist, clonidine. This suggests that blockade of alpha 1 receptors may be a more useful strategy for causing relaxation of the prostate than blockade of alpha 2 receptors.

Adrenergic alpha-Agonists↗

PubMed1989

Intercalating agents with covalent bond forming capability. A novel type of potential anticancer agents. 2. Derivatives of chrysophanol and emodin.

Fifty-one new C-methyl-modified derivatives of the anthraquinones chrysophanol and emodin or their various methyl ethers were prepared for structure-activity relationship studies of anticancer activity against mouse leukemia L1210 and human leukemia HL-60 cells. Representative compounds were spectrophotometrically studied for their capacity to interact with natural and denatured DNA. In general, those anthraquinones bearing an amino function interact with DNA. 1,8-Dimethoxyanthraquinones are incapable of intercalating into DNA. 1- or 8-Monohydroxymono-methoxyanthraquinones, however, interact with DNA to some extent. No straightforward correlation is apparent between the DNA-affinity data of the compounds studied spectrophotometrically and their cytotoxic effects. Cytotoxic potencies of these compounds on cell growth inhibition during a 72-h period are inversely correlated to their potencies when inhibiting [3H]TdR incorporation into DNA during the initial 30 min of exposure. Surprisingly, some compounds that showed more cytotoxicity did not inhibit initial TdR incorporation (0-30 min), while some others that strongly inhibited TdR incorporation initially did not exhibit cytotoxicity in 72 h. The results suggest that the cytotoxicity produced by these compounds is time dependent and is not a direct result of initial inhibition of DNA replication.

Animals↗

PubMed1989

Synergistic inhibition of Epstein-Barr virus: transformation of B lymphocytes by alpha and gamma interferon and by 3'-azido-3'-deoxythymidine.

We analyzed the effects of 3'-azido-3'deoxythymidine (AZT) and alpha and gamma interferon (IFN-alpha and IFN-gamma) on transformation of human umbilical cord lymphocytes (HUCLs) by Epstein-Barr virus (EBV). B lymphocytic outgrowth from HUCLs infected with EBV was monitored by focus formation; the presence of EBV genomes in transformed foci was confirmed by in situ cytohybridization and EBV nuclear antigen. The 50% inhibitory doses for preventing focus formation were 0.14 microM for AZT, 10 units (U)/mL for IFN-alpha, and 1 U/mL for IFN-gamma. To determine whether inhibition resulted from direct cytotoxic effects, we assessed the viability of nontransformed HUCLs exposed to the agents for 30 d. The nontoxic doses were 1 microM for AZT, 30 U/mL for IFN-alpha, and 3 U/mL for IFN-gamma. Combining IFN-alpha or IFN-gamma with AZT or IFN-alpha with IFN-gamma at nontoxic doses showed synergistic decreases in numbers of transformed foci. Transformation of HUCLs by EBV was sensitive to, but not abolished by, these agents at doses below those required for cell killing.

B-Lymphocytes↗

PubMed1989

Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by recombinant soluble CD4 and 3'-azido-3'-deoxythymidine.

A combination of antiviral therapies that target different sites in the human immunodeficiency virus type 1 (HIV-1) replicative cycle may be necessary for optimal treatment of HIV-1 infections. We evaluated the interactions of a soluble virus receptor (recombinant soluble CD4 or rsT4) and a reverse transcriptase inhibitor (azidothymidine, AZT) against HIV-1 replication in vitro. A variety of cell types was studied including peripheral blood mononuclear cells, a CD4-positive T-cell line, and a CD4-positive human monocyte cell line. The combination of rsT4 and AZT inhibited HIV-1 synergistically over a broad range of drug concentrations and multiplicities of infection in several different HIV-1 replication assays. Drug interactions were evaluated by the median-effect principle and the isobologram technique using a computer analysis. In all of the cell types tested, combinations of rsT4 and AZT were synergistic in vitro, without additive cytotoxicity.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1989

Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3'-azido-3'-deoxythymidine.

Castanospermine and 3'-azido-3'-deoxythymidine (zidovudine) were evaluated in combination against human immunodeficiency virus (HIV) replication in vitro. Castanospermine and 3'-azido-3'-deoxythymidine inhibited HIV type 1 synergistically in acutely infected H9 cells. In addition, they synergistically inhibited both HIV type 1 and HIV type 2 in peripheral blood mononuclear cells. There were no additional toxic effects of these agents in combination. Drug interactions were evaluated by the median-effect principle and the isobologram technique. Combinations of a glycosylation inhibitor, such as castanospermine, with 3'-azido-3'-deoxythymidine deserve consideration for HIV-related chemotherapeutic intervention.

Alkaloids↗

PubMed1989

Nucleosides. CXXXV. Synthesis of some 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purines and their biological activities.

Seven purine nucleosides containing the 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl moiety were synthesized and tested for their antitumor activity. Direct condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (1) with N6-benzoyladenine in CH2Cl2 followed by saponification of the product afforded the adenine nucleoside (I, 2'-F-ara-A). Deamination of I with NaNO2 in HOAc gave the hypoxanthine analogue (II, 2'-F-ara-H). The 6-thiopurine nucleoside (III, 2'-F-ara-6MP) was prepared by condensation of 1 with 6-chloropurine by the mercury procedure followed by thiourea treatment and saponification of the product. Methylation of III gave the 6-SCH3 analogue (IV). Raney Ni desulfurization of III afforded the unsubstituted purine nucleoside (V, 2'-F-ara-P). Condensation of 1 with 2-acetamido-6-chloropurine by the silyl procedure afforded the protected 2-acetamido-6-chloropurine nucleoside which served as the precursor for both the guanine and 6-thioguanine nucleosides (VI, 2'-F-ara-G and VII, 2'-F-ara-TG, respectively). Thus, alkaline hydrolysis of the precursor gave VI. Thiourea treatment prior to alkaline hydrolysis gave VII. The new nucleoside, 2'-F-ara-G (VI) is found to be selectively toxic to human T-cell leukemia CCRF-CEM.

Animals↗

PubMed1989

Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells.

Azidothymidine (AZT) and interferon alpha (IFN-alpha) are among the drugs showing strong in vitro activity against the human immunodeficiency virus type-1 (HIV-1). Each drug, however, has significant toxicity against normal marrow progenitor cells that frequently proves dose-limiting in patients. In this study, AZT and recombinant IFN-alpha 2a (rIFN-alpha 2a) were tested as single agents and in combination against normal myeloid (CFU-GM) and erythroid (BFU-E) colony forming cells in a standard methylcellulose culture assay. The data were analyzed using a quantitative computerized analysis based on the median-effect principle and the isobologram equation as described by Chou and Talalay (Adv Enz Regul 22:27, 1984). The ED90 for BFU-E and CFU-GM inhibition was then compared with previously measured in vivo plasma levels of each drug and the ED90 for the anti-HIV-1 effect in vitro. We demonstrate that (a) the drugs are strongly synergistic in inhibiting marrow progenitor cell growth and that this synergism occurs at drug levels that are within the range of measured plasma levels in phase I clinical trials, (b) BFU-E are more sensitive than CFU-GM to the inhibiting effects of AZT, rIFN-alpha 2a or both drugs in combination, (c) the drug concentrations in combination that synergistically inhibit bone marrow progenitors are much higher than those required to inhibit HIV-1 replication in vitro, and (d) the anti-HIV-1 effect for the combination of AZT and rIFN-alpha 2a was clearly superior to the effect of AZT or rIFN-alpha 2a alone as indicated by the combination index and the dose-reduction index. These data suggest that substantially lower doses of AZT and rIFN-alpha than those currently being tested in clinical trials might not only maintain a strong synergistic anti-HIV-1 effect but might also avoid significant hematologic toxicity.

Bone Marrow↗

PubMed1989

Analogues of taurine as stimulators and inhibitors of ATP-dependent calcium ion uptake in rat retina: combination kinetics.

Taurine is an amino acid that plays important roles in maintaining both the structural integrity and function of the retina. Thus, the effects of taurine, taurine analogues, and their combinations were studied in the ATP-dependent calcium ion uptake system at low calcium ion concentrations (10 microM) in a rat retinal membrane preparation. (+/-)-(trans)-2-Aminocyclopentanesulfonic acid (TAPS), a cyclic taurine analogue previously determined to inhibit ATP-dependent calcium ion uptake was demonstrated to be noncompetitive (Ki = 0.055 mM) with respect to taurine, that is, the values for the half-saturation concentrations calculated from varying concentrations of taurine compared with varying concentrations of taurine in the presence of a fixed concentration of TAPS (80 microM) did not change. However, the values for the maximal rates of change were significantly different. 1,2,3,4-Tetrahydroquinoline-8-sulfonic acid (THQS), a less potent inhibitor of ATP-dependent calcium ion uptake than TAPS, was also shown to be noncompetitive with taurine, with an inhibition constant (Ki) of 23.8 mM. Thus, it is presumed that both compounds (TAPS and THQS) are acting at receptor site(s) other than the taurine binding site. When TAPS and THQS were tested in a mixture that maintains a ratio (fixed ratio mixture) of 1 part TAPS and 25 parts THQS (by concentration, in mM), varied over a wide range of concentrations, and were then analyzed by median-effect plots and equation, the inhibitory effects are strongly synergistic, as shown by the combination index and the dose-reduction index. The parallel nature of the median-effect plots of TAPS and THQS indicates that the two inhibitors have a similar mode of action, that is, mutually exclusive. (+/-)-3-Aminotetrahydrothiophene-1,1-dioxide (ATS) and (+/-)-piperidine-3-sulfonic acid (PSA) are an agonist and partial agonist that demonstrated stimulatory effects on ATP-dependent calcium ion uptake. When tested in combination (1:1) with taurine, they were also determined to be mutually exclusive. It was demonstrated that ATS and taurine induced the same maximal rates of change of calcium ion uptake; however, PSA was less potent than taurine. The combination of taurine plus ATS was additive, whereas the combination of taurine plus PSA was synergistic. Structure-activity relationships of the taurine analogues and their topological relationships are discussed.

Adenosine Triphosphate↗