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PubMedDate not supplied

[Comparison of light-scattering index 50% (LSI50) and inhibitory concentration 50% (CI50) (author's transl)].

The "Autobac" apparatus permitted the rapid determination of the light-scattering index 50% (LSI50) and inhibitory concentration 50% (CI50) of eight antibiotics -- kanamycin, amikacin, lividomycin, gentamicin, tobramycin, sisomicin, netilmicin and colistin -- for the strain of Escherichia coli ATCC-25922. The results were compared with those of the reference method using an agar dilution method. The percentage of inhibition (% I) was obtained from LSI by applying the formula % I = 10(-(GIXLSI)). The growth index (GI) has an influence on the values of the rapid method. The best results were observed in the GI ranges of 1.2 to 1.7. For all the antibiotics except tobramycin and colistin, the CI50 values of the two methods were very similar. The values of LSI50 were not assimiliated to those of CI50. These three parameters had a small variability. The averages of standard deviation were 0.23 log2 for the CI50 of the reference method, 0.24 log2 for the CI50 of the rapid method and 0.32 log2 for the LSI50. The "Autobac" enables the determination of CI50 by a simpler and faster technique.

Anti-Bacterial Agents↗
PubMed2001

In vitro efficacy of chemotherapeutics as determined by 50% inhibitory concentrations in cell cultures of mammary gland tumors obtained from dogs.

OBJECTIVE: To determine the 50% inhibitory concentration (IC-50) of carboplatin, cisplatin, and doxorubicin in cell cultures of mammary gland tumors obtained from dogs and to assess whether in vitro efficacy was within the range of clinically relevant concentrations, SAMPLE POPULATION: 30 mammary gland tumors excised from dogs. PROCEDURE: Cell cultures were established from the 30 tumors. Cultures then were treated with carboplatin, cisplatin, or doxorubicin. Growth inhibition of cultures was assessed via DNA measurement 24, 48, and 72 hours after treatment. The IC-50 values were calculated by use of linear interpolation. RESULTS: Cultures varied in their pattern of susceptibility. Doxorubicin induced significantly lower IC-50 values than the platinum derivatives. Cisplatin and carboplatin had comparable effects. The IC-50 values for carboplatin and doxorubicin were in the range of clinically relevant concentrations, but only part of the cisplatin cultures had IC-50 values within clinically relevant concentrations. We did not detect differences in the in vitro susceptibility among subtypes of tumors (ie, adenocarcinoma, solid carcinoma, malignant mixed tumor). CONCLUSION AND CLINICAL RELEVANCE: The IC-50 values determined in this study allowed assessment of in vitro drug efficacy of chemotherapeutics in cultures of mammary gland tumors obtained from dogs. Variations in susceptibility were evident and emphasize the importance of assessing susceptibility and resistance patterns for each tumor. Prospective studies to assess direct correlations between in vitro and in vivo efficacy must be performed to determine the clinical predictive value of this in vitro chemosensitivity assay for treatment of dogs with mammary gland tumors.

Adenocarcinoma↗
PubMed1996

Quantitating immunosuppression. Estimating the 50% inhibitory concentration for in vivo cyclosporine in mice.

Cyclosporine (CsA) blocks T cell responses in vitro by inhibiting the phosphatase activity of calcineurin (CN) and thus preventing the activation of cytokine transcription. In the study presented here, we measured the extent of inhibition of these functions in the tissues of CsA-fed mice. Mice fed increasing doses of CsA were assessed for CsA blood and tissue levels, spleen cell CN activity, ex vivo spleen cell cytokine induction by A23187, and in vivo interferon-gamma induction during an allogeneic response. The CN activity of spleen homogenates and cell suspensions and the ex vivo cytokine responses of spleen cells from CsA-treated mice were inhibited with a 50% inhibitory concentration (IC50) greater than 300 microg/L. The in vivo interferon-gamma response to an allogeneic ascites tumor was also inhibited by CsA treatment, with IC50s between 517 and 886 microg/L. The true IC50 for CsA in vivo may be even higher, as CsA levels in spleen and kidney were 4-fold higher than concomitant blood levels. We conclude that inhibition of CN activity by systemically administered CsA leads to a parallel reduction in cytokine gene induction in response to an allogeneic stimulus. In light of our previous clinical findings that therapeutic levels of CsA in renal transplant patients were associated with only partial inhibition of CN activity, these current results support the concept that partial CN inhibition can account for both the immunosuppression and the immunocompetence of CsA-treated patients.

Animals↗
PubMed2002

Selective antagonism of the NPY Y5 receptor does not have a major effect on feeding in rats.

Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC(50) (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat.

Animals↗
PubMed1998

Structure-based design of novel dihydroalkoxybenzyloxopyrimidine derivatives as potent nonnucleoside inhibitors of the human immunodeficiency virus reverse transcriptase.

Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-on e, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 microM.

Binding Sites↗
PubMed1990

Expression of 11 beta-hydroxysteroid dehydrogenase using recombinant vaccinia virus.

Ligand specificity of the type I steroid receptor is apparently conferred by the activity of 11 beta-hydroxysteroid dehydrogenase. To determine the kinetic properties of this enzyme, rat liver cDNA was expressed in cultured cells using recombinant vaccinia virus. Although this enzyme catalyzes only dehydrogenation when purified from rat liver, the recombinant enzyme obtained from cell lysates catalyzed both 11 beta-dehydrogenation of corticosterone to 11-dehydrocorticosterone and the reverse 11-oxoreduction reaction. At pH 8.5, the first order rate constant Kcat/Km for dehydrogenase activity exceeded that for reductase (63 vs. 38 min-1 x 10(-4], whereas the rate constants for the two reactions were nearly equal (48 vs. 47 min-1 x 10(-4] at pH 7.0. These results are consistent with the previously determined pH optima for these activities in liver microsomes. Removal (with glucose-6-phosphate dehydrogenase) of NADP+ produced by the reductase reaction significantly increased reductase activity. Glycyrrhetinic acid, a known inhibitor of the dehydrogenase reaction, also inhibited the reductase reaction at slightly higher concentrations (50% inhibitory concentration, less than 5 nM for dehydrogenase, 10-20 nM for reductase). Partial inhibition of glycosylation with A1-tunicamycin decreased dehydrogenase activity 50% without affecting reductase activity. The data demonstrate that a single polypeptide catalyzes both dehydrogenation and reduction, although the presence of additional enzyme forms catalyzing one or the other activity has not been ruled out.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Regression of human breast tumor xenografts in response to (E)-2'-deoxy-2'-(fluoromethylene)cytidine, an inhibitor of ribonucleoside diphosphate reductase.

(E)-2'-Deoxy-2'-(fluoromethylene)cytidine (MDL 101,731) is a mechanism-based inhibitor of ribonucleoside diphosphate reductase (J. Stubbe, personal communication), an enzyme involved in DNA synthesis and therefore a potential target for cancer chemotherapy. In the present report, we show that MDL 101,731 inhibits the proliferation of several human breast cancer cell lines, including the estrogen-dependent cell line, MCF-7, and the estrogen-independent cell lines MDA-MB-231, MDA-MB-468, and MDA-MB-435 in vitro at nanomolar concentrations (50% inhibitory concentration, 15-26 nM). Administration of MDL 101,731 caused marked regression of tumors which formed after s.c. inoculation of all four of the cell lines in athymic (nude) mice. MDA-MB-231 tumors were found to be most sensitive to MDL 101,731 with a 90-100% cure rate at doses of MDL 101,731 between 2 and 20 mg/kg, given as once daily i.p. injections, 5 days/week for as little as 3 weeks. Almost complete cessation of MDA-MB-231 tumor growth was obtained with a dose of 0.5 mg/kg MDL 101,731 following the same dosing regimen. MDA-MB-468, MDA-MB-435, and MCF-7 tumors were not as sensitive as MDA-MB-231, but tumor regression of 50, 65, and 80%, respectively, was obtained after 5-6 weeks of treatment. The effects of MDL 101,731 on spontaneous metastasis of MDA-MB-435 cells from the mammary fat pad to the lung was also examined, and it was found that the number of lung metastases was significantly decreased if mice received MDL 101,731 while the primary tumors were growing and after primary tumors were surgically excised. Additionally, preliminary evidence raises the possibility that MDL 101,731 may induce apoptosis in MDA-MB-231 tumors. Our data suggest that the use of MDL 101,731 for the treatment of breast cancer and possibly other solid tumors should be pursued.

Animals↗
PubMed1999

Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice.

The objectives of our studies are to characterize the ability of dietary soybean components to inhibit the growth of prostate cancer in mice and alter tumor biomarkers associated with angiogenesis. Soy isoflavones (genistein or daidzein) or soy phytochemical concentrate inhibit the growth of prostate cancer cells LNCaP, DU 145 and PC-3 in vitro, but only at supraphysiologic concentrations, i.e., 50% inhibitory concentration (IC(50)) > 50 micromol/L. G2-M arrest and DNA fragmentation consistent with apoptosis of prostate cancer cells are also observed at concentrations causing growth inhibition. In contrast, the in vitro proliferation of vascular endothelial cells was inhibited by soy phytochemcials at much lower concentrations. We evaluated the ability of dietary soy phytochemical concentrate and soy protein isolate to inhibit the growth of the LNCaP human prostate cancer in severe combined immune-deficient mice. Mice inoculated subcutaneously with LNCaP cells (2 x 10(6)) were randomly assigned to one of the six dietary groups based on the AIN-76A formulation for 3 wk. A 2 x 3 factorial design was employed with two protein sources (20%, casein vs. soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). Soy components did not alter body weight gain or food intake. Compared with casein-fed controls, the tumor volumes after 3 wk were reduced by 11% (P = 0.45) by soy protein, 19% (P = 0.17) by 0.2% soy phytochemical concentrate, 28% by soy protein with 0.2% soy phytochemical concentrate (P < 0.05), 30% by 1.0% soy phytochemical concentrate (P < 0.05) and 40% by soy protein with 1.0% soy phytochemical concentrate (P < 0.005). Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased apoptosis and reduced microvessel density. The angiogenic protein insulin-like growth factor-I was reduced in the circulation of mice fed soy protein and phytochemical concentrate. Our data suggest that dietary soy products may inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature.

Animals↗
PubMed2000

Characterization of VIM-2, a carbapenem-hydrolyzing metallo-beta-lactamase and its plasmid- and integron-borne gene from a Pseudomonas aeruginosa clinical isolate in France.

Pseudomonas aeruginosa COL-1 was identified in a blood culture of a 39-year-old-woman treated with imipenem in Marseilles, France, in 1996. This strain was resistant to beta-lactams, including ureidopenicillins, ticarcillin-clavulanic acid, cefepime, ceftazidime, imipenem, and meropenem, but remained susceptible to the monobactam aztreonam. The carbapenem-hydrolyzing beta-lactamase gene of P. aeruginosa COL-1 was cloned, sequenced, and expressed in Escherichia coli DH10B. The deduced 266-amino-acid protein was an Ambler class B beta-lactamase, with amino acid identities of 32% with B-II from Bacillus cereus; 31% with IMP-1 from several gram-negative rods in Japan, including P. aeruginosa; 27% with CcrA from Bacteroides fragilis; 24% with BlaB from Chryseobacterium meningosepticum; 24% with IND-1 from Chryseobacterium indologenes; 21% with CphA-1 from Aeromonas hydrophila; and 11% with L-1 from Stenotrophomonas maltophilia. It was most closely related to VIM-1 beta-lactamase recently reported from Italian P. aeruginosa clinical isolates (90% amino acid identity). Purified VIM-2 beta-lactamase had a pI of 5.6, a relative molecular mass of 29.7 kDa, and a broad substrate hydrolysis range, including penicillins, cephalosporins, cephamycins, oxacephamycins, and carbapenems, but not monobactams. As a metallo-beta-lactamase, its activity was zinc dependent and inhibited by EDTA (50% inhibitory concentration, 50 microM). VIM-2 conferred a resistance pattern to beta-lactams in E. coli DH10B that paralleled its in vitro hydrolytic properties, except for susceptibility to ureidopenicillins, carbapenems, and cefepime. bla(VIM-2) was located on a ca. 45-kb plasmid that in addition conferred resistance to sulfamides and that was not self-transmissible either from P. aeruginosa to E. coli or from E. coli to E. coli. bla(VIM-2) was the only gene cassette located within the variable region of a novel class 1 integron, In56, that was weakly related to the bla(VIM-1)-containing integron. VIM-2 is the second carbapenem-hydrolyzing metalloenzyme characterized from a P. aeruginosa isolate outside Japan.

Amino Acid Sequence↗
PubMed2003

Influence of feedstock and bleaching technologies on methanogenic toxicity of kraft mill wastewater.

Chlorine-bleached effluent is problematic for anaerobic wastewater treatment due to its high toxicity against methanogenic bacteria. To date, alternative bleaching processes are being introduced, such as elemental chlorine-free (ECF) and total chlorine-free (TCF). The purpose of this study was to investigate the influence of bleaching technologies and different types of feedstock on methanogenic activity. In order to compare the toxicity of the different bleaching sequences per unit of COD, the 50%-inhibitory concentration (50% IC) for methanogenic bacteria of the different bleaching effluents were compared. The results show that there is no direct relationship between the effluent's methanogenic toxicity and the bleaching sequences. Methanogenic toxicity ranged from 0.6 to 2.4 g COD/L.

Bacteria, Anaerobic↗
PubMed1992

Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes.

Cell-mediated immunity and macrophage activity, especially that of Kupffer cells, are impaired during cholestasis. Some evidence exists that bile acids play a role in these immune defects. The purpose of this study was to evaluate the effects of individual bile acids on immunity and to determine whether monocytes could be a target. We assessed the effects of chenodeoxycholic acid, an endogenous bile acid, ursodeoxycholic acid, which has been shown to partially correct the immunological abnormalities observed in primary biliary cirrhosis, and their tauroconjugates on the production of interleukin-1, interleukin-6 and tumor necrosis factor-alpha. Chenodeoxycholic acid had a dose-dependent inhibitory effect on interleukin-1 (inhibitory concentration 50% = 60 mumol/L), interleukin-6 (inhibitory concentration 50% = 80 mumol/L) and tumor necrosis factor-alpha (inhibitory concentration 50% = 80 mumol/L) production; inhibition was almost complete at 250 mumol/L. In contrast, ursodeoxycholic acid had lesser or minimal inhibitory effects (inhibitory concentration 50% = 100 mumol/L for interleukin-1 and above 200 mumol/L for interleukin-6 and tumor necrosis factor-alpha). The inhibitory effects of taurochenodeoxy-cholic acid and tauroursodeoxycholic acid were similar to those of chenodeoxycholic acid and ursodeoxycholic acid, respectively. Ursodeoxycholic acid did not reverse the chenodeoxycholic acid-induced inhibition of interleukin-6 or tumor necrosis factor-alpha production. In conclusion, chenodeoxycholic acid exerts strong inhibitory effects on monocyte activity in vitro, whereas the effects of ursodeoxycholic acid are minor.

Cell Survival↗
PubMed2003

The effect of flavopiridol on the growth of p16+ and p16- melanoma cell lines.

Flavopiridol is the first cyclin-dependent kinase inhibitor to enter clinical trials. Flavopiridol has been shown to mimic, in part, the effect of the cell cycle control gene p16, which is frequently lost or mutated in malignant melanoma, making it an ideal candidate for targeted therapy in this disease. In these studies we investigated the effect of flavopiridol, at various concentrations, on the growth and gene expression of nine human melanoma cell lines with intact, absent or mutated p16. A cytostatic effect of flavopiridol on the growth of six melanoma cell lines with a mutated or non-expressed p16 (p16-) was seen at low concentrations of flavopiridol (mean 50% inhibitory concentration [IC(50)] = 12.5 nM), while the three melanoma cell lines with intact p16 (p16+) required higher concentrations (mean IC(50) = 25 nM) to produce this effect. Apoptotic cell death increased with increasing concentrations of flavopiridol in both p16- and p16+ cells. Exposure of cells to high flavopiridol concentrations (>100 nM) resulted in decreased expression of genes downstream in the normal p16 cell cycle control pathway (Rb and E2F) and the anti-apoptotic gene BCL2. No change in BCL2 expression was found after exposure to IC(50) concentrations of flavopiridol. These data indicate that flavopiridol in low, clinically achievable concentrations may have significant cytostatic effects, particularly in p16- melanoma cells, and may provide new molecular-based therapies for melanoma, particularly when combined with agents that target anti-apoptotic mechanisms.

Antineoplastic Agents↗
PubMed2001

Effects of the extract of the bark of Magnolia obovata and its biphenolic constituents magnolol and honokiol on histamine release from peritoneal mast cells in rats.

We have previously reported that saiboku-to, an Oriental herbal remedy composed of a mixture of 10 different herbal extracts, possesses anti-histamine release effect on mast cells in rats. This effect may be due mainly to the extract of the bark of Magnolia obovata (M. obovata), a constituent herb of saiboku-to. In the present study, it was demonstrated that the bark extract inhibited compound 48/80 (C48/80)-induced histamine release from mast cells in a concentration-dependent manner (50 % inhibitory concentration, IC(50) = 56.98 microg/ml). Furthermore, the inhibitory activity was found in the methanol fraction, but not in water and 50 % aqueous methanol fractions derived from the bark extract. Magnolol and honokiol isolated from the methanol fraction inhibited C48/80-induced histamine release from mast cells. The potency of magnolol (IC(50) = 1.04 microg/ml) was greater than that of honokiol (IC(50) = 2.77 microg/ml). Furthermore, the actual amount of magnolol (49.76 +/- 1.14 mg) contained in the bark of M. obovata (5 g) was greater than that (8.58 +/- 0.19 mg) of honokiol. Taken together, the present results suggest that magnolol may be responsible for the biological efficacy of the bark extract of M. obovata.

Animals↗
PubMed1998

Selective antitumor activity of MKT-077, a delocalized lipophilic cation, on normal cells and cancer cells in vitro.

BACKGROUND AND OBJECTIVES: 1-Ethyl-2-¿[3-ethyl-5-(3-methylbenzothiazolin-2-yliden)]-4-+ ++oxothiazolidin-2-ylidenemethyl¿pyridium chloride (MKT-077, formerly known as FJ776), a delocalized lipophilic cation, is known to accumulate in the mitochondria, according to the negative potential inside the mitochondria, and exert its cytotoxicity. METHODS: The single-cell suspensions of human cancer cell lines, human spleen cells, and fresh cancer specimens obtained from patients with gastric carcinoma were used for the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. RESULTS: The antitumor activity of MKT-077 was dose and concentration related, and 50% inhibitory concentrations (IC50) ranged from 1.7 to 14.3 microg/ml, with a mean +/- standard deviation (SD) of 8.4 +/- 4.6 microg/ml. The IC50 of fresh surgical spleen-cell specimens ranged from 0.34 microg/ml to >100 microg/ml in a 48 h incubation, with a mean +/- SD of 66.5 +/- 37.7 microg/ml. When the antitumor activity of MKT-077 was compared between gastric cancer cells and spleen cells obtained from the same patient, the concentration-dependent antitumor activity of this agent was obvious in the cancer cells, while no significant cytotoxicity was observed in the spleen cells. The fresh surgical specimens of gastric cancer showed higher sensitivity to MKT-077 than did spleen cells at a concentration of 30 microg/ml, with a statistically significant difference at P < 0.05. CONCLUSIONS: The selective antitumor activity of MKT-077 was confirmed using fresh surgical specimens and warrants further investigation.

Antineoplastic Agents↗
PubMed1988

Increased resistance to cis-diamminedichloroplatinum(II) in NIH 3T3 cells transformed by ras oncogenes.

The genetic basis of cellular resistance to the anticancer drug cis-diamminedichloroplatinum(II) (CP) is not well understood. In the course of identifying genes from human tumors capable of conferring resistance to CP, we tested the ability of several types of cellular and viral ras oncogene (H, K, and N) to alter the CP response of mouse cells. Using clonogenic assays, we found that NIH 3T3 fibroblasts transformed with missense mutation-activated ras oncogenes demonstrated substantially increased resistance to 1-h exposures to CP (P less than 0.05 to less than 0.001, at different drug concentrations), with 50% inhibitory concentration ratios (compared to NIH 3T3) of 4.5-8.5. Cells transformed with v-mos v-fms, and with a normal ras protooncogene activated by overproduction driven by an MLV ltr, demonstrate intermediate resistance (50% inhibitory concentration ratio, approximately 2.0). Cells transfected with the pSV2neo plasmid or with human genomic DNA that is not transforming had survival curves no different from those of NIH 3T3. ras genes are highly conserved in mammalian cells. Should these findings also prove to apply to human tumors, the presence of activated ras genes might help predict clinical response to CP.

Animals↗
PubMed1996

Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil.

2'-Fluoro-5-methyl-beta-L-arabinofuranosyl uracil (L-FMAU) was discovered to have potent antiviral activity against hepatitis B virus (HBV). L-FMAU was more potent than its D-enantiomer and produced dose-dependent inhibition of the viral DNA replication in 2.2.15 cells (human HepG2 cells with the HBV genome), with a 50% inhibitory concentration of 0.1 microM. There was no inhibitory effect on HBV transcription or protein synthesis. In the 2.2.15 cell system, L-FMAU did not show any toxicity up to 200 microM, whereas the D-enantiomer was toxic, with a 50% inhibitory concentration of 50 microM. Repeated treatments of HepG2 cells with L-FMAU at a 1 microM concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely. Also at concentrations as high as 200 microM, L-FMAU did not adversely affect mitochondrial function as determined by lactic acid production by L-FMAU-treated hepatoma cells. L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates, A dose-dependent inhibition of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mode of action of this compound could involve viral polymerase. However, L-FMAU was not incorporated into the cellular DNA. Considering the potent inhibition of the viral DNA synthesis and the nontoxicity of L-FMAU towards the host DNA synthetic machinery, this compound should be further explored for development as asn anti-HBV drug.

Antiviral Agents↗
PubMed1992

Ammine/amine platinum(IV) dicarboxylates: a novel class of platinum complex exhibiting selective cytotoxicity to intrinsically cisplatin-resistant human ovarian carcinoma cell lines.

Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c,t,c-[PtCl2(OCOR1)2NH3(RNH2)]. A clear relationship existed between increasing the number of carbons in the R1 substituent and increasing cytotoxicity up to R1 = C5H11. In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains (e.g., JM300, R = cyclohexyl, R1 = C6H13) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines (e.g., for HX/62, cisplatin 50% inhibitory concentration, 12.6 microM; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 microM and 41 M; cisplatin 50% inhibitory concentration, 0.23 microM; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 (R = cyclohexyl, R1 = C3H7) and JM244 (R = n-propyl, R1 = C6H5) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a "third-generation" agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

Antineoplastic Agents↗