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Y C Cheng

Publications and source records attributed to Y C Cheng.

At least 73 records · Page 4Linked to original sources
PubMed1998

Interaction of human plasma membrane proteins and oligodeoxynucleotides.

Two oligodeoxynucleotide (oligodN) binding proteins of 100-110 kDa on plasma membranes of human cell lines were recently identified by us. These two proteins seemed to play a role in oligodN uptake. In this study, the impact of the chain length and the sequence of the oligodN on the interaction with those two proteins was investigated. Chain length of oligodN was an important determinant, but not the sole determinant for the interaction. Binding affinity of oligodNs was determined predominantly by base composition, where pyrimidine bases but not purine bases were required in the sequence to retain high affinity. The binding kinetics of the homopolymers of deoxycytidine (dC21) and deoxythymidine (dT21) suggests that the proteins may have different binding sites, with one site preferring thymine bases and the other cytosine bases. Moreover, some additional plasma membrane proteins were identified, with an apparent molecular mass ranging from 40 to 58 kDa, which could bind thymine bases but not cytosine bases.

Base Composition↗
PubMed1998

Unique inhibitory effect of 1-(2'-deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil 5'-triphosphate on Epstein-Barr virus and human DNA polymerases.

1-(2'-Deoxy-2'-fluoro-beta-L-arabinofuranosyl)-5-methyluracil (L-FMAU) was shown to have potent antiviral activity against Epstein-Barr virus (EBV) without any cellular toxicity at concentrations up to 200 microM (Yao et al., Biochem Pharmacol 51: 941-947, 1996). The 5'-triphosphate of L-FMAU was not a substrate for EBV or cellular DNA polymerases, but could inhibit the elongation reaction, 3'-to-5' exonuclease activity, and nucleotide turnover catalyzed by EBV DNA polymerase. DNA synthesis catalyzed by human DNA polymerases was inhibited to a lesser extent. The inhibition pattern of EBV DNA polymerase by L-FMAU-5'-triphosphate (L-FMAU-TP) was consistent with an uncompetitive mechanism when dNTP or template-primer were used as the variable substrates. The Ki values were 38+/-10 microM for the elongation reaction, and about 50+/-10 microM for both nucleotide exchange and 3'-to-5' exonuclease reactions, values that were 10-20 times less than that for GMP. L-FMAU-TP is the first nucleoside 5'-triphosphate shown to have such unique behavior toward DNA polymerases. EBV DNA polymerase could be one of the targets for the inhibitory effect of L-FMAU-TP on EBV replication.

Antiviral Agents↗
PubMed1998

Decreased drug accumulation without increased drug efflux in a novel MRP-overexpressing multidrug-resistant cell line.

KB/7D cells represent a multidrug-resistant subclone of human nasopharyngeal carcinoma KB cells generated by continuous exposure to the topoisomerase II inhibitor VP-16 (etoposide). KB/7D cells also show cross-resistance to doxorubicin and vincristine. Phenotypic traits of the cell line include a 2-fold decrease in topoisomerase II levels and a decrease in the uptake of VP-16 without an increase in the rate of drug efflux or expression of P-glycoprotein, suggesting a novel mechanism associated with the uptake of anticancer drugs. This study demonstrated that the multidrug-resistance associated protein (MRP) is overexpressed in KB/7D cells, and that the loss of resistance in revertant cells correlates with the loss of MRP. The resistance to VP-16 and doxorubicin could be overcome, partially, and resistance to vincristine could be overcome completely, by the L-enantiomer of verapamil, but not by the D-enantiomer or by BIBW 22 (4-[N-(2-hydroxy-2-methyl-propyl)-ethanolamino]-2,7-bis[cis-2,6-++ +dimethylmorpholino)-6-phenylpteridin), an inhibitor of MDR-1. L-Verapamil was shown to be significantly more potent than D-verapamil in modulating the accumulation defect in KB/7D cells towards doxorubicin, as measured by flow cytometry and confocal microscopy, and towards VP-16, as measured by increases in protein-linked DNA strand breaks. This suggests that KB/7D cells are multidrug resistant due to decreases in topoisomerase II levels and the overexpression of MRP, that MRP leads to a decrease in drug accumulation, and that L-verapamil can modulate the MRP-associated accumulation defect and drug-resistance phenotype. This contrasts with previous studies that suggest that MRP causes multidrug resistance by exporting cytotoxic drugs out of the cell and that did not show modulation of MRP by verapamil.

ATP-Binding Cassette Transporters↗
PubMed1998

(Z)- and (E)-2-((hydroxymethyl)cyclopropylidene)methyladenine and -guanine. New nucleoside analogues with a broad-spectrum antiviral activity.

New nucleoside analogues 14-17 based on a methylenecyclopropane structure were synthesized and evaluated for antiviral activity. Reaction of 2,3-dibromopropene (19) with adenine (18) led to bromoalkene 20, which was benzoylated to give N6,N6-dibenzoyl derivative 23. Attempts to convert 20 or 23 to bromocyclopropanes 21 and 22 by reaction with ethyl diazoacetate catalyzed by Rh2(OAc)4 were futile. By contrast, 2,3-dibromopropene (19) afforded smoothly (E)- and (Z)-dibromocyclopropane carboxylic esters 24 + 25. Alkylation of adenine (18) with 24 + 25 gave (E)- and (Z)-bromo derivatives 21 + 22. Base-catalyzed elimination of HBr resulted in the formation of (Z)- and (E)-methylenecyclopropanecarboxylic esters 26 + 27. More convenient one-pot alkylation-elimination of adenine (18) or 2-amino-6-chloropurine (30) with 24 + 25 afforded (Z)- and (E)-methylenecyclopropane derivatives 26 + 27 and 31 + 32. The Z-isomers were always predominant in these mixtures (Z/E approximately 2/1). Reduction of 26 + 27 and 31 + 32 with DIBALH afforded (Z)- and (E)-methylenecyclopropane alcohols 14 + 16 and 33 + 34. The latter were resolved directly by chromatography. Compounds 14 + 16 were converted to N6-(dimethylamino)methylene derivatives 28 and 29 which were separated and deprotected to give 14 and 16. Reaction of 33 and 34 with HCO2H led to guanine analogues 15 and 17. The 1H NMR spectra of the Z-analogues 14 and 15 are consistent with an anti-like conformation of the nucleobases. By contrast, 1H NMR and IR spectra of bromo ester 21 are indicative of syn-conformation of adenine. Several Z-(hydroxymethyl)methylenecyclopropanes exhibited in vitro antiviral activity in micromolar or submicromolar range against human and murine cytomegalovirus (HCMV and MCMV), Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), varicella zoster virus (VZV), and hepatitis B virus (HBV). Analogues 14, 15, and 33 were the most effective agents against HCMV (IC50 1-2.1, 0.04-2.1, and 0.8-5.6 microM), MCMV (IC50 2.1, 0.3, and 0.3 microM) and EBV in H-1 (IC50 0.2, 0.3, and 0.7 microM) and Daudi cells (IC50 3.2, 5.6, and 1.2 microM). Adenine analogue 14 was active against HBV (IC50 2 microM), VZV (IC50 2.5 microM), and HHV-6 (IC50 14 microM). Synadenol (14) and the E-isomer (16) were substrates of moderate efficiency for adenosine deaminase from calf intestine. The E-isomer 16 was more reactive than Z-isomer 14. The deamination of 14 effectively stopped at 50% conversion. Synadenol (14) was also deaminated by AMP deaminase from aspergillus sp.

Adenosine↗
PubMed1998

Inhibitory effect of 2'-fluoro-5-methyl-beta-L-arabinofuranosyl-uracil on duck hepatitis B virus replication.

The antiviral activity of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), a novel L-nucleoside analog of thymidine known to be an inhibitor of hepatitis B virus (HBV) replication in hepatoma cells (2.2.1.5 cell line), was evaluated in the duck HBV (DHBV) model. Short-term oral administration (5 days) of L-FMAU (40 mg/kg of body weight/day) to experimentally infected ducklings induced a significant decrease in the level of viremia. This antiviral effect was sustained in animals when therapy was prolonged for 8 days. The histological study showed no evidence of liver toxicity in the L-FMAU-treated group. By contrast, microvesicular steatosis was found in the livers of dideoxycytidine-treated animals. L-FMAU administration in primary duck hepatocyte cultures infected with DHBV induced a dose-dependent inhibition of both virion release in culture supernatants and intracellular viral DNA synthesis, without clearance of viral covalently closed circular DNA. By using a cell-free system for the expression of an enzymatically active DHBV reverse transcriptase, it was shown that L-FMAU triphosphate exhibits an inhibitory effect on the incorporation of dAMP in the viral DNA primer. Thus, our data demonstrate that L-FMAU inhibits DHBV replication in vitro and in vivo. Long-term administration of L-FMAU for the eradication of viral infection in animal models of HBV infection should be evaluated.

Administration, Oral↗
PubMed1998

Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase.

2'-Fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) is the first L-nucleoside analog with low cytotoxicity discovered to have potent antiviral activities against both hepatitis B virus and Epstein-Barr virus but not human immunodeficiency virus. This spectrum of activity is different from those of the other L-nucleoside analogs examined. L-FMAU enters cells through equilibrative-sensitive and -insensitive nucleoside transport as well as through nonfacilitated passive diffusion. L-FMAU is phosphorylated stepwise in cells to its mono-, di-, and triphosphate forms. In the present study the enzymes responsible for the first step of L-FMAU phosphorylation were identified. This is the first thymidine analog shown to be a substrate not only for cytosolic thymidine kinase and mitochondrial deoxypyrimidine kinase but also for deoxycytidine kinase. This finding suggests that the antiviral activity of L-FMAU will not be limited by the loss or alteration of any of these deoxynucleoside kinases.

Antiviral Agents↗
PubMed1998

Metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine and its activity in combination with clinically approved anti-human immunodeficiency virus beta-D(+) nucleoside analogs in vitro.

2',3'-Dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine [L(-)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of L(-)Fd4C plus 2',3'-didehydro-2'-3'-dideoxythymidine (D4T, or stavudine) or 3'-azido-3'-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with L(-)Fd4C in combination with 2',3'-dideoxycytidine (ddC, or zalcitabine) or 2',3'-dideoxyinosine (ddI, or didanosine). This beta-L(-) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 microM. As we previously reported for other beta-L(-) nucleoside analogs, L(-)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the K(m) is 100 microM. L(-)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also, L(-)Fd4C was not a substrate for deoxycytidine deaminase. L(-)Fd4C 5'-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by L(-)Fd4C in two-drug combinations favors the further development of L(-)Fd4C as an anti-HIV agent.

Anti-HIV Agents↗
PubMed1998

Anti-hepatitis B virus activity and metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine.

2',3'-Dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine [L(-)Fd4C] was found to be at least 10 times more potent than beta-L-2',3'-dideoxy-3'-thiacytidine [L(-)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of L(-)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations upto 10 microM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with L(-)Fd4C than with L(-)SddC (3TC). L(-)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of L(-)Fd4C phosphorylation to the 5'-triphosphate metabolite was higher than the degree of L(-)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparent K(m) of L(-)Fd4C phosphorylated metabolites formed intracellularly was higher than that for L(-)SddC (3TC). This may be due in part to a difference in the behavior of L(-)Fd4C and L(-)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, L(-)Fd4C 5'-triphosphate was retained longer within cells than L(-)SddC (3TC) 5-triphosphate. L(-)Fd4C 5'-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a Ki of 0.069 +/- 0.015 microM. Given the antiviral potency and unique pharmacodynamic properties of L(-)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.

Antiviral Agents↗
PubMed1998

Beta-L-1,3-dioxolane-cytidine: a novel nucleoside that inhibits proliferation and induces differentiation of keratinocytes in vitro.

beta-L-1,3-Dioxolane-cytidine (L-(-)-OddC) is a novel L-nucleoside, and its antitumor activity is under investigation in clinical trials. To evaluate the potential of L-(-)-OddC for treating hyperproliferative diseases of the skin, we examined its activity in human keratinocytes in vitro. The dose of L-(-)-OddC that inhibited the rate of proliferation of keratinocytes by 50% was 50 nM. L-(-)-OddC was about as cytotoxic as 9-beta-D-arabinofuranosylcytosine but was about 1,000 time more potent than 3'-azidothymidine. L-(-)-OddC caused irreversible growth arrest and induced differentiation of keratinocytes. L-(-)-OddC altered morphology, increased the cell size of keratinocytes and increased the expression of involucrin. These data suggest that L-(-)-OddC may have potential as a therapeutic agent against hyperproliferative skin diseases.

Antimetabolites, Antineoplastic↗
PubMed1998

Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent.

Preclinical aspects of a potent anti-hepatitis B virus (HBV) L-nucleoside, 1-(2-fluoro-5-methyl-beta-L-arabino-furanosyl)uracil (L-FMAU) are described. L-FMAU was prepared from L-ribose derivatives via either L-xylose or L-arabinose. L-FMAU shows potent antiviral activity against hepatitis B virus (EC50 5.0 microM in H1 cells) with high selectivity in vitro. L-FMAU is not incorporated into mitochondrial DNA and no significant lactic acid production was observed in vitro. L-FMAU is phosphorylated by thymidine kinase as well as deoxycytidine kinase, ultimately to the triphosphate, which inhibits HBV DNA polymerase as the mechanism of antiviral action. Preliminary in vivo toxological studies suggest no apparent toxicity for 30 days at 50 mg/kg/day in mice and for 3 months in woodchucks (10 mg/kg/day). L-FMAU also has respectable bioavailability in rats. L-FMAU shows potent anti-HBV activity in vivo against woodchuck hepatitis virus in chronically infected woodchucks and there is no significant virus rebound after cessation of the drug treatment.

Animals↗
PubMed1998

Interaction of beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluoro-CTP with human immunodeficiency virus-1 reverse transcriptase and human DNA polymerases: implications for human immunodeficiency virus drug design.

The work reported in this article has evaluated the relative molecular activity of the 5'-triphosphate of a novel beta-L-nucleoside with an unsaturated ribose residue, beta-L-2', 3'-dideoxy-2',3'-didehydro-5-fluorocytidine (beta-L-Fd4CTP), with that of beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FddCTP) and 2', 3'-dideoxycytidine (ddCTP), on DNA strand elongation by human immunodeficiency virus-1 reverse transcriptase (HIV RT) and human DNA polymerases alpha (pol alpha), beta (pol beta), gamma (pol gamma), and epsilon (pol epsilon). The concentrations of beta-L-Fd4CTP that inhibited the yield of products by 50% were 0.20 micro M, 1.8 micro M, and 4.0 micro M for HIV RT, pol gamma, and pol beta, respectively. The beta-L-Fd4CTP at a concentration as high as 40 micro M had no inhibitory effect on pol epsilon, but could inhibit pol alpha by 10-20% at 20 micro M. The Km and relative Vmax values of beta-L-Fd4CTP, beta-L-FddCTP, and ddCTP for incorporation into the standing start point of 5'-[32P]-oligonucleotide primer annealed with M13mp19 phage DNA by HIV RT and human DNA polymerases were evaluated. The efficiency of incorporation (Vmax/Km) of beta-L-Fd4CTP by HIV RT was about 4-fold and 12-fold higher than that of ddCTP and beta-L-FddCTP, respectively. In contrast, the Vmax/Km ratio of beta-L-Fd4CTP for pol gamma was 7-fold lower than that of ddCTP, but 4-fold higher than that of beta-L-FddCTP. Pol alpha could use beta-L-Fd4CTP as a substrate, but only at a high concentration (>20 micro M). Incorporation of beta-L-Fd4CTP by pol epsilon could not be detected. A hypothesis about the preferable recognition of the 2',3'-dideoxy-2',3'-didehydro- structure of beta-L-Fd4CTP to that of the 2',3'-dideoxy-structure of beta-L-FddCTP by HIV RT is discussed.

Anti-HIV Agents↗
PubMed1998

Preoperative localization procedures for initial surgery in primary hyperparathyroidism.

The experience of the surgeon and precise localization of abnormal parathyroid glands determine the success of surgery for primary hyperparathyroidism (HPT). In HPT patients undergoing repeat surgery, the use of localization studies improved the ability to identify the remaining abnormal parathyroid tissue. This study investigated the roles of preoperative localization techniques for initial surgery for primary HPT. From 1985 through 1997, two noninvasive localization procedures, ultrasonography (US) and 201thallium chloride-99mtechnetium pertechnetate subtraction scanning (Tl-Tc), were used prior to initial exploration for primary HPT in 76 patients. Their accuracy was determined on the basis of surgical and pathologic results. The surgical success rate was 96% (73/76). The sensitivities of US and Tl-Tc were 71% and 49%, respectively. The sensitivity of Tl-Tc was higher for the lower parathyroid glands. In 21 of 26 patients who underwent fine-needle aspiration (FNA) of the suspected enlarged parathyroid gland, the diagnosis of parathyroid adenoma was confirmed preoperatively. We conclude that the concomitant use of US and FNA is a safe and convenient method for preoperative localization of the parathyroid glands prior to initial surgical exploration in patients with primary HPT. Bilateral neck exploration by an experienced surgeon should be the routine procedure. US and Tl-Tc alone offer limited localization information, and unilateral exploration should be reserved for selected cases in which the results of these two imaging studies are consistent with one another.

Adult↗
PubMed1998

(Z)- and (E)-2-(hydroxymethylcyclopropylidene)-methylpurines and pyrimidines as antiviral agents.

Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4-2 microM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4-29 and 11-24 microM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 microM). Syncytol was the most potent against EBV (EC50 < 0.41 and 2.5 microM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 microM) and the Z-2-amino-6-cyclopropyl-aminopurine derivative (EC50 11.8 microM). Syncytol was also most effective against VZV (EC50 3.6 microM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 microM against HSV-1 (ELISA) and 1.3 microM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and > 74 microM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 microM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.

Animals↗
PubMed1997

Structure-activity relationships of 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides.

Following the recent discoveries that some L-nucleosides are more or equal potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-difluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. Compound 2 was oxidatively cleaved and coupled with ethyl bromodifluoroacetate in the presence of activated zinc under Reformatsky conditions to obtain a diasteomeric mixture of 4(R) and 4(S), in a 4:1 ratio. The major 4(R) isomer was cyclized and treated appropriately to obtain the mesylate 8a or 8b, which was condensed with various silyl-protected pyrimidines. Condensation of the alcohol 7a or 7b with 6-chloropurine under Mitsunobu conditions afforded the 6-chlorpurine analogs 53a or 53b and 54a or 54b. Further treatment of the compounds 53a, 54a and 53b, 54b afforded the inosine and adenine derivatives 57-60, respectively. The condensation of 2-amino-6-chloropurine with compound 8a and subsequent treatment with 2-mercaptoethanol/sodium methoxide afforded the guanine analogs 63 and 64. All of the synthesized nucleosides 31-52, 57-60, 63, and 64 were evaluated for antiviral activity and for cellular toxicity. Adenine derivative 57 showed a moderate activity against HIV-1 in PBM cells (3.4 microM). None of the other compounds showed any significant activities against HIV-1, HBV, HSV-1, HSV-2, and toxicity in Vero, CEM, and PBM cell lines up to 100 microM. The X-ray structure of the 5-iodocytosine analog showed a 2'-exo/3'-endo conformation for the carbohydrate moiety, which is different from those of the biologically active compounds (-)-FTC and L-FMAU.

Antiviral Agents↗
PubMed1997

Synthesis and anti-hepatitis B virus activity of 9-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl) purine nucleosides.

Since the discovery of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU) as a potent anti-HBV and anti-EBV agent, we have studied the structure-activity relationships of 2'-deoxy-2'-fluoro-beta-L-arabinofuranosylpyrimidine nucleosides as anti-HBV agents. Therefore it is rational to extend this study to the purine nucleosides. Thus, 3,5-di-O-benzoyl-2-deoxy-2-fluoro-beta-L-arabinofuranosyl bromide (1), which was prepared from L-xylose via a multistep procedure, was coupled with several purines by the sodium salt method. From this general synthesis, 10 purine nucleosides containing the 2-deoxy-2-fluoro-beta-L-arabinofuranosyl moiety have been obtained. The anti-HBV activity and toxicity of the synthesized nucleosides were evaluated in HepG2 2.2.15 cells. Among them, the adenine (10) and hypoxanthine (15) derivatives exhibit good in vitro anti-HBV activity (EC50 = 1.5 and 8 microM, respectively) without significant toxicity up to 200 microM.

Antiviral Agents↗
PubMed1997

Altered formation of topotecan-stabilized topoisomerase I-DNA adducts in human leukemia cells.

Topotecan (TPT) is a topoisomerase I (topo I) poison that has shown promising antineoplastic activity in solid tumors and acute leukemia. In the present study, a band depletion assay was used to evaluate the ability of TPT to stabilize topo I-DNA adducts in human leukemia cell lines and in clinical leukemia samples ex vivo. This assay showed that 50% of the cellular topo I in HL-60 human myelomonocytic leukemia cells became covalently bound to DNA at an extracellular TPT concentration of 4 micromol/L. In contrast, in 13 clinical specimens of human leukemia harvested before treatment of patients with TPT, the TPT concentration required to stabilize 50% of the cellular topo I in topo I-DNA complexes ranged from 3 to greater than 100 micromol/L (median, 30 micromol/ L). Flow microfluorimetry showed that cellular TPT accumulation varied over only a twofold range and failed to provide evidence for transport-mediated resistance in the clinical samples. These observations raise the possibility that formation of topo I-DNA adducts is diminished in many specimens of refractory/relapsed acute leukemia by a mechanism that might alter topo I sensitivity to TPT.

Antineoplastic Agents↗
PubMed1997

Antitumor agents--CLXXIII. Synthesis and evaluation of camptothecin-4 beta-amino-4'-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents.

Two conjugates composed of a camptothecin and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells.

Animals↗