Biomedical subjects

Y C Cheng

Publications and source records attributed to Y C Cheng.

At least 127 records · Page 7Linked to original sources

PubMed1994

Antitumor agents. 148. Synthesis and biological evaluation of novel 4 beta-amino derivatives of etoposide with better pharmacological profiles.

A series of novel 4 beta-amino derivatives of etoposide (1), which can form water-soluble salts and demonstrate excellent activity against mdr- and topo II-resistant cell lines, have been synthesized. Compared with etoposide, compounds 5-6, 8, and 10-16 show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex formation assay, compounds 5-6, 8, 10-14, and 16 are more potent than 1. A dose-response study of 8 shows that it is 20 times more active in formation of protein-linked DNA breaks than etoposide. Furthermore, both 8 and its free base 7 were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also evaluated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparison of the log10 GI50 mean graph midpoints of 5-19 (-4.89 to -7.30) with that of 1 (-4.08) shows these new analogs to be 6-1659-fold more active than 1.

Antineoplastic Agents↗

PubMed1994

Antitumor agents. 144. New gamma-lactone ring-modified arylamino etoposide analogs as inhibitors of human DNA topoisomerase II.

The trans-fused gamma-lactone ring of etoposide is readily epimerized to its cis epimer, which is biologically inactive, or is metabolized to the inactive ring-opened hydroxy acids. Modification of this gamma-lactone ring of 4 beta-(arylamino)-4'-O-demethyl-4-desoxypodophyllotoxin resulted in several compounds (15-16, 21-22, and 24) that should block this epimerization and the resulting biological deactivation. In a topoisomerase II inhibition assay, compounds 21, 22, and 24 showed comparable activity to etoposide. In a protein-linked DNA complex formation assay, compounds 21 and 22 were more active than etoposide.

Antineoplastic Agents↗

PubMed1994

Antiviral activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-FddC) and 2',3'-dideoxy-beta-L-cytidine (beta-L-ddC) against hepatitis B virus and human immunodeficiency virus type 1 in vitro.

2',3'-Dideoxy-beta-L-5-fluorocytidine (beta-L-FddC) and 2',3'-dideoxy-beta-L-cytidine (beta-L-ddC), two nucleosides with "unnatural L-configuration," have been synthesized and found to have potent antiviral activity against hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) in vitro with very little toxicity. At 1 microM, both beta-L-ddC and beta-L-FddC inhibited the growth of HBV by more than 90%, while at the same concentration the D-configuration counterparts, 2',3'-dideoxy-beta-D-cytidine (ddC) and 2',3'-dideoxy-beta-D-5-fluorocytidine (beta-D-FddC), did not show antiviral activity against HBV. The order of anti-HIV-1 activity was beta-L-FddC > ddC; beta-D-FddC > beta-L-ddC. The dose-limiting toxicity of ddC is neuropathy which is believed to be caused by the inhibition of the synthesis of mitochondrial DNA. ddC severely inhibited the mitochondrial DNA synthesis of CEM cells yielding an IC50 value of 0.022 microM. Conversely, both beta-L-FddC and beta-L-ddC did not demonstrate any inhibition against mitochondrial DNA synthesis up to 100 microM concentration.

Antiviral Agents↗

PubMed1994

High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness.

Forty-one patients with chronic fatigue syndrome (CFS), 76 healthy controls matched with the patient group for age range, sex, race, and socioeconomic class, and 22 symptomatic patients with seasonal affective disorder (SAD) had serum sampled for antibodies against 2 Epstein-Barr virus (EBV) replicating enzymes. Abnormal titers of antibodies were found twice as often in CFS patients as controls (34.1% vs. 17.1%), with SAD patients having an intermediate frequency (27.3%). Stratifying for disease severity sharpened the differences considerably, with the sicker CFS and SAD patients having 52% and 50% abnormal tests, respectively; more mildly afflicted CFS and SAD patients had a frequency of abnormal tests in the normal range. Antibodies to EBV DNA polymerase (DNAP) were the more sensitive of the two tests in that they were positive in all cases but one. These findings suggest that antibodies against EBV DNAP may be a useful marker in delineating a subset of patients with severe fatiguing illness for appropriate treatment trials and for monitoring their outcomes.

Adult↗

PubMed1994

Anti-AIDS agents, 10. Acacetin-7-O-beta-D-galactopyranoside, an anti-HIV principle from Chrysanthemum morifolium and a structure-activity correlation with some related flavonoids.

An active anti-HIV principle, acacetin-7-O-beta-D-galactopyranoside, has been isolated from Chrysanthemum morifolium. Seven additional flavonoids isolated from this plant, 13 known related flavonoids, and 14 synthetic flavonoids were also evaluated as inhibitors of HIV replication in H9 cells. A known flavone, chrysin, was found to be the most promising compound in this series. Flavonoids with hydroxy groups at C-5 and C-7 and with a C-2-C-3 double bond were more potent inhibitors of HIV growth. In general, the presence of substituents (hydroxyl and halogen) in the B-ring increased toxicity and/or decreased activity.

Antiviral Agents↗

PubMed1994

Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides.

The toxic effects of various concentrations of 2',3'-dideoxycytidine (ddC), 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), and 2',3'-dideoxyinosine (ddI) on CEM cells after 4 days of culture were assessed by measuring cell viability, mitochondrial DNA (mtDNA) content, and mitochondrial morphology. Cell viability and mtDNA content in drug-treated cultures were significantly reduced in a concentration-dependent fashion in comparison with cell viability and mtDNA content in untreated cultures. Cells in the treated cultures also showed significant changes in their mitochondrial morphologies which included distortion and reduction of the cristae and numerous vesicles. Unique features of the morphological changes were associated with each drug. The decrease in cell viability and mtDNA content and the increase in mitochondrial ultrastructural changes were directly related to the concentrations of the drugs used. The potencies of these compounds in reducing cell viability, mtDNA content, and normal mitochondria were in the order ddC > D4T > ddI. Comparison of the three assays used demonstrated that mtDNA content is a significantly more sensitive measure of drug toxicity than cell viability and mitochondrial morphology for the three compounds studied.

Cell Survival↗

PubMed1994

Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

PURPOSE: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. PATIENTS AND METHODS: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved. RESULTS: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. CONCLUSION: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Study of low-temperature thermoplastic modified custom-molded cervical orthosis for cervical spine fixation.

The purpose of this experiment is to use a low-temperature thermoplastic material (Aquaplast) to make a modified custom-molded cervical orthosis. Sixteen normal young subjects who do not have previous cervical problems are tested in this study. This modified orthosis is applied on these volunteers so that external fixation of the cervical spine can be tested. Various roentgenograms for cervical flexion and extension, as well as neutral position and lateral bending, are taken to determine the fixation property of the cervical spine. A study of rotation of the cervical spine is also carried out through goniometer measurements. This clinical study proves that this low-temperature thermoplastic cervical orthosis provides good fixation for the cervical spine, especially in flexion and rotation, but is not suitable for C1- and C2-injured patients.

Adult↗

PubMed1993

Identification of the amino acid in the human immunodeficiency virus type 1 reverse transcriptase involved in the pyrophosphate binding of antiviral nucleoside triphosphate analogs and phosphonoformate. Implications for multiple drug resistance.

A recombinant clone of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) with reduced sensitivity to 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) and phosphonoformate (PFA), a pyrophosphate analog, has been obtained from the RNA of HTLV-IIIB infected cells using the polymerase chain reaction. The mutant HIV-1 RT retained polymerase activity and was cross-resistant to triphosphate forms of other nucleoside analogs including 2',3'-dideoxycytidine 5'-triphosphate, 2',3'-dideoxyadenosine 5'-triphosphate, and 3'-deoxy-2',3'-didehydrothymidine 5'-triphosphate (D4TTP), but remained sensitive to the non-nucleoside HIV-1 RT inhibitors, such as nevirapine and TIBO R82150. Sequence analysis of the mutant HIV-1 RT revealed a single amino acid substitution (Val-->Ala) at amino acid 90. The substitution of amino acid 90 by the closely related amino acids, such as Thr and Gly, also showed decreased sensitivity to AZTTP, D4TTP, and PFA. All these mutations at amino acid 90 also caused an alteration of Km for thymidine triphosphate. These results suggest that Val at this site plays a role in determining the interaction of the HIV-1 RT enzyme with the pyrophosphate group of deoxynucleoside triphosphate (dNTP) and that the hydrophobicity of the amino acid at this position was the most important determinant in the binding of HIV-1 RT to dNTP.

Amino Acids↗

PubMed1993

The biochemical basis for the differential anti-human immunodeficiency virus activity of two cis enantiomers of 2',3'-dideoxy-3'-thiacytidine.

Two cis stereoisomers of 2',3'-dideoxy-3'-thiacytidine (SddC) were investigated for their activity against human immunodeficiency virus type 1 (HIV-1) in human acute lymphoblastic leukemia H-9 cells. (-)-SddC is six times more potent against HIV-1 and at least 1.7-fold less cytotoxic than (+)-SddC. Metabolism studies showed that the intracellular accumulation of the active triphosphate form of (-)-SddC is more than 2-fold greater than that of (+)-SddCTP in H-9 cells. In contrast, (+)-SddCTP is approximately 1.5 times more potent than (-)-SddCTP as an inhibitor of HIV-1 reverse transcriptase using a rRNA template (Ki = 0.22 and 0.034 microM, respectively) and gapped DNA (Ki = 0.53 and 1.02 microM, respectively). The enantiomers are comparable as substrates for incorporation into DNA by the RNA-dependent HIV-1 reverse transcriptase; however, neither analog is incorporated as readily as dCTP. The above observations do not explain the difference in the anti-HIV potency between the enantiomers. A novel 3'-5' exonuclease was partially purified from the cytosol of H-9 cells and assayed for the removal of (+)- and (-)-SddCMP-terminated DNA. Removal of (+)-SddCMP was approximately two to three times faster from 3'-terminals of single-stranded and double-stranded DNA, whereas on DNA/RNA substrates, the exonucleolytic cleavage of (+)-SddCMP proceeded approximately six times faster than that of (-)-SddCMP. This result correlates with the observed difference in the anti-HIV effect between the two compounds and suggests that this novel enzyme may be an important determinant of their antiviral activities.

Antiviral Agents↗

PubMed1993

Antisense oligonucleotides as therapeutic agents--is the bullet really magical?

Because of the specificity of Watson-Crick base pairing, attempts are now being made to use oligodeoxynucleotides (oligos) in the therapy of human disease. However, for a successful outcome, the oligo must meet at least six criteria: (i) the oligos can be synthesized easily and in bulk; (ii) the oligos must be stable in vivo; (iii) the oligos must be able to enter the target cell; (iv) the oligos must be retained by the target cell; (v) the oligos must be able to interact with their cellular targets; and (vi) the oligos should not interact in a non-sequence-specific manner with other macromolecules. Phosphorothioate oligos are examples of oligos that are being considered for clinical therapeutic trials and meet some, but not all, of these criteria. The potential use of phosphorothioate oligos as inhibitors of viral replication is highlighted.

Animals↗

PubMed1993

BIBW 22, a dipyridamole analogue, acts as a bifunctional modulator on tumor cells by influencing both P-glycoprotein and nucleoside transport.

BIBW 22, a phenylpteridine analogue of dipyridamole (DPM), enhanced vincristine cytotoxicity approximately 10 times more than DPM in a multidrug-resistant (MDR) KB V20C cell line. Using rhodamine 123 accumulation in KB V20C cells as an indicator of MDR phenotype, BIBW 22 was shown to be about 100 times more potent than DPM in inhibiting the MDR-associated efflux of rhodamine 123. Photolabeling of P-glycoprotein in KB V20C plasma membranes with 0.2 microM [3H]azidopine was strongly inhibited by 1 microM BIBW 22, indicating that this compound reverses the MDR phenotype by interfering with MDR-associated P-glycoprotein. In addition, BIBW 22 at 1 microM could also enhance the cytotoxicity of 5-fluorouracil in KB cells about 20-fold. Its potency in inhibiting nucleoside transport is 7-fold more potent than that of DPM. These results suggest that BIBW 22 is a potent bifunctional modulator which influences both P-glycoprotein and nucleoside transport in tumor cells. Potential use of this compound as a modulator of combination chemotherapy involving antimetabolites and drugs affected by MDR should be explored.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Syntheses and biological evaluations of 3'-deoxy-3'-C-branched-chain-substituted nucleosides.

Various 3'-deoxy-3'-C-(hydroxymethyl)-, 3'-deoxy-3'-C-(fluoromethyl)-, 3'-deoxy-3'-C-(azidomethyl)-, and 3'-deoxy-3'-C-(aminomethyl)-substituted nucleosides (total 12 compounds) have been synthesized and evaluated against L1210, P388, S-180, and CCRF-CEM cells and HSV-1, HSV-2, and HIV-1 in culture. Only 3'-deoxy-3'-C-(hydroxymethyl)thymidine (36) was found to show significant anticancer activity against L1210, P388, S-180, and CCRF-CEM cells with ED50 values of 50, 5, 10, and 1 microM, respectively. None of these compounds demonstrated significant antiviral activity against HSV-1, HSV-2, or HIV-1. These compounds were also evaluated against thymidine kinases derived from HSV-I (strain KOS), HSV-2 (strain 333), and mammalian (K562) cells. The thymidine kinase (HSV-1 strain KOS) was inhibited significantly by both 3'-deoxy-3'-C-(hydroxymethyl)- and 3'-deoxy-3'-C-(fluoromethyl)thymidine.

Animals↗

PubMed1993

Antitumor agents. 126. Novel 4 beta-substituted anilino derivatives of 3',4'-O,O-didemethylpodophyllotoxin as potent inhibitors of human DNA topoisomerase II.

A series of derivatives of 3',4'-O,O-didemethylpodophyllotoxin have been synthesized and evaluated for their inhibitor activity against neoplastic cell growth (KB) and against human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results show that the compounds possessing a 4 beta-anilino moiety either unsubstituted or substituted at the para (F, COOCH3, COCH3, CN, CH2CN, NO2) or meta (OH) positions or with an ethylenedioxy moiety showed the same or greater activity than etoposide in causing cellular protein-linked DNA breakage and in inhibiting DNA topoisomerase II. However, compared to the corresponding 4'-O-demethyl analogues, the 3',4'-O,O-didemethyl compounds have a similar potency in inhibition of DNA topoisomerase II but are less active in causing cellular protein-linked DNA breakage. Complete correlation between the three biological activities--cytotoxicity, inhibition of DNA topoisomerase II, and induction of protein-linked DNA breakage--was also not observed. This supports the possibility that the biological determinants of action among these compounds may be different.

Antineoplastic Agents↗

PubMed1993

Antitumor agents. 125. New 4 beta-benzoylamino derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin and 4 beta-benzoyl derivatives of 4'-O-demethylpodophyllotoxin as potent inhibitors of human DNA topoisomerase II.

A series of 4 beta-benzoylamino (5-17) derivatives of 4'-O-dimethyl-4- desoxypodophyllotoxin and 4 beta-benzoyl (18-20) derivatives of 4'-O-demethyl podophyllotoxin have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. Compounds 5-13 and 15-17 are more potent than etoposide in causing DNA breakage, while compounds 9, 10, 13, 14, 16, and 20 are more active than etoposide in their inhibition of the human DNA topoisomerase II. The order for the enzyme inhibitory activity of the derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin is 4 beta-arylamino > 4 beta-benzylamino > 4 beta-benzoylamino.

Antineoplastic Agents↗

PubMed1993

Potent inhibition of Epstein-Barr virus by phosphorothioate oligodeoxynucleotides without sequence specification.

We found that 28-mer phosphorothioate oligodeoxynucleotides (S-oligos) with and without sequence specificity complementary to Epstein-Barr virus (EBV) genes are potent inhibitors of EBV replication in cell culture. The decrease in the amount of EBV DNA, the activity of intracellular viral DNA polymerase, and virus production were dose dependent, with a 90% inhibitory dose of approximately 0.5 microM. No inhibition of cell growth was observed with the S-oligos at concentrations up to 20 microM. The mechanism of action appears to be the inhibition of EBV DNA synthesis. The reversibility of anti-EBV action is dependent on the dose and duration of drug exposure. S-oligos should be considered a new class of anti-EBV agents.

Acyclovir↗

PubMed1993

A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1- jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150).

Tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives (e.g., R82150) are potent, human immunodeficiency virus-1 (HIV-1)-specific, inhibitors of reverse transcriptase (RT) that are undergoing initial evaluation in clinical trials. Because HIV-1 has become resistant to other RT inhibitors, we investigated the potential for viral resistance to TIBO R82150 by serial in vitro passage of HIV-1IIIB in the presence of drug. R82150-resistant variants (> 100-fold increase in IC50) dominated the replicating virus population after only three or four passages. R82150-resistant virus was partially cross-resistant to other HIV-1-specific RT inhibitors, including nevirapine (approximately 10-fold increase in IC50) and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (approximately 3.5-fold increase) but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. DNA sequencing of cloned resistant RT, combined with site-specific mutational analyses and construction of mutant recombinant proviruses, demonstrated that a single, conservative amino acid substitution (Leu100 to Ile) in HIV-1 RT is responsible for high level R82150 resistance and partial nevirapine resistance. These studies indicate that a subtle mutation in HIV-1 RT can dramatically affect viral susceptibility to an HIV-1-specific RT inhibitor. The clinical efficacy of TIBO derivatives and other HIV-1-specific RT inhibitors may be limited by the emergence of drug-resistant viral strains.

Antiviral Agents↗

PubMed1993

Cellular pharmacology of phosphorothioate homooligodeoxynucleotides in human cells.

The uptake and distribution of phosphorothioate oligodeoxynucleotides by human cells were studied using 35S-labeled 28-mer phosphorothioate oligodeoxycytidine [S-(dC)28]. Accumulation of intracellular S-(dC)28 was found to be higher in the carcinoma cells (grown in monolayers) than in the leukemia cells (grown in suspension culture). A hepatoma cell line transfected with hepatitis B virus, 2215, was chosen for further studies. The uptake of S-(dC)28 was partially dependent on temperature and energy. The intracellular concentration was significantly higher than that in the medium and the amount accumulated was dependent on the extracellular concentration. It appears that the uptake of S-(dC)28 involves mechanisms of both fluid-phase pinocytosis and adsorptive endocytosis. Neither oligonucleotides nor 5'-phosphorylated nucleotides inhibited S-(dC)28 uptake. Unlike horseradish peroxidase, which was primarily associated with endosomes once it was taken into the cell, S-(dC)28 was found to be present in both nuclear and cytoplasmic fractions. Efflux of S-(dC)28 from the cell was multiphasic; a trapping mechanism that could be due to a potent interaction of S-(dC)28 with cellular proteins was implicated. This trapping mechanism could be responsible for the lack of biological activity such as cytotoxicity and antisense activity of phosphorothioate oligodeoxynucleotides in some human cells.

Carcinoma↗