Showing papers by "Yung-Chi Cheng published in 1994"

Synthesis and biological evaluation of 2',3'-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).

Abstract: Various 2',3'-dideoxy-L-cytidine,2',3'-dideoxy-L-uridine, and 3'-deoxy-L-thymidine analogues have been synthesized and evaluated in vitro as potential anti-HIV and anti-HBV agents. Coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (1) with silylated derivatives of 5-fluorocytosine, cytosine, 5-fluorouracil, uracil, and thymine in the presence of ethylaluminum dichloride gave the corresponding nucleosides 2, 3, 4, 5, 10, 11, 12, 16, 17, and 18 as a mixture of alpha- and beta-anomers, which were then deblocked to yield the corresponding 2',3'-dideoxy-L-5-fluorocytidine derivatives, 6 and 7, 2',3'-dideoxy-L-cytidine derivatives, 8 and 9, 2',3'-dideoxy-beta-L-fluorouridine (13), 2',3'-dideoxy-beta-L-uridine (14), and 3'-deoxy-L-thymidine derivatives, 15 and 19. Among these 2',3'-dideoxy-L-nucleoside analogues, 2',3'-dideoxy-beta-L-5-fluorocytidine (6, beta-L-FddC) was found to be the most active against HIV-1, which is approximately 3 and 4 times more active against HIV-1 in vitro than 2',3'-dideoxy-beta-D-cytidine (ddC) and 2',3'-dideoxy-beta-D-5-fluorocytidine (beta-D-FddC) with ED50 values of 0.5, 1.5, and 2 microM, respectively. The dose-limiting toxicity of ddC is severe neuropathy which may be caused by the inhibition of the synthesis of mitochondrial DNA. ddC has an IC50 value of 0.022 microM against host mitochondrial DNA synthesis. Conversely, the IC50 values for beta-L-FddC and beta-L-ddC are > 100 microM; therefore, neuropathy may not present itself to be a problem with beta-L-FddC and beta-L-ddC as chemotherapeutic agents. In addition, beta-L-FddC and 2',3'-dideoxy-beta-L-cytidine (8, beta-L-ddC) demonstrated equally potent activity against HBV in vitro by having the same ED50 value of 0.01 microM. Both beta-L-FddC and beta-L-ddC, which have an "unnatural" L-configuration in the sugar moiety, are approximately 1000 and 280 times more potent, respectively, against HBV than the D-configuration beta-D-FddC and ddC which have an ED50 values of 10 and 2.8 microM. In view of the potent antiviral activity of beta-L-FddC against both HIV-1 and HBV and potent antiviral activity of beta-L-ddC against HBV in vitro, their low cytotoxicity, and especially the negligible inhibitory effect on host mitochondrial DNA synthesis, beta-L-FddC and beta-L-ddC merit further development as potential anti-HIV and anti-HBV agents.

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.

Abstract: 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.

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

Abstract: 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.

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

Abstract: PURPOSETo 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 METHODSSeventeen 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.RESULTSSevere 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 c...

Characterization of a Hydroxyurea-resistant Human KB Cell Line with Supersensitivity to 6-Thioguanine

Abstract: Hydroxyurea (HU) is currently used in the clinic for the treatment of chronic myelogenous leukemia, head and neck carcinoma, and sarcoma. One of its drawbacks, however, is the development of HU resistance. To study this problem, we developed a HU-resistant human KB cell line which exhibits a 15-fold resistance to HU. The characterization of this HU-resistant phenotype revealed a gene amplification of the M2 subunit of ribonucleotide reductase (RR), increased levels of M2 mRNA and protein, and a 3-fold increase of RR activity. This HU-resistant cell line also expressed a “collateral sensitivity” to 6-thioguanine (6-TG), with a 10-fold decrease in the dose inhibiting cell growth by 50% as compared to the KB parental line. The mechanism responsible for this supersensitivity to 6-TG is believed to be related to an increasingly efficient conversion of 6-TG to its triphosphate form, which is subsequently incorporated into DNA. After passage of the resistant cells in the absence of HU, the cell line reverts. The revertant cells lose their resistance to HU and concomitantly their sensitivity to 6-TG. This phenomenon is due to the return of RR to levels comparable to that of the KB parental cell line. These observations and their relevance to cancer chemotherapy will be discussed in this paper. Our results suggest that a clinical protocol could be designed which would allow for a lower dose of 6-TG to be used by taking advantage of the increased RR activity in HU-refractory cancer patients. Two drugs which display collateral sensitivity are known as a “Ying-Yang” pair. Alternate treatment with two different Ying-Yang pairs is the rationale for the “Ying-Yang Ping-Pong” theory in cancer treatment. This rationale allows for effective cancer chemotherapy with reduced toxicity.

High titers of anti-epstein-barr virus DNA polymerase are found in patients with severe fatiguing illness

Abstract: 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 liters 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. © 1994 Wiiey-Liss, Inc.

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

Abstract: 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.

An in Vivo Comparison of Oral 5-Iodo-2′-deoxyuridine and 5-Iodo-2-pyrimidinone-2′-deoxyribose Toxicity, Pharmacokinetics, and DNA Incorporation in Athymic Mouse Tissues and the Human Colon Cancer Xenograft, HCT-116

Abstract: 5-iodo-2-pyrimidinone-2′-deoxyribose (IPdR) was recently reported to be converted to 5-iodo-2′-deoxyuridine (IUdR) by an aldehyde oxidase, most concentrated in liver tissue. We questioned whether IPdR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR-DNA incorporation into liver tumors compared to normal liver with acceptable systemic toxicity. Athymic nude mice with human colon cancer (HCT-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mg/kg/day and was associated with a >10% weight loss and a high percentage of IUdR-DNA incorporation (>5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gm/kg/day without weight loss and with less (1.5–4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic analysis of p.o. IPdR showed peak plasma levels of IPdR and IUdR within 15–45 min, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2–3 times greater percentage of IUdR-DNA incorporation in tumor with IPdR than IUdR at the highest doses used. However, no differential effect in the percentage of IUdR-DNA incorporation was noted between liver metastases and s.c. tumors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radiosensitization) than a similar schedule of IUdR.

Antitumor Agents. 148. Synthesis and Biological Evaluation of Novel 4.beta.-Amino Derivatives of Etoposide with Better Pharmacological Profiles

Abstract: A series of novel 4β-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 eto- poside, compounds (5-6), (8), and (10-16) show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex for- mation 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. Furt- hermore, both (8) and its free base (7) were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also eva- luated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparaison of the log 1 0 GI50 mean graph mid- points 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)

Sterol modified oligonucleotide duplexes having anticancer activity

Abstract: Oligonucleotides having approximately 8 to 18 nucleotide units and a 3'-tail which includes asteroid structure attached to the 3'-end through the A ring of the steroid skeleton and which form substantially stable duplexes at physiological temperature, have selective cytotoxic activity against certain tumor cell lines.

Temperature dependence of electronic conduction in thin nitrided oxides

Abstract: This work reports the temperature dependence of electronic conduction in thin nitrided oxides for temperatures ranging from 298 to 423 K. It was found that the conduction currents in the nitrided oxides have different temperature dependencies from those of conventional thermal oxides. At low electric fields (∼6 MV/cm), the temperature dependencies of the nitrided oxides can be divided into two segments which are attributed to the shallow trap‐assisted conduction for temperature less than 400 K and Poole–Frenkel or thermionic emission for temperatures greater than 400 K, whereas the temperature dependence of thermal oxide is governed by exp(−0.143/kT) for the entire temperature range of this study. At high electric fields (∼12 MV/cm), the conduction current of nitrided oxides is mainly governed by Fowler–Nordheim tunneling for temperatures less than 340 K. In studying the temperature dependencies of the electronic trapping in nitrided oxides, we found that the density of trapped charge decreases as large a...

Discovery of short, 3'-cholesterol-modified DNA duplexes with unique antitumor cell activity.

Abstract: A new class of modified oligodeoxynucleotides with unique, selective cytotoxic properties has been discovered Self-complementary, 3′-cholesterol-modified oligodeoxynucleotides caused morphology changes and death in certain cancer cell lines, whereas other cell lines were unaffected Susceptible cells were killed in a dose-dependent manner at submicromolar concentrations Optimum potency was exhibited by phosphodiester duplexes approximately 10 base pairs in length, and base composition was important only in the context of duplex stability Phosphorothioate analogues were less potent Although the molecular mechanism of action of these unique compounds is not yet known, they offer potential applications in cancer therapy and in studies of cell death In addition, the path toward elucidation of the structure-based biological activity of these oligonucleotides should be especially instructive for researchers studying sequence-specific effects

2'-deoxyribose Toxicity, Pharmacokinetics, and DNA Incorporation in Athymic Mouse Tissues and the Human Colon Cancer Xenograft, HCT-116'

Abstract: Iodo-2-pyrimidinone-2'-deoxyribose (ll'dR) was recently reported to be converted to 5-iodo-2'-deoxyuridine (IUdR) by an nldehyde oxidase, most concentrated In liver tissue. We questioned whether H'dR could be used as a p.o. hepatotropic prodrug to increase the percentage of IUdR DNA incorporation into liver tumorscomparedto normalliver with acceptable systemic tOxicity.Athymic nude mice with human colon cancer (Hcr-116) xenograft tumors as liver metastases and s.c. flank tumors received daily p.o. boluses (via gastric tubes) of IUdR or IPdR for 6 days. The maximum tolerated dose of IUdR was 250 mglkg/day and was asso elated with a >10% weight loss and a high percentage of IUdR-DNA incorporation (>5%) into normal bone marrow and intestine. In contrast, animals tolerated escalating doses of IPdR to 1 gun/kg/daywithout weight loss and with less (13-4%) IUdR-DNA incorporation in normal tissues. Pharmacokinetic analysis ofp.o. IPdR showed peak plasma levels of IPdR and IUdR within 15â€"45mm, suggesting efficient conversion of IPdR to IUdR. Aldehyde oxidase activity was found in normal liver tissue but not in other normal or tumor tissues. Additionally, we found a 2-3 times greater percentage of flJdR-DNA incorporation in tumor with IPdR than HJdR at the highest doses used. However, no differential effect in the percentage of RJdR-DNA incorporation was noted between liver metas tases and s.c. twnors with either IPdR or IUdR. We conclude that p.o. IPdR offers a greater therapeutic index for tumor incorporation (and presumably radlosensitization) than a similar schedule of lUdit