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Biomedical subjects

C O Lee

Publications and source records attributed to C O Lee.

At least 37 records · Page 2Linked to original sources
PubMed2000

Synthesis and cytotoxicity of 2-methyl-1-substituted-imidazo [4,5-g]quinoline-4,9-dione and 7,8-dihydro-10H-[1,4]oxazino[3',4':2,3]imidazo[4,5-g]quinoline-5,12-dio ne derivatives.

2-Methyl-1-substituted-imidazo[4,5-g]quinoline-4,9-diones and 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19) derivatives have been synthesized from 6,7-dichloro-5,8-quinolinedione for developing the new anticancer drugs. Our study on the cytotoxicity of imidazoquinolinedione derivatives has revealed that 7,8-dihydro-10H-[1,4]oxazino-[3',4':2,3]imidazo[4,5-g]quinoline-5, 12-dione (19), a tetracyclic heteroquinone analogue, exhibited high cytotoxicity on human colon tumor cell (HCT 15) in vitro SRB assay. The IC50 value of this compound was 0.026 microg/mL whereas those of doxorubicin and cisplatin were 0.023 microg/mL and 1.482 microg/mL, respectively. Meanwhile compounds 5-7 and 12 in the series of 1-substituted-imidazoquinolinediones showed relatively good activity on human brain tumor cell lines (XF 498).

Antineoplastic Agents↗
PubMed2000

New acetylenic compounds from the stony coral Montipora sp.

Six new acetylenic compounds (1-6) with cytotoxic activities against human solid tumor cell lines (SK-OV-3, SK-MEL-2, XF498, and HCT15) have been isolated from the stony coral Montipora sp. Structures of the compounds 1-6 were elucidated based on analysis of the NMR and MS data.

Animals↗
PubMed2000

Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline.

1. Amitriptyline has been known to induce QT prolongation and torsades de pointes which causes sudden death. We studied the effects of amitriptyline on the human ether-a-go-go-related gene (HERG) channel expressed in Xenopus oocytes and on the rapidly activating delayed rectifier K(+) current (I(Kr)) in rat atrial myocytes. 2. The amplitudes of steady-state currents and tail currents of HERG were decreased by amitriptyline dose-dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by amitriptyline is voltage dependent. IC(50) for amitriptyline block of HERG current was progressively decreased according to depolarization: IC(50) values at -30, -10, +10 and +30 mV were 23.0, 8.71, 5.96 and 4.66 microM, respectively. 3. Block of HERG by amitriptyline was use dependent: exhibiting a much faster block at higher activation frequency. Subsequent decrease in frequency after high activation frequency resulted in a partial relief of HERG blockade. 4. Steady-state block by amitriptyline was obtained while depolarization to +20 mV for 0.5 s was applied at 0.5 Hz: IC(50) was 3.26 microM in 2 mM [K(+)](o). It was increased to 4. 78 microM in 4 mM [K(+)](o), suggesting that the affinity of amitriptyline on HERG was decreased by external K(+). 5. In rat atrial myocytes bathed in 35 degrees C, 5 microM amitriptyline blocked I(Kr) by 55%. However, transient outward K(+) current (I(to)) was not significantly affected. 6. In summary, the data suggest that the block of HERG currents may contribute to arrhythmogenic side effects of amitriptyline.

Amitriptyline↗
PubMed2000

Effects of KR-30035, a novel multidrug-resistance modulator, on the cardiovascular system of rats in vivo and on the cell cycle of human cancer cells in vitro.

The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.

Animals↗
PubMed2000

Synthesis and antitumor activity of cyclotriphosphazene-(diamine)platinum(II) conjugates.

A new class of water-soluble cyclotriphosphazene-(diamine)platinum(II) conjugate drugs [NP(Am-Li2)(Am.PtA2)]3 (Am: dicarboxylic amino acid; A2: diamine) has been synthesized and characterized by means of elemental analysis, multinuclear (1H, 31P, 13C, 195Pt) NMR and IR spectroscopies. All the title compounds were subjected to both in vitro and in vivo assays against the murine leukemia L1210 cell line and selected human tumor cells. Most of the title compounds have shown higher in vivo antitumor activity than cisplatin and carboplatin, and, in particular, [NP(L-Glu-Li2)(L-Glu.Pt(-dach)]3 (Glu=glutamate, dach=trans(+/-)-1,2-diaminocyclohexane) showed extraordinary high activity (ILS>500%) equally against both parent and cisplatin-resistant leukemia L1210 cell lines. Furthermore, this candidate compound (KI 60606) exhibited a wider spectrum of in vitro activity by showing higher cytotoxicity against all the selected human tumor cells than cisplatin and, therefore, was subjected to preclinical studies which are now near completion.

Animals↗
PubMed2000

Role of protein kinase C in alpha(1)-adrenergic regulation of a(Na)(i) in guinea pig ventricular myocytes.

We investigated the role of protein kinase C (PKC) in alpha(1)-adrenergic regulation of intracellular Na(+) activity (a(Na)(i)) in single guinea pig ventricular myocytes. a(Na)(i) and membrane potentials were measured with the Na(+)-sensitive indicator sodium-binding benzofuran isophthalate and conventional microelectrodes, respectively, at room temperature (24-26 degrees C) while myocytes were stimulated at a rate of 0.25-0.3 Hz. The PKC activator 4beta-phorbol 12-myristate 13-acetate (PMA) decreased a(Na)(i) in a concentration-dependent manner. PMA (100 nM) produced a maximal decrease in a(Na)(i) of 1.5 mM from 6.5 +/- 0.4 to 5.0 +/- 0.4 mM (means +/- SE, n = 12, P < 0.01). The PMA concentration required for a half-maximal decrease in a(Na)(i) was 0.46 +/- 0.13 nM (n = 3, P < 0.01). An inactive phorbol, 4alpha-phorbol 12-myristate 13-acetate, did not decrease a(Na)(i). The decrease caused by PMA could be blocked by the PKC inhibitors staurosporine and bisindolylmaleimide I (GF-109203X). Stimulation of the alpha(1)-adrenoceptor with 50 microM phenylephrine decreased a(Na)(i) from 6.1 +/- 0.3 to 4.6 +/- 0.3 mM (n = 11, P < 0.01). The decrease in a(Na)(i) produced by phenylephrine was blocked by pretreatment with staurosporine, GF-109203X, or PMA. The decrease in a(Na)(i) produced by PMA was not prevented by pretreatment with tetrodotoxin but was blocked by pretreatment with strophanthidin or high extracellular K(+) concentration. The results suggest that alpha(1)-adrenergic receptor activation results in a decrease in a(Na)(i) via PKC-induced stimulation of the Na(+)-K(+) pump in cardiac myocytes.

Adrenergic alpha-Agonists↗
PubMed2000

Cytotoxic effects of pyridino[2,3-f]indole-4,9-diones on human tumor cell lines.

The cytotoxicities of pyridino[2,3-f]indole-4,9-dione derivatives were examined against human lung tumor cell lines (A 549), human ovarian tumor cell lines (SK-OV-3), human melanoma tumor cell lines (SK-MEL-2), human CNS tumor cell lines (XF 498) and human colon tumor cell lines (HCT 15) in vitro using a Sulforhodamine B assay. 3-Ethoxycarbonyl-1-(2-methoxyethyl)-2-methyl-1H-pyridino[2,3-f]ind ole-4,9-dione (5) showed excellent cytotoxicity against XF 498 and HCT 15. The ED50 values of 5 were 0.006 microg/ml against XF 498 and 0.073 microg/ml against HCT 15, while those of doxorubicin were 0.012 and 0.264 microg/ml, respectively. 1-Benzyl-3-ethoxycarbonyl-2-methyl-1H-pyridino[2,3-f]indole-4,9-di one (7) (ED50 value 0.065 microg/ml) was also significantly more cytotoxic against HCT 15 compared with doxorubicin.

Antineoplastic Agents↗
PubMed1999

Effects of endothelin-1 on Ca2+ signaling in guinea-pig ventricular myocytes: role of protein kinase C.

The effects of ET-1 on contraction, Ca2+ transient and L-type Ca2+ current (ICa.L) were studied in single cells isolated from ventricles of guinea-pig hearts. The aim of our study was to elucidate the mechanism of the positive inotropic effect during endothelin receptor stimulation by focusing on the role of PKC. ET-1 at concentrations of 5 and 10 nM produced a biphasic pattern of inotropism: a first decrease in contraction by 34.4 +/- 2.5% of the control followed by a sustained increase in contraction by 66.6 +/- 8.4% (mean +/- SEM, n = 9). The Ca2+ transient decreased by 13.5 +/- 1.0% during the negative inotropic phase, while it increased by 58.1 +/- 8.4% (n = 10) during the positive inotropic phase. Using the whole-cell voltage-clamp technique with conventional microelectrodes, the application of ET-1 (5 nM) increased the ICa.L by 32.6 +/- 5.1% (n = 10), which was preceded by a short-lived decrease in ICa.L. Incubation of myocytes with pertussis toxin (PTX, at 2 micrograms/ml for > 3 h at 35 degrees C) failed to block the ET-1-induced enhancement of ICa.L. The increases in contraction, Ca2+ transient, and ICa.L by ET-1 were inhibited by pretreatment with 5-N-methyl-N-isobutyl amiloride (MIA; 10 microM), an amiloride analog, and a novel selective Na+/H+ exchange inhibitor HOE694 (10 microM). To determine whether activation of protein kinase C (PKC) is responsible for the enhancement of ICa.L by ET-1, we tested a PKC inhibitor, GF109203X, and found that it does exert an inhibitory effect on the ET-1-induced ICa.L increase. Our study suggests that during ET receptor stimulation an increase in ICa.L due to stimulation of Na+/H+ exchange via PKC activation causes an increase in Ca2+ transients and thereby in the contractile force of the ventricular myocytes.

Amiloride↗
PubMed1999

Cytotoxicity of two novel cisplatin analogues, (CPA)2Pt[DOLYM] and (DACH)Pt[DOLYM], to human cancer cells in vitro.

Despite the impressive antitumor activity of cisplatin, two major limitations of the drug, that is severe side effects and drug-resistance of cancer cells, make its use difficult for cancer therapy. These limitations have resulted in a great deal of effort having been expended into structural modifications of cisplatin. In this study, we tested two novel cisplatin analogues, (CPA)2Pt [DOLYM] (COMP-I) and (DACH)Pt[DOLYM] (COMP-II), for the mode of cytotoxic action against human tumor cells comparing with cisplatin and carboplatin in vitro. These two novel analogues had considerable cytotoxic activities against five kinds of human solid tumor cells, and especially COMP-II was more effective on HCT15 colon cancer cells than other compounds. In addition, COMP-II had cytostatic activity at low concentrations (10-0.3 microgram/ml), but other compounds revealed little effect on tumor growth at the low concentration.

Antineoplastic Agents↗
PubMed1999

A new cytotoxic acyclic diterpene from Carpesium divaricatum.

A new acyclic diterpene (1) and a known acyclic diterpene, 12(S)-hydroxygeranylgeraniol (2) were isolated from the aerial parts of Carpesium divaricatum. The structure of 1 was determined to be (2E,10E)-1,12-dihydroxy-18-acetoxy-3,7,15-trimethylhexadeca- 2,10,14-triene (1) on the basis of spectroscopic studies. Compounds 1 and 2 exhibited cytotoxicity against cultured human tumor cell lines, A549, SK-OV-3, SK-MEL-2, XF498, and HCT15, with ED50 values ranging from 4.3-10.2 micrograms/ml and 4.1-8.3 micrograms/ml, respectively.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Role of PKC in the effects of alpha1-adrenergic stimulation on Ca2+ transients, contraction and Ca2+ current in guinea-pig ventricular myocytes.

The effects of alpha1-adrenoceptor stimulation on intracellular Ca2+ transients, contractility and L-type Ca2+ current (ICa,L) were studied in single cells isolated from ventricles of guinea-pig hearts. The aim of our study was to elucidate the mechanisms of the positive inotropic effect of alpha1-adrenergic stimulation by focussing on the role of protein kinase C (PKC). Phenylephrine, an alpha1-adrenergic agonist, at concentrations of 50-100 microM elicited a biphasic inotropic response: a transient negative inotropic response (22.9+/-6.0% of control) followed by a sustained positive inotropic response (61.0+/-8.4%, mean+/-SE, n=12). The Ca2+ transient decreased by 10.2+/-3.9% during the negative inotropic phase, while it increased by 67.7+/-10% (n=12) during the positive inotropic phase. These effects were inhibited by prazosin (1 microM), a alpha1-adrenergic antagonist. Phenylephrine increased the ICa,L by 60.8+/-21% (n=5) during the positive inotropic phase. To determine whether activation of PKC is responsible for the increases in Ca2+ transients, contractile amplitude and ICa,L during alpha1-adrenoceptor stimulation, we tested the effects of 4beta-phorbol 12-myristate 13-acetate (PMA), a PKC activator, and of bisindolylmaleimide I (GF109203X) and staurosporine, both of which are PKC inhibitors. PMA mimicked phenylephrine's effects on Ca2+ transients, contractile amplitude and ICa,L. PMA (100 nM) increased the Ca2+ transient, contractile amplitude and ICa,L by 131+/-17%, 137+/-25% (n=8), and 81.1+/-26% (n=5), respectively. Prior exposure to GF109203X (1 microM) or staurosporine (10 nM) prevented the phenylephrine-induced increases in Ca2+ transients, contractile amplitude and ICa,L. Our study suggests that during alpha1-adrenoceptor stimulation increase in ICa,L via PKC causes an increase in Ca2+ transients and thereby in the contractile force of the ventricular myocytes.

Action Potentials↗
PubMed1999

Blockade of HERG channels expressed in Xenopus oocytes by external H+.

We have investigated the effect of external H+ concentration ([H+]o) on the human-ether-a-go-go-related gene (HERG) current (IHERG), the molecular equivalent of the cardiac delayed rectifier potassium current (IKr), expressed in Xenopus oocytes, using the two-microelectrode voltage-clamp technique. When [H+]o was increased, the amplitude of the IHERG elicited by depolarization decreased, and the rate of current decay on repolarization was accelerated. The activation curve shifted to a more positive potential at lower external pH (pHo) values (the potential required for half-maximum activation, V1/2, was: -41.8 mV, -38.0 mV, -33.7 mV, -26.7 mV in pHo 8.0, 7.0, 6.6, 6.2, respectively). The maximum conductance (gmax) was also affected by [H+]o: a reduction of 7.9%, 14.6%, and 22.8% was effected by decreasing pHo from 8.0 to 7.0, 6.6, and 6.2, respectively. We then tested whether this pH effect was affected by the external Ca2+ concentration, which is also known to block HERG channels. When the extracellular Ca2+ concentration was increased from 0.5 mM to 5 mM, the shift in V1/2 caused by increasing [H+]o was attenuated, suggesting that these two ions compete for the same binding site. On the other hand, the decrease in gmax caused by increasing [H+]o was not significantly affected by changing external Ca2+ levels. The results indicate that HERG channels are inhibited by [H+]o by two different mechanisms: voltage-dependent blockade (shift of V1/2) and the decrease in gmax. With respect to the voltage-dependent blockade, the interaction between H+ and Ca2+ is competitive, whereas for the decreasing gmax, their interaction is non-competitive.

Animals↗
PubMed1999

Blockade of HERG channels expressed in Xenopus laevis oocytes by external divalent cations.

We have investigated actions of various divalent cations (Ba2+, Sr2+, Mn2+, Co2+, Ni2+, Zn2+) on human ether-a-go-go related gene (HERG) channels expressed in Xenopus laevis oocytes using the voltage clamp technique. All divalent cations inhibited HERG current dose-dependently in a voltage-dependent manner. The concentration for half-maximum inhibition (Ki) decreased at more negative potentials, indicating block is facilitated by hyperpolarization. Ki at 0 mV for Zn2+, Ni2+, Co2+, Ba2+, Mn2+, and Sr2+ was 0.19, 0.36, 0. 50, 0.58, 2.36, and 6.47 mM, respectively. The effects were manifested in four ways: 1) right shift of voltage dependence of activation, 2) decrease of maximum conductance, 3) acceleration of current decay, and 4) slowing of activation. However, each parameter was not affected by each cation to the same extent. The potency for the shift of voltage dependence of activation was in the order Zn2+ > Ni2+ >/= Co2+ > Ba2+ > Mn2+ > Sr2+, whereas the potency for the decrease of maximum conductance was Zn2+ > Ba2+ > Sr2+ > Co2+ > Mn2+. The kinetics of activation and deactivation were also affected, but the two parameters are not affected to the same extent. Slowing of activation by Ba2+ was most distinct, causing a marked initial delay of current onset. From these results we concluded that HERG channels are nonselectively blocked by most divalent cations from the external side, and several different mechanism are involved in their actions. There exist at least two distinct binding sites for their action: one for the voltage-dependent effect and the other for reducing maximum conductance.

Animals↗
PubMed1999

Synthesis and biology of 3'-N-acyl-N-debenzoylpaclitaxel analogues.

The, 3'-N-acyl-N-debenzoylpaclitaxel analogues 1a-d were synthesized and evaluated on biological systems. Some of the analogues 1a-d exhibited higher cytotoxicities (up to 20-fold) and stronger abilities to induce apoptosis than paclitaxel. In an in vivo experiment against i.p. implanted B16 melanoma, the most cytotoxic compound 1b in vitro caused tumor growth inhibition more than paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Cytotoxic polyacetylenes from the marine sponge Petrosia sp.

Three C46 (1-3) and three C30 (4-6) polyacetylenic alcohols with cytotoxic activity against a small panel of human solid-tumor cell lines have been isolated from the marine sponge Petrosia sp. Although compound 1 was identified as the stereoisomer of petrocortyne A, the structures of compounds 2-5 have not been previously reported and were established by spectral methods. Compound 6 was identified as the known compound petrosiacetylene D. The stereochemistry of compounds 1-5 was determined by the modified Mosher's method.

Acetylene↗
PubMed1999

KR025, a new cytotoxic compound from Myxococcus fulvus.

A new bithiazole, KR-025 (1), was isolated from Myxococcus fulvus. Its structure was elucidated by spectroscopic analysis. In addition to 1, the strain produced relatively large quantities of a second, closely related antibiotic, myxothiazol. These compounds demonstrated potent cytotoxicity against human tumor cells.

Antibiotics, Antineoplastic↗
PubMed1999

New cytotoxic polyacetylenes from the marine sponge Petrosia.

New polyacetylenic alcohols with a C(45) carbon skeleton (2) and with an enone moiety in the alkyl chain (C(46), 1) were isolated from the marine sponge Petrosia sp. The gross structures of 1 and 2 were established by spectral methods, and the absolute stereochemistry was determined by the modified Mosher's method. Compounds 1 and 2 displayed considerable cytotoxicity against a small panel of human solid tumor cell lines. Significant inhibitions on DNA replication by 1 and 2 were also observed which could be explanative of their cytotoxicity.

Acetylene↗