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PubMedDate not supplied

Pharmacological properties of a new alpha-aminophosphonic acid derivative of vinblastine.

S 12363 is a new vinca alkaloid derivative obtained by grafting an optically active alpha-aminophosphonate at the C23 position of O4-deacetyl vinblastine. This compound was as potent as Vincristine (VCR), and less potent than Vinblastine (VLB), in inhibiting in vitro tubulin polymerization. However, S 12363 was found to be 7 to 553 and 12 to 74-fold more cytotoxic than VCR and VLB, respectively, when tested on a panel of 2 murine and 6 human tumor cell lines using the Microculture Tetrazolium Assay. S 12362, which differs only by the configuration of the asymmetric carbon atom of the side chain, was 18 to 59-fold less cytotoxic. At equitoxic doses, all these compounds induced a "G2 + M" phase accumulation of L1210 cells, suggesting a similar mechanism of action. S 12363, administered i.p. or i.v., was at least as active as reference compounds on two murine transplantable tumors (P388 leukemia and B16 melanoma) while the optimal dosage was 20-fold lower: 0.15-0.20 mg/kg versus 2-5 mg/kg, respectively. S 12362 was practically inactive at 1-3 mg/kg. The hematological toxicity of S 12363 (0.1 mg/kg) was similar to that of VLB (4 mg/kg). The exceptionally high potency of S 12363 did not appear to be due to a better interaction with tubulin, its intracellular target, but rather to some properties conferred by the alpha-aminophosphonic acid, such as a facilitated uptake and/or a better cellular retention.

Animals↗
PubMed2004

Spontaneous generation of reactive oxygen species in the mixture of cyanide and glycerol.

Reactive oxygen species are involved in tumor promotion or apoptosis. In assaying prooxidant or antioxidant activities, cyanide has been commonly used as an inhibitor of mitochondrial oxidases, peroxidases, or Cu,Zn-superoxide dismutase, which have an influence on intracellular levels of reactive oxygen species. It has also been used to chemically mimic hypoxia. On the other hand, glycerol has been widely used as a stabilizer of various enzymes. In particular, glycerol is required to maintain the enzymatic activities of membrane-bound NAD(P)H oxidases extracted from surrounding phospholipids. Since both cyanide and glycerol are relatively inert, they have been used concomitantly regardless of any mutual interference. In this study, we demonstrate that a mixture of glycerol and cyanide reduced cytochrome c and nitroblue tetrazolium, both of which are superoxide anion indicators. The mixture also enhanced the production of superoxide anion in the presence of redox-cycling compounds. Superoxide production by the mixture was confirmed by electron spin resonance spectra. Moreover, the mixture induced lipid peroxidation and hemolysis in human erythrocytes. These results suggest that cyanide and glycerol should be used carefully in reaction systems used to measure superoxide production or antioxidant activity. However, sucrose and sodium azide in combination do not produce such artifacts and thus may be used as an alternative.

Cyanides↗
PubMed2000

Isolation and characterization of free radical scavenging activities peptides derived from casein.

A peptide having the strong free radical scavenging activities was separated from casein protein hydrolysate by chromatographic analyses such as ion-exchange and gel filtration. SP-II fraction obtained by SP-Sephadex C-25 chromatography showed the most potent superoxide anion scavenging activity (SOSA), and it was further separated into a peptide using an octadecylsilano-high performance liquid chromatography. The amino acid sequence of the peptide was Tyr-Phe-Tyr-Pro-Glu-Leu (YFYPEL). The concentration of the test compound required to reduce the produced superoxide anion to one-half (IC(50)) value for SOSA was 79.2 microM using tetrazolium salt 3'-{1-[(phenylamino)-carbonyl]-3,4-tetrazolium}-bis(4-methoxy-6-nitro)benzenesulfonic acid hydrate method. The IC50 value for the 1,1-diphenyl-2-picrylhydrazyl radical and hydroxyl radical scavenging activities were 98 and 251 microM, respectively, based on the electron spin resonance method. We characterized SOSA of the C-terminal sequence using EL, PEL, YPEL, and FYPEL. The activities preferred sequences were EL>YFYPEL>FYPEL>YPEL>PEL, suggesting that the Glu-Leu sequence is important for the activity.

Journal Article↗
PubMed2001

Dammarane triterpene saponin from Bacopa monniera as the superoxide inhibitor in polymorphonuclear cells.

The hydroalcoholic extract of the whole plant of Bacopa monniera Wettst. (Scrophulariaceae), exhibited an inhibitory effect on superoxide released from polymorphonuclear (PMN) cells in the nitroblue tetrazolium (NBT) assay. The major saponin bacoside A(3) was found to be responsible for this effect in the herb. This compound showed 85, 91.66, 91.66, and 83 % inhibitions of NBT reduction at the concentrations of 200, 100, 50, and 25 microg/ml, respectively, with an IC(50) value of 10.22 microg/ml. These inhibitory effects were compared with those of the standard positive controls, quercetin and ascorbic acid with IC(50) of 111 and 14.16 microg/ml, respectively. Another major saponin bacopasaponin C was found to be much less potent as compared to bacoside A(3) whereas the remaining two mixtures of saponins were found to be inactive.

Carbohydrate Sequence↗
PubMed1996

The lack of efficacy of 4,6,6'-trimethylangelicin to induce immune suppression in an animal model for photopheresis: a comparison with 8-MOP.

Photopheresis is an extracorporeal form of photochemotherapy with 8-methoxypsoralen (8-MOP) and UVA (PUVA). Patients ingest 8-MOP and then a psoralen-rich buffy coat is obtained by centrifugation and mixed with saline. This mixture is recirculated through a UVA radiation field and then reinfused. Photopheresis appears to be effective for several T cell-mediated disorders, because the treatment results in a specific immune response against the pathogenic clone of T cells involved. With PUVA therapy, the whole body of the patient is exposed to UVA, after ingestion of 8-MOP. Upon UVA exposure 8-MOP binds to, amongst others, DNA and induces DNA monoadducts and interstrand cross-links. As a result of these photoadducts photocarcinogenicity is a risk in PUVA. In PUVA for psoriasis, it proved that angular furocoumarins, although almost incapable of inducing DNA cross-links (less carcinogenic), are still effective. In order to determine if monoadducts induced by photopheresis could also be effective we used, specifically, 4,6,4'-trimethylangelicin (TMA). In this report, we compare the photodegradation of both TMA and 8-MOP under conditions relevant to the in vivo situation, as well as the effect both compounds have on the viability of rat lymphocytes as measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. We show that TMA did not induce immunosuppression in vivo, even after extensive irradiation. In addition a dose dependency of 8-MOP/UVA versus the induced immune suppression was carried out. It was shown that there is a log dose/response correlation of r=0.9205.

Animals↗
PubMedDate not supplied

Structure-cytotoxicity relationships of a series of natural and semi-synthetic simple coumarins as assessed in two human tumour cell lines.

The cytotoxicity of 22 natural and semi-synthetic simple coumarins was evaluated in GLC4, a human small cell lung carcinoma cell line, and in COLO 320, a human colorectal cancer cell line, using the microculture tetrazolium (MTT) assay. With IC50 values > 100 microM, following a continuous (96 h) incubation, most coumarins exhibited only low cytotoxicity. Several compounds, however, displayed significant potencies. As far as the structure--cytotoxicity relationship is concerned, it is conspicuous that all the potentially active natural compounds possess at least two phenolic groups in either the 6,7- or 6,8-positions. In addition, the 5-formyl-6-hydroxy substituted semi-synthetic analogue was found to be potent, reflecting the importance of at least two polar functions for high cytotoxicity.

Carcinoma, Small Cell↗
PubMed1988

Modulation of interleukin-1 activity on murine thymocytes by various inhibitors of arachidonic acid oxygenation.

A variety of cyclooxygenase (FCO) and 5-lipoxygenase (5-LPO) inhibitors were tested for their ability to modulate murine thymocyte proliferation induced by IL-1 and suboptimal levels of the mitogen phytohemagglutinin (PHA). The contribution of drug toxicity to inhibition of 3H-thymidine incorporation was estimated by measuring MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) formazan production in the thymocyte cultures at the end of the assay. Cyclosporin A and dexamethasone, two positive control compounds, potently inhibited thymocyte proliferation at extremely low concentrations (0.01 and 0.001 micrograms/ml respectively), although activity roughly paralleled toxicity. In contrast, 5-LPO inhibitors (AA-861, BW-755c, and ETYA), but not selective FCO inhibitors (ibuprofen and indomethacin), suppressed lymphoproliferation at nontoxic concentrations, suggesting that products of the 5-LPO pathway may mediate the thymocyte proliferative response induced by IL-1/PHA. Attempts to counteract the suppressive activity of 5-LPO inhibitors by addition of leukotriene (LT) B4, LTC4, LTE4, 5-HETE, and 15-HETE were unsuccessful.

Animals↗
PubMed1992

Nitroblue tetrazolium reduction and bone resorption by osteoclasts in vitro inhibited by a manganese-based superoxide dismutase mimic.

Oxygen-derived free radicals are produced by osteoclasts. Oxygen radical formation occurs at the osteoclast/bone surface interface. This location next to bone implies that oxygen radicals, including but not limited to superoxide, are needed for bone resorption. Compounds that scavenge superoxide are being developed as pharmaceutical agents to inhibit the damaging effects of oxygen radical formation on tissues. One such scavenger is the Desferal-manganese complex (DMnC). DMnC reduced the amount of formazan staining produced by the interaction of oxygen radicals with nitroblue tetrazolium (NBT) in both individual mouse calvarial osteoclasts in tissue explants and isolated osteoclasts. As a result of the reduced concentrations of oxygen radicals, DMnC inhibited bone resorption by calvarial explants and isolated osteoclasts. Superoxide dismutase (SOD) inhibited NBT reduction and bone resorption by isolated osteoclasts but to a lesser degree than DMnC. Inhibition of bone resorption in the isolated osteoclast system increased in parallel to the concentration of DMnC in cultures. Desferal without Mn had no effect on bone resorption by isolated osteoclasts. These results support the hypothesis that osteoclasts produce oxygen radicals as part of the process of bone resorption.

Analysis of Variance↗
PubMed2005

Gastroprotective activity of a new semi-synthetic solidagenone derivative in mice.

The gastroprotective activity of the new semi-synthetic solidagenone derivative 15,16-epoxy8(9),13(16),14-labdatrien-7 beta-methoxy-6 beta-ol (ELMO) has been assessed on the model of HCl/EtOH-induced gastric lesions in mice. Human gastric epithelial cells (AGS) and fibroblasts (MRC-5) were used to determine its mode of action. The effect of ELMO on the prostaglandin E2 content, cellular reduced glutathione (GSH) and protection against damage induced by sodium taurocholate was assessed against AGS cells. The effect of ELMO on the growth of AGS and fibroblast cultures was evaluated. The superoxide anion scavenging capacity of the compound was studied also. The cytotoxicity of ELMO, expressed as cell viability, was assessed using two independent endpoints: neutral red uptake (NRU) and the reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for MRC-5 fibroblasts and NRU for AGS cells. A single oral dose of ELMO (10 and 20 mg kg(-1)) inhibited the appearance of gastric lesions in mice displaying similar values to lansoprazole at 20 mg kg(-1). At 40 microM ELMO increased the prostaglandin E2 content but not GSH in AGS cells. The compound showed no effect on sodium taurocholate-induced damage and was devoid of superoxide anion scavenging activity. Concentrations of 0.5, 1, 2 and 4 microM stimulated fibroblast but not AGS cell proliferation. The compound showed weak cytotoxicity with values (IC50) of 411 (NRU) and 418 microM (MTT) for fibroblasts and 261 microM (NRU) for AGS cells. The results support further pharmacological study of this compound as a potential new anti-ulcerogenic drug.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1997

The role of vitamin D derivatives and retinoids in the differentiation of human leukaemia cells.

The capabilities of 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), and two novel vitamin D analogues, EB1089 and KH1060, to induce the differentiation of two established leukaemia cell lines, U937 and HL-60, were assessed alone or in combination with the retinoid compounds, 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (ATRA). The vitamin D derivatives acted to increase the differentiation of U937 and HL-60 cell cultures in a dose-dependent manner, as determined by nitroblue tetrazolium (NBT) reduction, with EB1089 and KH1060 being more effective than the native hormone. As an additional index of leukaemic cell differentiation, induction of expression of the phenotypic cell surface antigen, CD14, and the beta2-integrins, CD11b and CD18 by the vitamin D and retinoid compounds were monitored using fluorescence activated cell sorting (FACS) analyses. Following 96-hr treatment of U937 and HL-60 cells with 5 x 10(-10) M of the vitamin D derivatives, a striking increase in CD14 antigen expression was apparent, indicating the promotion by these compounds of a monocyte/macrophage lineage of cells. CD11b and CD18 antigen expression were also raised above control levels. In contrast, both retinoid compounds used at the higher concentration of 1 x 10(-8) M were not effective inducers of CD14 antigen expression. However, CD11b and CD18 were both readily increased in U937 and HL-60 cell cultures. Treatment of U937 cell cultures with the vitamin D compounds and the retinoids resulted in cooperative effects on induction of differentiation, with correlation by both NBT reduction and FACS analyses of CD14 antigen expression. The presence of 9-cis RA or ATRA appeared to contribute to the further increase of CD14 in these cells. HL-60 cell cotreatment with these compounds also displayed enhanced cooperative effects in phagocytic function by NBT reduction. However, analysis of CD14 revealed a dramatic diminution in HL-60 cells treated with the combinations of the vitamin D derivatives and the retinoids. Assessment of HL-60 cell morphology treated with these combinations demonstrated the presence of a mixed population of monocytes and granulocytes. CD11b and CD18 antigen expression was also enhanced in both cell lines with cotreatment. The ability of EB1089 and KH1060 to induce leukaemic cell differentiation may provide an additional option for therapeutic use alone or together with other differentiation agents such as 9-cis RA or ATRA.

Alitretinoin↗
PubMed1992

Activity of two platinum-linked phosphonic acids against autochthonous rat colorectal cancer as well as in two human colon-cancer cell lines.

Two new platinum-containing phosphonate compounds, cis-diammine[nitrilotris(methylphosphonato)(2-)- O1,N1]platinum(II) (AMDP) and cis-cyclohexane-1,2-diamine[nitrilotris(methylphosphonato) (2-)-O1,N1]platinum(II) (DADP) were investigated in acetoxy-methyl-methylnitrosamine-induced autochthonous colorectal rat adenocarcinoma in vivo as well as in two human colon-cancer cell lines (SW707 and SW948) in vitro. In the in vivo model, the two compounds were given i.v. at doses of 8 and 13 mg/kg as well as p.o. at 16 and 26 mg/kg twice a week for 10 weeks, respectively. AMDP produced more intensive toxicity at both doses but showed higher antitumour activity only following i.v. administration. On the other hand, DADP caused significant tumour-growth inhibition after both modes of application, but as it produced only low toxicity, its use should be favoured. The in vitro assays were performed using two cell lines derived from human colorectal adenocarcinomas. According to the microculture tetrazolium test (MTT) AMDP (IC50, 34 and 59 microM in SW707 and SW948, respectively) was more effective than DADP (IC50, 412 and 660 microM in SW707 and SW948, respectively) in inhibiting cell growth. Based on cell counts AMDP (IC50, 8 and 11 microM in SW707 and SW948, respectively) and DADP (IC50, 266 and 285 microM in SW707 and SW948, respectively) showed more intensive antiproliferative efficacy as determined by the Coulter Counter method vs the MTT assay. The promising activities of these new platinum-linked phosphonic acids in autochthonous rat colorectal carcinoma and in human colorectal cancer cell lines warrant further investigations of compounds of this class to elucidate their role in the treatment of colorectal cancer.

Adenocarcinoma↗
PubMed2003

Synthesis and biological activity of a platinum(II) 6-phenyl-2,2'-bipyridine complex and its dimeric analogue.

We have synthesized (pyridyl)-(6-phenyl-2,2'-bipyridine)platinum(II) hexafluorophosphate (1) and its corresponding dimer, micro-N,N'-bis(isonicotinyl)-1,6-hexanediamino bis-[6-phenyl-2,2'-bipyridine-platinum(II)] dichloride (2). The DNA binding constants of 1 and 2 at 20 degrees C were determined by absorption titration to be 2.25 x 10(4) M(-1) and 3.07 x 10(6) M(-1), respectively. Compound 1 showed an AT preference, while 2 had no base preference. The binding site sizes of 2 for [poly(dA-dT)](2), calf thymus DNA (ctDNA), and [poly(dG-dC)](2), as determined by fluorescence titration, were 6.6, 4.0, and 2.8 bp, respectively. Compound 2 probably bound to [poly(dA-dT)](2) through bisintercalation, and to [poly(dG-dC)](2) by monointercalation. Binding of DNA by both complexes is favorable, since the binding free energies of 1 and 2 were estimated to be -5.8 and -8.7 kcal mol(-1), respectively. The results of viscosity measurements and gel mobility shift assay demonstrated that binding of 1 and 2 caused DNA lengthening. The cytotoxicities of the complexes in various human cancer cell lines were determined by MTT assay. Complex 2 exhibited cytotoxicity comparable to that of cisplatin, and was more toxic than 1 by an order of magnitude.

Algorithms↗
PubMed1993

Characterization of the glycine-dependent redox-cycling activity in animal fluids and tissues using specific inhibitors and activators: evidence for presence of PQQ.

Pyrroloquinoline quinone, a redox cofactor first isolated from bacteria, efficiently catalyzes the nonenzymatic oxidation of glycine in the presence of nitroblue tetrazolium. We report that certain metallic cations and heterocyclic aromatic cations, like the N-methyl phenazonium cation and aryl-iodonium compounds, strongly and specifically inhibit this redoxcycling activity. The inhibition by metal cations is reversed by Tiron and that of the aromatic cations by Tiron and thyroxine. These inhibitors and activators affect authentic PQQ and the redox-activity of putative PQQ isolated from biological sources in a similar manner. This indicates that pyrroloquinoline quinone occurs naturally in animal tissues and fluids.

Animals↗
PubMed2004

FK506 abrogates delayed neuronal death via suppression of nitric oxide production in rats.

BACKGROUND AND PURPOSE: The mechanism of the neuroprotective effect of FK506 in relation to nitric oxide (NO) production has not been clarified in vivo. We have investigated the effect of FK506 on ischemia-induced NO production in association with the pathogenesis of delayed neuronal death (DND) in rats. METHODS: In vivo microdialysis was performed in the hippocampus of male Sprague-Dawley rats (250-350 g). Dialysate samples were collected every 3 min. In the ischemia group (n=16), global ischemia was induced for 21 min and reperfusion was achieved. In the FK506 treatment group (n=25), FK506 (1 mg/kg, i.v.) was administered 21 min prior to the onset of global ischemia. Sham operations were done (n=15). The levels of NO(2)(-) in the dialysate samples were determined by the Griess reaction. The animals were decapitated 7 days after ischemia. Coronal brain sections were stained with hematoxylin and eosin. RESULTS: In the ischemia group, the NO(2)(-) level significantly increased during ischemia. In the FK506 treatment group, there was no significant change in the NO(2)(-) level during ischemia. In histological examinations, FK506 treatment showed a neuroprotective effect against DND. CONCLUSIONS: The effect of FK506 inhibiting NO production contributes to the neuro-protective effect of FK506 on DND in the hippocampus.

Analysis of Variance↗
PubMed2006

Antagonistic effects of methyl-mercury and PCB153 on PC12 cells after a combined and simultaneous exposure.

The study of interactions for those substances which tend to accumulate in food and affect the nervous system appears to be a fundamental point to characterize the combined exposure in vitro. In this study we included two food contaminants which are known neurotoxicants: methyl-mercury (Me-Hg) and the ortho-substituted PCB 153. PC12 cells were treated with Me-Hg (range 1e-7, 2e-6 M) and PCB153 (range 1e-5, 4e-4 M) in single and combined synchronous experiments and a mathematical model was set up according to the Loewe additivity criterion to evaluate the level of interaction between toxicants, using viability as end-point. At some concentrations (Me-Hg 5e-7 M and PCB153 1e-4 and 2e-4 M; Me-Hg 1e-6M and PCB153 5e-5 M; Me-Hg 1e-7 M and PCB153 4e-4 M), a statistically significant antagonist effect was observed. No interaction was observed for other combinations. The analysis of other toxicological parameters known to be modified in single exposure experiments (TBARS and intra-cellular dopamine) confirmed the viability results. The results of our work represent a starting point to generate novel information on the interactions between PCB153 and Me-Hg in vitro, as well as a new relevant experimental and mathematical approach useful to investigate the effects of different toxicant mixtures.

Animals↗
PubMed2003

The protective effect of ganstigmine against amyloid beta 25-35 neurotoxicity on chicken cortical neurons is independent from the cholinesterase inhibition.

Ganstigmine (CHF2819), a novel genserine derived acetylcholinesterase inhibitor and its enantiomer CHF3360 have been investigated for neuroprotective activity in two different in vitro assay systems using isolated cortical neurons from 9 day old chicken embryos. In the first in vitro model cells were lesioned by growth factor deprivation for 8 days achieved by reduced serum supplementation (2%) to the tissue culture medium. In the second lesion model neurodegeneration due to the addition of pre-aggregated beta-amyloid(25-35) has been achieved. Neuronal viability of treated neurons evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromid reduction assay was compared to that of untreated control cells. In a dose range between 1.0 and 10.0 microM both compounds significantly prevent progressive neuronal cell death due to growth factor deprivation. Furthermore Ganstigmine and its enantiomer in concentrations between 0.1 and 3 microM also significantly decrease neurodegeneration achieved by the addition of beta-amyloid(25-35) by approximately 50%. Dose response curves of both substances were identical concerning effect size and concentration. Because CHF3360 does not show any acetylcholine inhibitor activity in the applied dose range it is concluded that Ganstigmine provides significant neuroprotection independent from its cholinergic activity.

Alkaloids↗