RESUMO
PURPOSE: To determine the most effective combination chemotherapy with S-1 against pancreatic cancer and to clarify the mechanism of synergy between S-1 and the partner drug. METHODS: We tested a combination of S-1 with the following antitumor drugs in an in vitro MTT assay against pancreatic cancer cell line MIA PaCa-2: gemcitabine (GEM), cisplatin (CDDP), irinotecan (CPT-11), mitomycin C, adriamycin, and paclitaxel. The efficacy of S-1, GEM, and a combination of S-1 and GEM was also tested in vivo by administering S-1 (10 mg/kg) orally to nude mice five times a week for 3 weeks, and GEM (100 mg/kg) intravenously every 2-3 days for a total of six times. A treated-to-control ratio (T/C) of relative mean tumor weight values less than 50% was determined to be effective. Furthermore, we investigated the mechanism of the synergistic effect of S-1 and GEM on the cell cycle by flow cytometry, because both S-1 and GEM are known as antimetabolic drugs. To verify cell death induced by a change in the distribution of the cell cycle phases, we investigated apoptosis by sub-G1 analysis and a TUNEL assay. RESULTS: From classical isobolography analysis of the in vitro MTT assay, the combination of S-1 plus GEM was found to be the most effective of the combinations tested. In vivo, T/C (percentage) with the combination of S-1 plus GEM was 48.2%, which was lower than that of S-1 or GEM alone, and the combination enhanced antitumor activity. Cell cycle analysis showed greater cell cycle delay with the combination treatment (S-1 plus GEM) than for each single drug treatment, and apoptotic cells were detected only in treatments including GEM. CONCLUSION: The combination chemotherapy of S-1 and GEM appears to be useful for pancreatic cancer. Both cycle delay by S-1 plus GEM and apoptosis induced by GEM are involved in this synergistic mechanism.
Assuntos
Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Doxorrubicina/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Irinotecano , Camundongos , Camundongos Endogâmicos BALB C , Mitomicina/farmacologia , Ácido Oxônico/farmacologia , Paclitaxel/farmacologia , Piridinas/farmacologia , Tegafur/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
Seven new indole alkaloids of the Aspidosperma type, jerantinines A-G (1-7), were isolated from a leaf extract of the Malayan Tabernaemontana corymbosa. The structures were established using NMR and MS analysis. Five of the alkaloids isolated and two derivatives (1-5, 8, 9) displayed pronounced in vitro cytotoxicity against human KB cells (IC50 < 1 microg/mL).
Assuntos
Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Tabernaemontana/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Malásia , Estrutura Molecular , Folhas de Planta/químicaRESUMO
Ten new indole alkaloids of the aspidofractinine type, in addition to several recently reported indole alkaloids and 20 other known alkaloids, were obtained from the leaf and stem-bark extract of the Malayan Kopsia singapurensis, viz., kopsimalines A-E (1-5), kopsinicine (6), kopsofinone (7), and kopsiloscines H-J (8-10). The structures of these alkaloids were determined using NMR and MS analysis. Kopsimalines A (1), B (2), C (3), D (4), and E (5) and kopsiloscine J (10) were found to reverse multidrug-resistance in vincristine-resistant KB cells, with 1 showing the highest potency.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Vincristina/farmacologia , Antineoplásicos Fitogênicos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células KB , Malásia , Estrutura Molecular , Casca de Planta/química , Folhas de Planta/químicaRESUMO
Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Plantas Medicinais/química , Alcaloides/química , Alcaloides/classificação , Antineoplásicos Fitogênicos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/química , Indolizinas/isolamento & purificação , Indolizinas/farmacologia , Células KB , Lactamas/química , Lactamas/isolamento & purificação , Lactamas/farmacologia , Malásia , Estrutura MolecularRESUMO
Nine new indole alkaloids, rhazinoline (1), 19(S)-methoxytubotaiwine (2), 19(R)-methoxytubotaiwine (3), kopsamidine A (4), kopsamidine B (5), kopsinidine A (6), kopsinidine B (7), paucidactine C (8), and pericine N-oxide (9), in addition to several recently reported novel indoles and 34 other known ones, were obtained from the stem-bark extract of the Malayan Kopsia arborea. The structures were determined using NMR and MS analysis. Valparicine (12) showed pronounced cytotoxic effects against KB and Jurkat cells (IC(50) 13.0 and 0.91 microM, respectively).
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides Indólicos/farmacologia , Plantas Medicinais/química , Antineoplásicos Fitogênicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Células Jurkat , Células KB , Malásia , Ressonância Magnética Nuclear Biomolecular , Casca de Planta/química , Caules de Planta/químicaRESUMO
Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.
Assuntos
Antineoplásicos Fitogênicos , Apocynaceae/química , Alcaloides Indólicos/isolamento & purificação , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Células KB , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Vincristina/farmacologiaRESUMO
Three strains of human esophageal carcinoma xenografts established in our institution were tested against combination chemotherapy in vivo and in vitro. TS-1 plus cisplatin (CDDP) was shown to be an effective combination against two carcinoma strains of moderately-differentiated type. Determination of the thymidylate synthase (TS) demonstrated a higher inhibition of the enzyme by adding CDDP to 5-FU, suggesting biochemical modulation. The remaining strain of poorly-differentiated type was resistant to the combination and an attempt was made to add docetaxel (DTX) to show that the three-drug combination was effective against the strain. Combination chemotherapy including TS-1 and CDDP thus appears to be useful treatment choice for esophageal carcinoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Animais , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Docetaxel , Combinação de Medicamentos , Sinergismo Farmacológico , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Ácido Oxônico/administração & dosagem , Ácido Oxônico/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Succinato Desidrogenase/antagonistas & inibidores , Taxoides/administração & dosagem , Taxoides/farmacologia , Tegafur/administração & dosagem , Tegafur/farmacologia , Timidilato Sintase/antagonistas & inibidores , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
While screening for novel IL-6 inhibitors, we synthesized 20S,21-epoxy-resibufogenin-3-acetate (ERBA). ERBA dose-dependently suppressed IL-6-induced cell growth with an IC(50) value of 5.3 microM and caused a parallel rightward shift of dose-response curves to IL-6. Analysis of data yields a pA2 of 5.83 and a slope of 0.99. ERBA did not affect IL-2-, IL-3-, and GCSF-dependent cell growth, or tumor necrosis factor alpha-induced growth suppression, nor did ERBA affect osteoclast formation induced by IL-11, leukemia inhibitory factor, and 1alpha,25-dihydroxyvitamin D(3). Receptor assay showed that ERBA dose-dependently suppressed IL-6 binding to IL-6 receptor (IL-6R). Furthermore, no band existing at the position of IL-6R in Western blots of ERBA-treated cells when stimulated with IL-6:ERBA suppresses IL-6 activity by blocking the binding of IL-6 to IL-6R. In an experimental model of colon 26-induced cancer cachexia, ERBA markedly inhibited body weight loss. ERBA is a specific small molecule with IL-6R-antagonist activity.