RESUMO
The SRB assay was used to test cytotoxicity against three human cancer cell lines and one normal cell line of 11 Thai medicinal plant species used by traditional doctors in treating cancer patients. The extraction procedures used were similar to those practised by Thai traditional doctors (ethanolic and water extracts). Extracts were tested against the human large cell lung carcinoma cell line COR-L23, the human breast adenocarcinoma cell line MCF-7 and human colon adenocarcinoma cell line LS-174T and normal human keratinocytes SVK-14. The results showed that three plants; Dioscorea membranacea Pierre ex Prain & Burkill, Dioscorea birmanica Prain & Burkill (Dioscoreaceae) and Siphonodon celastrineus Griff. (Celastraceae), exhibited high cytotoxic activity showing a certain degree of selectivity against the different cell types.
Assuntos
Extratos Vegetais/farmacologia , Plantas Medicinais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , TailândiaRESUMO
Three N10-(4-nitrobenzyl)carbamate-protected PBD prodrugs (9a, 9b and 15) have been synthesized and evaluated for potential use in nitroreductase-based ADEPT and GDEPT therapies. An approximately 100-fold activation was observed for the DC-81 prodrug 9a.
Assuntos
Benzodiazepinas/síntese química , Benzodiazepinas/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , NAD/farmacologia , Nitrorredutases/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Thirteen indole alkaloids isolated from the root bark of Alstonia macrophylla and a semisynthetic bisindole O-acetylmacralstonine have been assessed for cytotoxic activity against two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma), using the SRB assay. Pronounced cytotoxic activity was exhibited by the bisindoles on both cell lines. This suggests that, in comparison with the corresponding monomeric indoles, at least part of both the ring systems present in the bisindoles is essential for cytotoxic activity. The potent alkaloids were further tested against a human normal cell line (breast fibroblasts) and other human cancer cell lines including StMI1 1a (melanoma), Caki-2 (renal cell carcinoma), MCF7 (breast adenocarcinoma), and LS174T (colon adenocarcinoma). The bisindoles O-acetylmacralstonine, villalstonine and macrocarpamine were found to possess pronounced activity against cancer cell lines with IC50 values in the range of 2-10 microM, with no discernible cell-type selectivity. However, O-acetylmacralstonine displayed discernibly less toxicity against the normal breast fibroblasts.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Indóis/farmacologia , Neoplasias Pulmonares/patologia , Plantas/química , Alcaloides/química , Antineoplásicos Fitogênicos/química , Divisão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Células Tumorais CultivadasRESUMO
The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase G2 are described. The best thiocarbamate inhibitor N-(p-methoxybenzenethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigations of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G2 conjugate and prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutamate) toward LS174T cells. This is the first report of a small-molecule enzyme inhibitor proposed for use in conjunction with the ADEPT approach.
Assuntos
Anticorpos/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Pró-Fármacos/farmacologia , gama-Glutamil Hidrolase/antagonistas & inibidores , Mostarda de Anilina/análogos & derivados , Mostarda de Anilina/farmacologia , Cromatografia em Camada Fina , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Células Tumorais Cultivadas , gama-Glutamil Hidrolase/farmacologiaRESUMO
Methanol extracts of root barks of Alstonia macrophylla, A. glaucescens, and A. scholaris, collected from Thailand, have been assessed for cytotoxic activity against two human lung cancer cell lines, MOR-P (adenocarcinoma) and COR-L23 (large cell carcinoma), using the SRB assay. Significant cytotoxic activity was exhibited by the extract of A. macrophylla on both cell lines. Activity-directed fractionation led to the isolation of a novel indole alkaloid, O-methylmacralstonine, from the most active fraction of A. macrophylla along with four known alkaloids, talcarpine, villalstonine, pleiocarpamine, and macralstonine. Structure elucidation of the novel alkaloid was based on spectroscopic methods, especially 2D-NMR. The bisindole villalstonine was found to possess pronounced activity on both cell lines with an IC50 value less than 5 muM, but was about 10(3) times less potent than vinblastine sulphate. The monomeric alkaloid, talcarpine, was found to be inactive. Pleiocarpamine, O-methylmacralstonine and macralstonine were all considerably less active than villalstonine.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias Pulmonares/patologia , Plantas Medicinais/química , Adenocarcinoma/patologia , Alcaloides/química , Antineoplásicos Fitogênicos/química , Carcinoma de Células Grandes/patologia , Humanos , Espectroscopia de Ressonância Magnética , Extratos Vegetais/farmacologia , Células Tumorais CultivadasRESUMO
Polyethylene glycol modification of the antibody--enzyme conjugate, F(ab')2-A5B7-CPG2, extends its duration in the circulation of nude mice bearing human colonic cancer xenografts (LS174T). Increased concentration of modified conjugate is achieved in the tumour, but residual non-specific enzyme concentrations in normal tissue and blood demonstrate the fundamental requirement to remove or inactivate non-specifically held enzyme in this system.