RESUMO
BACKGROUND: The differential sensitivity of some tumors to paclitaxel and docetaxel raises questions regarding the specific mechanisms responsible for the discrepant sensitivity to these taxanes. MATERIALS AND METHODS: Docetaxel and paclitaxel were evaluated and compared at maximum tolerated doses (MTD) and 0.5 MTDs against the human pediatric tumor xenograft models SK-N-MC and IMR32 (neuroblastoma), RH1 and RH30 (rhabdomyosarcoma) and KHOS/NP (osteosarcoma), with 8-10 animals per group. The drug effects on the expression of the beta-tubulin isotypes, Bcl-2, Bax, Bcl-XL and proteomic profiles were evaluated by immunobloting and SELDI mass spectrometry in tumor xenografts dosed at 0.5 MTDs. RESULTS: At MTDs, docetaxel was superior in neuroblastoma and osteosarcoma, while paclitaxel was more active in the rhabdomyosarcoma models. Docetaxel showed remarkable efficacy in KHOS/NP even at 0.5 MTD. The drugs had significantly different, yet highly heterogeneous effects on the tumor levels of betaI-tubulin (RH30), betaIII-tubulin (IMR32, KHOS/NP, RH]), Bax (IMR32, SK-N-MC) and Bcl-XL (KHOS/NP). In contrast, six protein species identified by proteomic profiling were consistently and differentially regulated by docetaxel and paclitaxel in all KHOS/NP xenografts. CONCLUSION: Anticancer activity showed no apparent correlation with drug effects on beta-tubulin isotypes and apoptotic markers. The mass spectrometry approach has potential for the discovery of proteomic biomarkers for drug sensitivity.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Paclitaxel/farmacologia , Rabdomiossarcoma/tratamento farmacológico , Taxoides/farmacologia , Animais , Neoplasias Ósseas/metabolismo , Criança , Docetaxel , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Neuroblastoma/metabolismo , Osteossarcoma/metabolismo , Proteômica , Rabdomiossarcoma/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The antineoplastic activity of AZD3409 was evaluated in relation to paclitaxel in human breast (MDA-MB-231, BT-474) and ovarian (A2780, A2780cp) cancer cell lines. Biomarkers of apoptosis, protein prenylation, survival, angiogenesis and cellular growth were determined. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTS assay, and apoptosis was evaluated by TUNEL. Biomarkers were measured by Western blots and ELISA. RESULTS: The IC50 concentrations of AZD3409 in MDA-MB-231, BT-474, A2780 and A2780cp were 19.16, 5.69, 3.19, and 8.86 microM, respectively. The corresponding apoptogenic EC50 concentrations were 6.81, 4.15, 1.54 and 4.59 microM. CONCLUSION: Famesylation of HDJ-2 was inhibited in all cell lines. Secretion of VEGF, bFGF and MMP-1 were inhibited in the breast lines but augmented in the ovarian lines. AZD3409 increased Akt activation in breast lines and decreased it in ovarian lines, without effect on MEK or ERK activation. AZD3409 cytotoxicity is mediated in part by inhibition of farnesylation.
Assuntos
Antineoplásicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Western Blotting , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Marcação In Situ das Extremidades CortadasRESUMO
BACKGROUND: Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated. MATERIALS AND METHODS: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints. RESULTS: The drug combination resulted in additive cytotoxicity. R115777 +/- paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf-1 and MEK and inhibited secretion of VEGF and MMP-1. CONCLUSION: The effect of R115777 on prenylation biomarkers is consistent with its mechanism of action. The drug interfered with tumor growth, survival and angiogenesis pathways in breast cancer models with low or overexpressed HER2/neu receptor. The combination of R115777 with paclitaxel might offer clinical advantage over monotherapies.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quinolonas/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/enzimologia , Proteínas de Transporte/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase , Proteínas de Choque Térmico HSP40 , Proteínas de Choque Térmico/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neovascularização Patológica/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Prenilação de Proteína/efeitos dos fármacos , Quinolonas/administração & dosagem , Receptor ErbB-2/biossíntese , Proteína rhoB de Ligação ao GTP/metabolismoRESUMO
BACKGROUND: Paclitaxel and docetaxel affect microtubule polymerization, yet surprising differences in tumor sensitivity to the taxanes have been observed. Docetaxel was superior to paclitaxel in inhibiting in vivo growth of human lung and prostate but not breast cancer models. MATERIALS AND METHODS: We compared drug cytotoxicity, effects on ß-tubulin isoforms, markers of apoptosis and proteomic profiles in human prostate (LNCaP), lung (SK-MES, MV-522) and breast (MCF-7, MDA-231) cancer cell lines in vitro. RESULTS: Cytotoxicity followed the order SK-MES
