RESUMEN
PURPOSE: Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance. EXPERIMENTAL DESIGN: Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice. RESULTS: In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013-0.414 µmol/L; docetaxel, 0.17-4.01 µmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT). CONCLUSIONS: Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Taxoides/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Proteínas de Microtúbulos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estabilidad Proteica/efectos de los fármacos , Taxoides/administración & dosificación , Taxoides/farmacocinéticaRESUMEN
Topoisomerase I inhibitors, such as CPT-11, are potent anticancer drugs against neuroblastoma (NB). Differentiating agents, such as retinoids, improve the survival of children with metastatic NB. To characterize the biological effects associated with exposure to CPT-11 in vivo, athymic mice bearing a human NB xenograft, named IGR-NB8 and characterized as an immature NB with poor prognostic markers, were treated with CPT-11. Prolonged stable disease was observed, resulting in an overall tumor growth delay of 115 days. During treatment, tumors differentiated into ganglioneuroblastomas (GGNB), which reverted into an immature phenotype when treatment was discontinued. In contrast, 13-cis retinoic acid failed to induce differentiation of IGR-NB8 in vivo. Tumor differentiation was associated with decreased N-myc expression, induction of p73 expression in the perinuclear area and cytoplasm, and a dramatic 35-fold decrease in topoisomerase I (topo I) catalytic activity. The full-length Mr 100,000 topo I protein was present in both pre and post-treatment immature NB xenografts. In contrast, differentiated GGNBs did not contain the Mr 100,000 protein but an intense Mr 48,000 topo I fragment. Furthermore, redistribution of the Mr 48,000 and 68,000 forms to the cytoplasm was observed in differentiated tumors. The same pattern of topo I expression and catalytic activity was observed in NBs and GGNBs obtained from pediatric patients. Our data suggest that prolonged in vivo exposure to CPT-11 induces differentiation of NB xenografts, which is associated with truncation of the topo I enzyme, relocation of the degraded forms to the cytoplasm, and decreased catalytic activity.
Asunto(s)
Camptotecina/análogos & derivados , Camptotecina/farmacología , Inhibidores Enzimáticos/farmacología , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/enzimología , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos Fitogénicos/farmacología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Niño , Preescolar , ADN-Topoisomerasas de Tipo I/metabolismo , Diterpenos , Femenino , Humanos , Lactante , Recién Nacido , Irinotecán , Masculino , Ratones , Ratones Desnudos , Neuroblastoma/patología , Retinaldehído/farmacología , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sirolimus/análogos & derivados , Acetiltransferasas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Hipoxia de la Célula , Everolimus , Histona Acetiltransferasas , Neoplasias/irrigación sanguínea , Neovascularización Patológica/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt , Sirolimus/uso terapéuticoRESUMEN
Taxanes are known to activate several cellular signals including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa B), tyrosine phosphorylation of Shc, and serine phosphorylation of Bcl-2. However, the mediators of these signaling pathways are unknown. Using U937 leukemic cells, we evaluated the effect of docetaxel on phosphatidylcholine (PC) and its metabolites, phosphatidic acid (PA) and diacylglycerol (DAG), and their impact on MAPK and NF-kappa B activation, as well as on Raf-1 and Bcl-2 phosphorylation. Metabolic labeling studies showed that docetaxel (10 nM) induced two waves of PA production (130-140%), which were detected at 1 and 10 min. Docetaxel also stimulated DAG production (130%), which followed the first PA wave. The initial PA burst was due to phospholipase D (PLD)-mediated PC hydrolysis. Subsequent DAG production was inhibited by the phosphatidate phosphohydrolase (PAP) inhibitor, propranolol. R59949, a DAG kinase inhibitor, increased DAG accumulation and blocked the second PA wave. These results suggest that docetaxel triggers a metabolic cascade consisting in PLD-mediated PC hydrolysis, PA release, PAP-dependent DAG production, and DAG kinase stimulation, leading to DAG conversion back to PA. Neither R59949 nor propranolol influenced docetaxel-induced Raf-1/ERK activation. However, R59949 abrogated both NF-kappa B activation and Bcl-2 phosphorylation, suggesting that DAG and/or DAG-derived PA contribute in regulating these events.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Diglicéridos/biosíntesis , Ácidos Fosfatidicos/biosíntesis , Fosfatidilcolinas/metabolismo , Transducción de Señal/efectos de los fármacos , Taxoides/farmacología , Diacilglicerol Quinasa/metabolismo , Docetaxel , Ensayo de Cambio de Movilidad Electroforética , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Humanos , Hidrólisis , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Fosforilación , Piperidinas/farmacología , Propranolol/farmacología , Proteínas Proto-Oncogénicas c-raf/metabolismo , Quinazolinas/farmacología , Quinazolinonas , Células U937Asunto(s)
Antineoplásicos/uso terapéutico , Factor de Crecimiento Epidérmico/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib , Alemania , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéuticoRESUMEN
This review describes the experimental and clinical properties of new taxanes and epothilones. Six new taxanes are currently in clinical trials: BMS 184476, BMS 188797, BMS 275183, IDN 5109/BAY 598862, RPR 109881A et RPR 116258 All these derivatives share the same feature which is a decreased recognition by Pgp-170, the product of the MDR1 gene. This confers innovative properties such as in vitro and in vivo activities on tumors expressing the Pgp-170, activity by the oral route. Identification of other families of molecules bearing the same mechanism of action as taxol has been a goal pursued by many groups. The discovery of epothilones led to the pharmaceutical development of two molecules: EPO 906 (which corresponds to the natural compound epothilone B) and BMS 247550. Phase I clinical trials have established that all these investigational drugs (taxanes and epothilones) can be safely administered in patients, the limiting toxicity being most of the time febrile neutropenia. Many tumor responses have been noted.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Paclitaxel/análogos & derivados , Taxoides , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Neutropenia/inducido químicamente , Paclitaxel/química , Paclitaxel/farmacología , Paclitaxel/uso terapéuticoRESUMEN
BACKGROUND: Growth inhibition by RPR-130401, a non-peptidomimetic farnesyltransferase inhibitor, was investigated without or with combined exposure to ionizing radiation in three human tumor cell lines (HCT-116, MiAPaCa-2 and A-549) bearing a point mutation in the K-Ras gene. RESULTS: RPR-130401 inhibited cell growth with an IC50 of 50 nM (HCT-116), 120 nM (MiAPaCa-2) and 710 nM (A-549), with a poor incidence of apoptosis. The drug brought about G1 and S phase depletion together with arrest of cells in G2 phase and induced a significant accumulation of hyperploid cells showing active S phase DNA synthesis, with HCT-116 and A-549 cells being the most and least responsive, respectively. The drug also produced dramatic changes of the nuclear lamin B pattern, without lamin B cleavage and perturbation of the actin cytoskeleton. On the other hand, RPR-130401 elicited strictly additive interaction in combined treatment with ionizing radiation with regard to cell kill, altered cell cycle progression and induced hyperploidy. CONCLUSIONS: The data suggest that disruption of orderly progression through mitosis and cytokinesis, is a major outcome of drug action and that this effect proceeds from inhibition of lamin B farnesylation. It is anticipated from the strict additivity of RPR-130401 and radiation that neither induced radiation resistance nor acute or late complications of radiotherapy, should occur in combined treatment with RPR-130401.