RESUMEN
AIM: To evaluate the anticancer efficacy of CKD-516, a novel vascular-disrupting agent, alone and in combination with doxorubicin in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In mice bearing luciferized HCC cells, therapeutic efficacy was assessed for seven days after single administration of CKD-516, doxorubicin, or combination of CKD-516 and doxorubicin. RESULTS: Bioluminescence-imaging (BLI) signals in the CKD-516 group abruptly decreased initially, but recovered at seven days after treatment. BLI signals in the doxorubicin group gradually decreased over the 7-day period. In the combination group, BLI signals were abruptly reduced and remained suppressed for the 7-day period. On histopathological examination, CKD-516-treated tumors showed extensive central necrosis, whereas the peripheral layers remained viable. Doxorubicin-treated tumors showed mild and scattered necrosis. Tumors from the combination group showed more extensive central and peripheral necrosis, with smaller viable peripheral layers than the CKD-516 group. CONCLUSION: Combination therapy can have additive effects for treatment of HCC compared with CKD-516 or doxorubicin monotherapy.
Asunto(s)
Benzofenonas/farmacología , Carcinoma Hepatocelular/patología , Doxorrubicina/farmacología , Neoplasias Hepáticas/patología , Valina/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Benzofenonas/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Evaluación Preclínica de Medicamentos , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Ratones , Necrosis , Neovascularización Patológica/tratamiento farmacológico , Carga Tumoral/efectos de los fármacos , Valina/administración & dosificación , Valina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. METHODS: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m(2)/d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m(2)) was administered on day 1, and capecitabine (1,000 mg/m(2) twice a day) was orally administered for 14 days of a 3-week cycle. RESULTS: In the group given the 10 mg/m(2)/d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m(2)/d, and the clinically recommended dose was 5 mg/m(2)/d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. CONCLUSION: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m(2)/d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/sangre , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Inhibidores de la Angiogénesis/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Camptotecina/uso terapéutico , Capecitabina , Cinamatos/farmacocinética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Ciclohexanos/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Compuestos Epoxi/farmacocinética , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/análogos & derivados , Fluorouracilo/sangre , Fluorouracilo/farmacocinética , Humanos , Irinotecán , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Modelos Biológicos , Modelos Estadísticos , Oxaloacetatos , República de Corea , Sesquiterpenos/farmacocinética , Análisis de Supervivencia , Insuficiencia del TratamientoRESUMEN
We conducted a phase I trial of the antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate (CKD-732). Our aims were to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profiles as well as identify the biologically active dose (BAD) from ex vivo pharmacodynamics (PD) and biomarkers of CKD-732. Using a dose escalation schedule, 19 patients with refractory solid tumors were enrolled at dose levels of CKD-732 ranging from 1 to 15 mg/m(2) given twice weekly for 2 weeks followed by a 1-week rest. No treatment-related deaths occurred in this study. Confusion and insomnia were dose-limiting toxicities (DLTs), and MTD was 15 mg/m(2). The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m(2) according to ex vivo PD. A decrement in soluble vascular endothelial growth factor receptor-3 (sVEGF-3) level was correlated with a reduction in tumor size (r = 0.54, P = 0.045). The results from this study showed an MTD of 15 mg/m(2) and a BAD of 5 mg/m(2).