RESUMEN
DNA vector-based short hairpin RNA (shRNA) as a means of effecting RNA interference (RNAi) is a promising mechanism for the precise disruption of gene expression to achieve a therapeutic effect. The clinical usage of shRNA therapeutics in cancer is limited by obstacles related to effective delivery into the nuclei of target cancer cells. Significant pre-clinical data have been amassed about biodegradable and non-biodegradable polymeric delivery vehicles that are relevant for shRNA delivery into humans. Here, we will review some leading candidates for clinical usage with a focus on studies relating to their potential for usage in cancer shRNA therapeutics and discuss some of the advantages and disadvantages of using biodegradable and non-biodegradable delivery vehicles.
Asunto(s)
Neoplasias/terapia , Polímeros/metabolismo , ARN/uso terapéutico , Silenciador del Gen , Humanos , Interferencia de ARNRESUMEN
PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNalpha-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 micro g/kg/wk of pegylated IFNalpha-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 micro g/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNalpha-2b at 12 weeks was 6.0 micro g/kg/wk. One year of 6.0 micro g/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNalpha-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNalpha-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 micro g/kg/wk.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Interferón-alfa , Interferón-alfa/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Polietilenglicoles , Adenocarcinoma/secundario , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Interferón-alfa/farmacocinética , Riñón/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Pulmón/patología , Masculino , Dosis Máxima Tolerada , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Recombinantes , Tasa de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
PDX1 is overexpressed in pancreatic cancer, and activates the insulin promoter (IP). Adenoviral IP-thymidine kinase and ganciclovir (TK/GCV) suppresses human pancreatic ductal carcinoma (PDAC) in mice, but repeated doses carry significant toxicity. We hypothesized that multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity compared to adenoviral IP-TK/GCV. SCID mice with intraperitoneal human pancreatic cancer PANC-1 tumor implants were given a single cycle of 35 µg iv L-IP-TK, or four cycles of 1, 10, 20, 30, or 35 µg iv L-IP-TK (n = 20 per group), followed by intraperitoneal GCV. Insulin and glucose levels were monitored in mice treated with four cycles of 35 µg iv L-IP-TK. We found that four cycles of 10-35 µg L-IP-TK/GCV ablated more PANC-1 tumor volume compared to a single cycle with 35 µg. Mice that received four cycles of 10 µg L-IP-TK demonstrated the longest survival (P < 0.05), with a median survival of 126 days. In comparison, mice that received a single cycle of 35 µg L-IP-TK/GCV or GCV alone survived a median of 92 days and 68.7 days, respectively. There were no significant changes in glucose or insulin levels following treatment. In conclusion, multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity, suggesting non-viral vectors are superior to adenoviral vectors for IP-gene therapy.
Asunto(s)
Antivirales/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Ganciclovir/uso terapéutico , Neoplasias Pancreáticas/terapia , Timidina Quinasa/genética , Proteínas Virales/genética , Adenoviridae/enzimología , Animales , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Terapia Genética , Humanos , Insulina/genética , Islotes Pancreáticos/patología , Liposomas , Masculino , Ratones SCID , Neoplasias Pancreáticas/patología , Regiones Promotoras Genéticas , Ratas , Timidina Quinasa/biosíntesis , Transfección , Carga Tumoral , Proteínas Virales/biosíntesis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123. METHODS: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria. RESULTS: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients. CONCLUSIONS: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.