RESUMEN
BACKGROUND/AIM: The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. RESULTS: The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. CONCLUSION: The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.
Asunto(s)
Liasas de Carbono-Azufre , Supervivencia Celular , Dioxoles , Sinergismo Farmacológico , Fibroblastos , Fibrosarcoma , Tetrahidroisoquinolinas , Trabectedina , Humanos , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/patología , Fibrosarcoma/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Trabectedina/farmacología , Liasas de Carbono-Azufre/farmacología , Liasas de Carbono-Azufre/administración & dosificación , Tetrahidroisoquinolinas/farmacología , Dioxoles/farmacología , Supervivencia Celular/efectos de los fármacos , Proteínas Recombinantes/farmacología , Línea Celular Tumoral , Antineoplásicos Alquilantes/farmacología , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacosRESUMEN
BACKGROUND/AIM: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks. RESULTS: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively). CONCLUSION: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.
Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Óseas/tratamiento farmacológico , Liasas de Carbono-Azufre/administración & dosificación , Docetaxel/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Tibia/efectos de los fármacos , Administración Oral , Adolescente , Animales , Neoplasias Óseas/patología , Humanos , Masculino , Ratones Desnudos , Osteosarcoma/patología , Proteínas Recombinantes/administración & dosificación , Tibia/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIM: Methionine addiction is a general and fundamental hallmark of cancer due to the excess use of methionine for transmethylation reactions, termed the "Hoffman Effect". Methionine addiction has been shown to be a highly-effective target for cancer therapy by methionine restriction with oral recombinant methioninase (o-rMETase) in preclinical studies, including patient- derived orthotopic xenograft (PDOX) mouse models of cancer. A clinical study of o-rMETase as a supplement showed a 70% reduction of PSA levels in a patient with bone-metastatic prostate cancer. MATERIALS AND METHODS: In the present study, two advanced prostate-cancer patients took o-rMETase as a supplement for approximately one month. RESULTS: One of the patients taking o-rMETase showed a 38% reduction of PSA levels and the second patient showed a 20% PSA reduction. CONCLUSION: o-rMETase shows promise for treating patients with advanced prostate cancer.
Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Anciano de 80 o más Años , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Progresión de la Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Terapia de Reemplazo Enzimático , Humanos , Masculino , Metionina/sangre , Metionina/efectos de los fármacos , Persona de Mediana Edad , Proyectos Piloto , Antígeno Prostático Específico/efectos de los fármacos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Proteínas Recombinantes/administración & dosificaciónRESUMEN
BACKGROUND/AIM: The aim of the study was to determine if oral recombinant methioninase (o-rMETase) can sensitize an orthotopic bladder tumor in nude mice to low-dose cisplatinum (CDDP). MATERIALS AND METHODS: The green fluorescent protein (GFP)-expressing UM-UC-3-GFP bladder cancer was surgically orthotopically implanted (SOI) to the bladder in nude mice. The treatment was initiated when the primary tumor volume reached 100 mm3 Mice were assigned to 3 groups: G1: Saline vehicle (0.1 ml per mouse, oral, twice per day); G2: low-dose CDDP (0.5 mg/kg, intraperitoneal twice per week); G3: o-rMETase + low-dose CDDP (100 units per mouse, oral, twice per day + 0.5 mg/kg, intraperitoneal twice per week, respectively). Tumor volume and body weight were measured twice per week. The expression of Ki-67 was detected by immunohistochemistry to evaluate cell proliferation. RESULTS: The combination of o-rMETase and low-dose CDDP increased inhibition efficacy compared to low-dose CDDP monotherapy, on primary-tumor growth (p=0.032) and metastasis (p=0.002). CONCLUSION: The combination of o-rMETase with low-dose CDDP has future clinical potential for bladder cancer.
Asunto(s)
Liasas de Carbono-Azufre/uso terapéutico , Cisplatino/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Oral , Animales , Liasas de Carbono-Azufre/administración & dosificación , Liasas de Carbono-Azufre/farmacología , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones Desnudos , Metástasis de la Neoplasia , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND/AIM: In the present study, we evaluated the efficacy of adjuvant administration of oral recombinant methioninase (o-rMETase) against recurrence and metastasis in a 4T1 murine breast-cancer syngeneic model. MATERIALS AND METHODS: 4T1 cells were orthotopically implanted into the 2nd mammary fat pad of BALB/c mice. The 4T1 orthotopic syngeneic models were randomized into 2 groups after primary tumor resection: untreated control and o-rMETase (100 units, oral, daily, 2 weeks). RESULTS: The frequency and extent of local recurrence were reduced by o-rMETase. The number of individual cancer cells and metastatic nodules on the lung surface was significantly lower in the o-rMETase-treated mice than the untreated control mice. CONCLUSION: Adjuvant o-rMETase inhibited local recurrence and lung metastasis after primary tumor resection.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Liasas de Carbono-Azufre/administración & dosificación , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Administración Oral , Animales , Línea Celular Tumoral , Quimioterapia Adyuvante , Esquema de Medicación , Femenino , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/cirugía , Ratones , Ratones Endogámicos BALB C , Recurrencia Local de Neoplasia/prevención & control , Proteínas Recombinantes/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Methionine addiction is a fundamental and general hallmark of cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted cancer cells increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced apoptosis, by increasing TRAIL-R2 expression in pancreatic cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Liasas de Carbono-Azufre/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/análisis , Proteínas Adaptadoras Transductoras de Señales/análisis , Administración Oral , Animales , Antígenos de Neoplasias/análisis , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Metionina/administración & dosificación , Metionina/sangre , Ratones , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Proteínas Recombinantes/administración & dosificaciónRESUMEN
ABP 798 is a proposed biosimilar to rituximab reference product (RP), an anti-CD20 monoclonal antibody. Pharmacokinetics (PK), pharmacodynamics (PD), and safety results from the comparative clinical study that evaluated the PK, PD, safety, efficacy, and immunogenicity of ABP 798 versus rituximab RP are presented here. Subjects with moderate to severe rheumatoid arthritis (RA) received 2 doses of ABP 798, United States-sourced RP (rituximab US) or European Union-sourced RP (rituximab EU), each consisting of two 1000-mg infusions 2 weeks apart. For the second dose (week 24), ABP 798- and rituximab EU-treated subjects received the same treatment; rituximab US-treated subjects transitioned to ABP 798. End points included area under the serum concentration-time curve from time 0 extrapolated to infinity and maximum observed serum concentration following the second infusion of the first dose (PK) and percentage of subjects with complete CD19+ cell depletion days 1-33 (PD). Primary analysis established PK similarity between ABP 798 and rituximab RP based on 90% confidence intervals of the adjusted geometric mean ratios being within a prespecified equivalence margin of 0.8 and 1.25. Complete CD19+ B-cell depletion on day 3 among groups confirmed PD similarity. These findings demonstrated PK/PD similarity between ABP 798 and rituximab RP in subjects with moderate to severe RA.
Asunto(s)
Antirreumáticos/farmacocinética , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/farmacocinética , Liasas de Carbono-Azufre/farmacocinética , Rituximab/farmacocinética , Adulto , Anciano , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/sangre , Antineoplásicos Inmunológicos/farmacocinética , Antineoplásicos Inmunológicos/farmacología , Antirreumáticos/administración & dosificación , Antirreumáticos/sangre , Antirreumáticos/farmacología , Área Bajo la Curva , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/sangre , Biosimilares Farmacéuticos/farmacología , Liasas de Carbono-Azufre/administración & dosificación , Liasas de Carbono-Azufre/sangre , Liasas de Carbono-Azufre/farmacología , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Rituximab/administración & dosificación , Rituximab/sangre , Rituximab/farmacología , Seguridad , Índice de Severidad de la Enfermedad , Equivalencia Terapéutica , Resultado del TratamientoRESUMEN
The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.
Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Liasas de Carbono-Azufre/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Metionina/metabolismo , Neumonía Viral/tratamiento farmacológico , Caperuzas de ARN/efectos de los fármacos , Procesamiento Postranscripcional del ARN/efectos de los fármacos , ARN Viral/efectos de los fármacos , Administración Oral , Antivirales/administración & dosificación , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/uso terapéutico , Betacoronavirus/fisiología , COVID-19 , Liasas de Carbono-Azufre/administración & dosificación , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Metaanálisis como Asunto , Metilación/efectos de los fármacos , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Pseudomonas putida/enzimología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , S-Adenosilmetionina/metabolismo , SARS-CoV-2 , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND/AIM: We have recently shown that oral recombinant methionase (o-rMETase) prevents obesity and diabetes onset in mice on a high-fat (HF) diet. The present study aimed to determine if o-rMETase can inhibit the onset of nonalcoholic fatty liver disease (NAFLD) onset in mice on a high-fat diet. MATERIALS AND METHODS: Male C57BL/6J mice in the control group were fed a normal-fat diet (NFD) (+6.5% fat), and other mice were fed a high-fat (HF) diet (+34.3% fat). Then, the mice on the HF diet were divided into two dietary groups: i) HF+phosphate buffered saline (PBS) group, and ii) HF+o-rMETase group. RESULT: The fatty change score in the livers of mice treated with HF+PBS increased to an average of 2.6 during the experimental period of 8 weeks. In contrast, the fatty change in the livers of mice on the HF+o-rMETase group had an average score of 0.92 (p=0.04, HF+PBS vs HF+o-rMETase). CONCLUSION: o-rMETase inhibited the onset of NAFLD as well as prevented obesity and the onset of diabetes on a high-fat diet, offering a possibility of a new paradigm to prevent liver cirrhosis or liver cancer via NAFLD.
Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Proteínas Recombinantes/administración & dosificación , Administración Oral , Animales , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/patología , Masculino , Metionina/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
BACKGROUND/AIM: We have recently shown that oral recombinant methionase (o-rMETase) prevents obesity in mice on a high-fat (HF) diet. The present study aimed to determine if o-rMETase can inhibit the onset of diabetes in mice on a HF diet. MATERIALS AND METHODS: The mice on a HF diet were divided into two groups: 1) HF+phosphate buffered saline (PBS) group; 2) HF+o-rMETase group. RESULTS: The blood glucose level in the HF+PBS group increased to average of 201 mg/dl during the experimental period of 8 weeks. In contrast, the blood glucose level in the HF+o-rMETase group maintained an average of 126 mg/dl (p<0.01, HF+PBS vs. HF+o-rMETase). The glucose tolerance test showed a significant increase in tolerance in the HF+o-rMETase group at 120 min after glucose injection compared to the HF+PBS group (p=0.04). Visceral adipose tissue was significantly less in the HF+o-rMETase group than the HF+PBS group (p=0.05). There was no difference in insulin levels, cholesterol or triglycerides between the HF+PBS and HF+o-rMETase groups. CONCLUSION: o-rMETase inhibited the onset of diabetes as well as prevented obesity on a high-fat diet, offering a possibility of a new and easy-to-use alternative to severe dieting or insulin injections.
Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Diabetes Mellitus Experimental/metabolismo , Hipoglucemiantes/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Animales , Biomarcadores , Glucemia , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/prevención & control , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Glucosa/metabolismo , Lípidos/sangre , RatonesRESUMEN
BACKGROUND/AIM: obesity is a world-wide recalcitrant problem leading to many diseases. Dietary methionine restriction (MR) has been shown to prevent obesity, but it is an onerous regimen. The present study aimed to determine the effects of oral recombinant methionase (o-rMETase), on preventing obesity in mice on a high-fat diet. MATERIALS AND METHODS: Male C57BL/6J mice in the control group were fed a control diet (CD) (+6.5% fat) for 25 days, and others were fed a high-fat (HF) diet (+34.3% fat) for 25 days. Then, the mice were divided into three dietary groups: 1) HF + phosphate buffered saline (PBS) group; 2) HF + o-rMETase group; and 3) untreated non-HF group. RESULTS: The mice on the CD increased in body weight by 14% during experimental period of 25 days; in contrast the mice in the HF+PBS group increased by 33%; however, the mice on the HF+o-rMETase group increased only by 14% (p=0.02, HF+PBS vs HF+o-rMETase). CONCLUSION: The HF+ o-rMETase group had the same weight increase as untreated mice on a normal fat diet, demonstrating the potential for o-rMETase to eliminate the need for dieting to maintain normal body weight.
Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Dieta Alta en Grasa , Obesidad/etiología , Obesidad/prevención & control , Proteínas Recombinantes/administración & dosificación , Animales , Peso Corporal , Modelos Animales de Enfermedad , Humanos , Masculino , RatonesRESUMEN
Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Liasas de Carbono-Azufre/metabolismo , Decitabina/farmacología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de los Músculos/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Administración Oral , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Liasas de Carbono-Azufre/administración & dosificación , Terapia Combinada , Decitabina/administración & dosificación , Femenino , Humanos , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias de los Músculos/patología , Neoplasias de los Músculos/cirugía , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/cirugía , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/metabolismo , Sarcoma/patología , Sarcoma/cirugíaRESUMEN
The aim of this study was to determine the efficacy of oral recombinant methioninase (o-rMETase) on a model of colon cancer growing on the peritoneal surface using a patients-derived orthotopic xenograft (PDOX) nude mouse model. Forty PDOX mouse models with colon cancer growing on the peritoneum were divided into 4 groups of 10 mice each by measuring the tumor size and fluorescence intensity: untreated control; 5-fluorouracil (5-FU) (50â¯mg/kg, once a week for two weeks, ip) and oxaliplatinum (OXA) (6⯠mg/kg, once a week for two weeks, ip); o-rMETase (100 units/day, oral 14 consecutive days); combination 5-FUâ¯+â¯OXA and o-rMETase. All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FUâ¯+â¯OXA plus o-rMETase was significantly more efficacious than the control and each drug alone and was the only treatment that caused tumor regression. The present study is the first demonstrating the efficacy of o-rMETase combination therapy on a PDOX model of peritoneal colon cancer, suggesting potential clinical development of o-rMETase in a recalcitrant cancer.
Asunto(s)
Liasas de Carbono-Azufre/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Peritoneo/patología , Platino (Metal)/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Oral , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Peso Corporal/efectos de los fármacos , Liasas de Carbono-Azufre/administración & dosificación , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Fluorescencia , Fluorouracilo/administración & dosificación , Humanos , Ratones Desnudos , Platino (Metal)/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: Osteosarcoma is a recalcitrant neoplasm which occurs predominantly in adolescents and young adults. Recently, using a patient-derived orthotopic xenograft (PDOX) model of malignant soft-tissue sarcoma (STS), we showed that oral recombinant methioninase (o-rMETase), in combination with caffeine, was more efficacious than o-rMETase alone in inhibiting STS tumor growth. In the present report, we determined the efficacy of o-rMETase combined with oral caffeine on a cisplatinum (CDDP)-resistant osteosarcoma PDOX model. MATERIALS AND METHODS: Osteosarcoma PDOX models were randomly divided into seven treatment groups (6 mice in each group): untreated control; CDDP alone; o-rMETase alone; o-rMETase with caffeine; CDDP plus o-rMETase; CDDP plus caffeine; and CDDP plus o-rMETase with caffeine. Tumor size and body weight were measured throughout the treatment. RESULTS: Tumors regressed after treatment with CDDP plus o-rMETase with caffeine. Tumors treated with CDDP plus o-rMETase with caffeine also had the most necrosis. CONCLUSION: The combination of o-rMETase and caffeine together with first-line chemotherapy was efficacious for drug-resistant osteosarcoma and has clinical potential in the treatment of this highly-resistant neoplasm.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Cafeína/administración & dosificación , Liasas de Carbono-Azufre/administración & dosificación , Cisplatino/administración & dosificación , Resistencia a Antineoplásicos , Administración Oral , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIM: Liver metastasis in colorectal-cancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patient-derived orthotopic xenograft (PDOX) model of colorectal-cancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. MATERIALS AND METHODS: Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. RESULTS: The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p<0.01 at day 15, Group 3). No significant body-weight differences were observed among the groups. CONCLUSION: The combination therapy of 5-FU and OXA with o-rMETase can overcome the resistance of first line drugs for colorectal-cancer liver metastasis.
Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Animales , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Liasas de Carbono-Azufre/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Modelos Animales de Enfermedad , Fluorouracilo/administración & dosificación , Humanos , Neoplasias Hepáticas/patología , Ratones , Oxaliplatino/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The aim of this study was to determine the efficacy of oral recombinant methioninase (o-rMETase) on a colon cancer primary tumor using a patient-derived orthotopic xenograft (PDOX) nude mouse model. Forty colon cancer primary tumor PDOX mouse models were divided into 4 groups of 10 mice each (total 40 mice) by measuring the tumor size. The groups were as follows: untreated control; 5-fluorouracil (5-FU) (50â¯mg/kg, once a week for two weeks, Nâ¯=â¯10 mice) and oxaliplatinum (OXA) (6â¯mg/kg, once a week for two weeks, Nâ¯=â¯10 mice); o-rMETase (100 units/day, oral 14 consecutive days, N = 10 mice); combination of 5-FU + OXA and o-rMETase (N = 10 mice). All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA and o-rMETase was significantly more efficacious than other treatments. The present study demonstrates the efficacy of o-rMETase combination therapy on a PDOX colon cancer primary tumor, suggesting potential clinical development of o-rMETase in recalcitrant cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Liasas de Carbono-Azufre/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Liasas de Carbono-Azufre/administración & dosificación , Neoplasias del Colon/patología , Modelos Animales de Enfermedad , Fluorouracilo/administración & dosificación , Humanos , Ratones , Ratones Desnudos , Ratones Transgénicos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
An excessive requirement for methionine (MET), termed MET dependence, appears to be a general metabolic defect in cancer and has been shown to be a very effective therapeutic target. MET restriction (MR) has inhibited the growth of all major cancer types by selectively arresting cancer cells in the late-S/G2 phase, when they also become highly sensitive to cytotoxic agents. Recombinant methioninase (rMETase) has been developed to effect MR. The present review describes the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of recalcitrant cancer, including the surprising result that rMETase administrated orally can be highly effective.
Asunto(s)
Liasas de Carbono-Azufre/uso terapéutico , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Liasas de Carbono-Azufre/administración & dosificación , Humanos , Metionina/metabolismo , Ratones Desnudos , Proteínas Recombinantes/administración & dosificación , Resultado del TratamientoRESUMEN
The elevated methionine (MET) requirement of cancer cells is termed MET dependence and is possibly the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo due to their elevated requirement for MET. rMETase can also potentiate chemotherapy drugs active in S phase due to the selective arrest of cancer cells in S/G2 phase during MET restriction (MR). We previously reported that rMETase, administrated by intraperitoneal injection (ip-rMETase), could inhibit tumor growth in mouse models of cancer including patient-derived orthotopic xenograft (PDOX) mouse models. We subsequently compared ip-rMETase and oral rMETase (o-rMETase) on a melanoma PDOX mouse model. o-rMETase was significantly more effective than ip-rMETase to inhibit tumor growth without overt toxicity. The combination of o-rMETase+ip-rMETase was significantly more effective than either monotherapy and completely arrested tumor growth. Thus, o-rMETase is effective as an anticancer agent with the potential of clinical development for chronic cancer therapy as well as for cancer prevention. o-rMETase may also have potential as an antiaging agent for healthy people, since MR has been shown to extend the life span of a variety of different organisms.
Asunto(s)
Envejecimiento/fisiología , Liasas de Carbono-Azufre/administración & dosificación , Liasas de Carbono-Azufre/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Anciano , Envejecimiento/efectos de los fármacos , Animales , Liasas de Carbono-Azufre/biosíntesis , Liasas de Carbono-Azufre/farmacología , Femenino , Humanos , Ratones Desnudos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The anti-cancer efficacy of methionine γ-lyase (MGL) from Clostridium sporogenes (C. sporogenes) is described. MGL was active against cancer models in vitro and in vivo. The calculated EC50 values for MGL were 4.4 U/ml for A549, 7.5 U/ml for SK-BR3, 2.4 U/ml for SKOV3, and 0.4 U/ml for MCF7 cells. The combination of doxorubicin (DOX) and MGL was more effective for A549 human lung cancer growth inhibition than either agent alone in vitro and in vivo. MGL reduced the EC50 of doxorubicin from 35.9 µg/mL to 0.01-0.265 µg/mL. The growth inhibitory effect of DOX + MGL on A549 xenografts in vivo was reflective of the results obtained in vitro. The inhibition rate of tumor growth in the combined arm was 57%, significantly higher than that in the doxorubicin (p = 0.033)-alone arm.
Asunto(s)
Liasas de Carbono-Azufre/administración & dosificación , Cisplatino/farmacología , Clostridium/enzimología , Doxorrubicina/farmacología , Sinergismo Farmacológico , Neoplasias/tratamiento farmacológico , Células A549 , Animales , Antibióticos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/enzimología , Neoplasias/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND/AIM: Synovial sarcoma (SS) is a recalcitrant neoplasm with low chemosensitivity. We recently reported that recombinant methioninase (rMETase) inhibited SS growth in a patient-derived orthotopic xenograft (PDOX) mouse model and was more effective when administered in combination with the first-line drug doxorubicin (DOX). Caffeine enhances the efficacy of anticancer drugs by overcoming drug-induced cell-cycle arrest and increasing subsequent apoptosis. Here, we determined the efficacy of oral recombinant methioninase (o-rMETase) in combined with caffeine on an SS-PDOX model. MATERIALS AND METHODS: Mice bearing SS-PDOX tumors were randomized into four treatment groups of six: Untreated control; o-rMETase alone; o-rMETase with caffeine; DOX plus o-rMETase with caffeine. Tumor size and body weight were measured during the treatment and plasma L-methionine (MET) levels were measured at the end of treatment. RESULTS: All treatments significantly inhibited SS-PDOX tumor growth. Combining caffeine with o-rMETase was more effective than o-rMETase alone. DOX combined with o-rMETase and caffeine led to regression of SS-PDOX. Plasma MET levels were reduced with o-rMETase treatment. CONCLUSION: These results suggest that combining o-rMETase and caffeine along with first-line chemotherapy can be highly effective for SS and has clinical potential for this recalcitrant disease.