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1.
Neoplasma ; 2021 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-34818028

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of malignancy with one of the worst prognoses amongst any type of cancer. Surgery is applicable only to the limited number of patients with locally resectable tumors and currently represents the only curative treatment option. Treatment with chemotherapy and radiotherapy can only extend patient survival. Despite advances in conventional therapies, the five-year survival of PDAC remained largely unchanged. New in vitro and in vivo models are therefore urgently needed to investigate this type of cancer. Here, we present the establishment and characterization of a novel pancreatic cancer cell line, isolated from a patient with PDAC. Cell line abbreviated as PANDA (PANncreatic Ductal Adenocarcinoma) was established with an optimized 3D culture protocol published previously by our group. The new cancer cell line "PANDA" represents a novel in vitro approach for PDAC cancer research and new therapy testing.

2.
Anticancer Res ; 41(10): 4715-4718, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593419

RESUMO

BACKGROUND/AIM: Primary osteosarcoma of the breast is an exceedingly-rare malignant tumor that shares histological characteristics with osteosarcoma of the bone. Since effective therapies have not yet been established, standard therapy for osteosarcoma of the bone was examined in the present study for efficacy against primary osteosarcoma of the breast in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. MATERIALS AND METHODS: The PDOX mouse models were established by surgical implantation of the primary osteosarcoma of the breast specimen into the mammary gland of nude mice. Mice with tumors were randomized into four groups, each n=4: control group; cisplatinum (CDDP)-treatment group; doxorubicin (DOX)-treatment group; and CDDP/DOX-combination-treatment group. Mice were treated for twenty-one days, three weeks after implantation. Tumor size and body weight were measured during three weeks of treatment. RESULTS: Significant tumor growth inhibition was observed, compared to the control, in the CDDP-treatment group, the DOX-treatment group, and the combination-treatment-group. Only the combination treatment regressed the tumor. CONCLUSION: CDDP and DOX which are standard first-line therapies for osteosarcoma, may be clinically effective against primary osteosarcoma of the breast, and in particular, their combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancer Genomics Proteomics ; 18(6): 715-721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697064

RESUMO

BACKGROUND/AIM: Sarcomas are considered a heterogeneous disease with incomplete understanding of its molecular basis. In the present study, to further understand general molecular changes in sarcoma, patient-derived xenograft (PDX) mouse models of the three most common soft-tissue sarcomas: myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS) and liposarcoma were established and the methylation status of histone H3 lysine marks was studied. MATERIALS AND METHODS: Immunoblotting and immunohistochemical staining were used to quantify the extent of methylation of histone H3K4me3 and histone H3K9me3. RESULTS: In all 3 sarcoma types in PDX models, histone H3K4me3 and H3K9me3 were found highly over-methylated compared to normal muscle tissue. CONCLUSION: Histone H3 lysine over-methylation may be a general basis of malignancy of the major sarcoma types.

4.
In Vivo ; 35(6): 3067-3071, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697138

RESUMO

BACKGROUND/AIM: Triple-negative matrix-producing breast carcinoma (MPBC) is rare, recalcitrant, and highly aggressive. The present study aimed to determine the efficacy of tumor-targeting leucine-arginine auxotroph Salmonella typhimurium (S. typhimurium) A1-R on a triple-negative MPBC in a patient-derived orthotopic xenograft (PDOX) model. MATERIALS AND METHODS: The PDOX MPBC model was established in the left second mammary gland of nude mice by surgical orthotopic implantation (SOI). PDOX models were randomized into two groups when the tumor volume reached over 70 mm3: a control group (n=6); and a tumor-targeting S. typhimurium A1-R group (n=7), [intravenous (i.v.) injection of S. typhimurium A1-R via the tail vein, weekly, for two weeks]. All mice were sacrificed on day 14. Tumor volume and body weight were measured once per week. RESULTS: S. typhimurium A1-R exquisitely targeted and arrested the growth of the MPBC PDOX compared to the control group (p=0.017). CONCLUSION: S. typhimurium A1-R has future clinical potential for triple-negative MPBC patients.


Assuntos
Salmonella typhimurium , Neoplasias de Mama Triplo Negativas , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Salmonella typhimurium/genética , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Genomics Proteomics ; 18(5): 637-643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34479916

RESUMO

BACKGROUND/AIM: Osteosarcoma is a recalcitrant heterogenous malignancy. The aim of the present study was to compare a series of multikinase inhibitors (MKIs) for efficacy on two drug-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) models in order to identify a clinical candidate. MATERIALS AND METHODS: The two osteosarcoma PDOX models were tested for response to the following MKIs: pazopanib, sunitinib, sorafenib, crizotinib, and regorafenib, in comparison to first-line treatment with cisplatinum and an untreated control. RESULTS: Regorafenib led to regression of osteosarcoma in both PDOXs. Total necrosis was observed pathologically in the regorafenib-treated tumors. Sorafenib arrested growth, without inducing regression, in one osteosarcoma model but not the other, and the other MKIs only slowed tumor growth. CONCLUSION: The present study demonstrated that regorafenib is much more effective than the other MKIs tested and has clinical potential against recalcitrant osteosarcoma.

6.
Gut Microbes ; 13(1): 1974795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34586012

RESUMO

An imbalance in the crosstalk between the host and gut microbiota affects the intestinal barrier function, which results in inflammatory diseases and colorectal cancer. The colon epithelium protects itself from a harsh environment and various pathogenic organisms by forming a double mucus layer, primarily comprising mucins. Recent studies are focusing on how dietary patterns alter the gut microbiota composition, which in turn regulates mucin expression and maintains the intestinal layers. In addition, modulation of gut microbiota by microbiotic therapy (involving fecal microbiota transplantation) has emerged as a significant factor in the pathologies associated with dysbiosis. Therefore, proper communication between host and gut microbiota via different dietary patterns (prebiotics and probiotics) is needed to maintain mucus composition, mucin synthesis, and regulation. Here, we review how the interactions between diet and gut microbiota and bacterial metabolites (postbiotics) regulate mucus layer functionalities and mucin expression in human health and disease.

7.
Am J Surg ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34407918

RESUMO

BACKGROUND: Fluorescence angiography (FA) using indocyanine green dye (ICG) has recently been introduced for real-time identification of parathyroid adenomas. However, time to peak fluorescence has not yet been critically evaluated. METHODS: This was a retrospective review of parathyroidectomies with ICG FA over a one-year period. RESULTS: There were 66 patients with average age of 64 years. The average time to initial fluorescence was 26.7 s and to peak fluorescence was 38.0 s. The time to saline flush administration significantly correlated with times to initial and peak fluorescence (p < .0001). The rate of in-situ fluorescence was 97%. The rates of suspected adenoma detection were 69% for sestamibi scan, 71% for ultrasound, and 96% for CT scan. Imaging was discordant in 13 cases (20%), with the adenoma located on the opposite side of the neck in 4 cases. CONCLUSIONS: ICG FA is a rapid and effective adjunct for the intraoperative identification of parathyroid adenomas.

8.
J Surg Oncol ; 124(7): 1121-1127, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34309885

RESUMO

BACKGROUND/OBJECTIVES: Nanobodies are the smallest biologic antigen-binding fragments derived from camelid-derived antibodies. Nanobodies effect a peak tumor signal within minutes of injection and present a novel opportunity for fluorescence-guided surgery (FGS). The present study demonstrates the efficacy of an anti-CEA nanobody conjugated to near-infrared fluorophore LICOR-IRDye800CW for rapid intraoperative tumor labeling of colon cancer. METHODS: LS174T human colon cancer cells or fragments of patient-derived colon cancer were implanted subcutaneously or orthotopically in nude mice. Anti-CEA nanobodies were conjugated with IRDye800CW and 1-3 nmol were injected intravenously. Mice were serially imaged over time. Peak fluorescence signal and tumor-to-background ratio (TBR) were recorded. RESULTS: Colon cancer tumors were detectable using fluorescent anti-CEA nanobody within 5 min of injection at all three doses. Maximal fluorescence intensity was observed within 15 min-3 h for all three doses with TBR values ranging from 1.3 to 2.3. In the patient-derived model of colon cancer, fluorescence was detectable with a TBR of 4.6 at 3 h. CONCLUSIONS: Fluorescent anti-CEA nanobodies rapidly and specifically labeled colon cancer in cell-line-based and patient-derived orthotopic xenograft (PDOX) models. The kinetics of nanobodies allow for same day administration and imaging. Anti-CEA-nb-800 is a promising and practical molecule for FGS of colon cancer.


Assuntos
Antígeno Carcinoembrionário/imunologia , Neoplasias do Colo/diagnóstico por imagem , Imagem Óptica , Anticorpos de Domínio Único , Animais , Modelos Animais de Doenças , Corantes Fluorescentes , Xenoenxertos , Humanos , Camundongos Nus , Neoplasias Experimentais
9.
In Vivo ; 35(4): 1979-1983, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182472

RESUMO

BACKGROUND/AIM: Sarcomas of the breast are extremely rare malignant tumors and comprise only 5% of all sarcomas and fewer than 1% of breast cancers. Primary osteosarcoma of the breast is histologically indistinguishable from osteosarcoma of the bone. Effective therapies of this recalcitrant disease have not yet been developed. MATERIALS AND METHODS: A patient-derived xenograft (PDX) mouse model of primary osteosarcoma of the breast was established by subcutaneous implantation of the surgical specimen, along with surrounding normal tissue. Hematoxylin and eosin (H&E) staining was performed on paraffin-embedded histological sections of the original tumor resected from the patient and from implanted tumors that grew in nude mice. RESULTS: Tumors grew in 46 of 51 mice implanted with the original surgical specimen. The H&E-stained slides of the mouse-grown tumor and the original patient tumor matched, both showing large areas of spindle-shaped cells, characteristic of osteosarcoma. CONCLUSION: The first PDX mouse model of primary breast osteosarcoma was established which will enable testing of novel therapeutics as well as basic research of osteosarcoma of the breast.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
10.
In Vivo ; 35(4): 1959-1963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34182469

RESUMO

BACKGROUND/AIM: During surgical resection of gastroesophageal-junction (GEJ) adenocarcinoma, the margin status is often difficult to visualize resulting in high recurrence rates. The aim of the present study was to develop a labelling technique that would allow improved visualization of GEJ tumor margins for surgeons to reduce recurrence rates in a patient-like model. MATERIALS AND METHODS: A patient GEJ tumor was obtained from an endoscopic biopsy and implanted subcutaneously in a nude mouse. A patient-derived orthotopic xenograft (PDOX) model was established by implanting tumor fragments grown from a subcutaneous model to the cardia of the stomach of nude mice. CC1/3/5-SAB, an antibody to carcinoembryonic-antigen-related cell-adhesion molecules, was conjugated with infrared dye IRDye800 to create SAB-IR800. Forty-eight hours after i.v. injection of SAB-IR800, GEJ-PDOX mice were imaged. RESULTS: Fluorescence imaging with SAB-IR800 brightly visualized the GEJ adenocarcinoma demonstrating specific targeting. In the PDOX model, injection of SAB-IR800 (50 µg) resulted in a tumor to background ratio of 1.78 at 48 hours and 1.86 at 72 hours. CONCLUSION: PDOX models of GEJ tumors can be established from patients by endoscopic biopsy without undergoing surgical resection. GEJ PDOX models should be useful for developing novel diagnostics and therapeutics for this recalcitrant disease.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Adenocarcinoma/diagnóstico , Animais , Neoplasias Esofágicas/diagnóstico , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Comput Struct Biotechnol J ; 19: 1986-1997, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995898

RESUMO

While the intratumor microbiome has become increasingly implicated in cancer development, the microbial landscape of papillary thyroid carcinoma (PTC) is essentially uninvestigated. PTC is characterized by varied prognosis between gender and cancer subtype, but the cause for gender and subtype-based dissimilarities is unclear. Women are more frequently diagnosed with PTC, while men suffer more advanced-staged PTC. In addition, tall cell variants are more aggressive than classical and follicular variants of PTC. We hypothesized that intratumor microbiome composition distinctly alters the immune landscape and predicts clinical outcome between PTC subtypes and between patient genders. Raw whole-transcriptome RNA-sequencing, Level 3 normalized mRNA expression read counts, and DNA methylation 450 k sequencing data for untreated, nonirradiated tumor, and adjacent normal tissue were downloaded from the Genomic Data Commons (GDC) legacy archive for 563 thyroid carcinoma patients. Microbe counts were extracted using Pathoscope 2.0 software. We correlated microbe abundance to clinical variables and immune-associated gene expression. Gene-set enrichment, mutation, and methylation analyses were conducted to correlate microbe abundance to characterize microbes' roles. Overall, PTC tumor tissue significantly lacked microbes that are populated in adjacent normal tissue, which suggests presence of microbes may be critical in controlling immune cell expression and regulating immune and cancer pathways to mitigate cancer growth. In contrast, we also found that microbes distinctly abundant in tall cell and male patient cohorts were also correlated with higher mutation expression and methylation of tumor suppressors. Microbe dysbiosis in specific PTC types may explain observable differences in PTC progression and pathogenesis. These microbes provide a basis for developing specialized prebiotic and probiotic treatments for varied PTC tumors.

13.
J Surg Res ; 264: 327-333, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33848831

RESUMO

BACKGROUND: It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment. MATERIALS AND METHODS: Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems. RESULTS: The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm. CONCLUSIONS: Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection.


Assuntos
Neoplasias do Colo/patologia , Hepatectomia/métodos , Neoplasias Hepáticas/diagnóstico , Fígado/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Anticorpos Monoclonais/administração & dosagem , Antígeno Carcinoembrionário/metabolismo , Cor , Corantes Fluorescentes/administração & dosagem , Proteínas Ligadas por GPI/metabolismo , Humanos , Verde de Indocianina/administração & dosagem , Injeções Intravenosas , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Camundongos , Imagem Molecular/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anticancer Res ; 41(4): 1745-1751, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813378

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Liases de Carbono-Enxofre/administração & dosagem , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Administração Oral , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Osteossarcoma/patologia , Proteínas Recombinantes/administração & dosagem , Tíbia/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Anticancer Res ; 41(4): 1779-1784, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813382

RESUMO

BACKGROUND/AIM: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic. MATERIALS AND METHODS: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined. RESULTS: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice. CONCLUSION: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Furanos/farmacologia , Cetonas/farmacologia , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Necrose , Osteossarcoma/patologia , Tíbia/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Biomolecules ; 11(2)2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670740

RESUMO

Tumor-specific fluorescence labeling is promising for real-time visualization of solid malignancies during surgery. There are a number of technologies to confer tumor-specific fluorescence. Antibodies have traditionally been used due to their versatility in modifications; however, their large size hampers efficient fluorophore delivery. Nanobodies are a novel class of molecules, derived from camelid heavy-chain only antibodies, that have shown promise for tumor-specific fluorescence labeling. Nanobodies are ten times smaller than standard antibodies, while maintaining antigen-binding capacity and have advantageous features, including rapidity of tumor labeling, that are reviewed in the present report. The present report reviews special considerations needed in developing nanobody probes, the status of current literature on the use of nanobody probes in fluorescence guided surgery, and potential challenges to be addressed for clinical translation.


Assuntos
Fluorescência , Neoplasias/imunologia , Neoplasias/cirurgia , Anticorpos de Domínio Único/análise , Cirurgia Assistida por Computador/métodos , Animais , Anticorpos , Humanos
17.
Cancer Chemother Pharmacol ; 88(1): 61-67, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33768300

RESUMO

PURPOSE: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). METHODS: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks. RESULTS: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). CONCLUSION: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Liases de Carbono-Enxofre/farmacologia , Carcinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacologia , Proteínas Recombinantes/farmacologia , Sarcoma de Células Claras/tratamento farmacológico , Animais , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Xenoenxertos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
18.
J Surg Oncol ; 123(8): 1716-1723, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33735448

RESUMO

BACKGROUND: Perioperative therapy is the standard-of-care for locally-advanced gastric cancer but many patients do not respond. There are currently no known factors that predict response to therapy. METHODS: This was a retrospective study aimed to evaluate treatment effect grade (TEG) in patients with locally advanced gastric cancer treated with neoadjuvant therapy and surgery at a single center. Ordinal logistic regression was performed to identify predictors of TEG, scaled from 0 to 3. RESULTS: Fifty patients were identified. The majority were male (n = 33) and 50% were Hispanic. The most common regimens given were: 5-fluorouracil/leucovorin, oxaliplatin, and docetaxel (n = 23, 46%), epirubicin, cis- or oxaliplatin, and 5-fluorouracil/leucovorin or Xeloda (n = 8, 16%), and 5-fluorouracil/leucovorin and oxaliplatin (n = 9, 18%). Twenty-seven patients (55%) had complete or partial response to therapy (TEG 0-2), and 23 patients (46%) had no response (TEG 3). Of numerous variables analyzed, only race and SRC histology were associated with TEG. TEG was associated with disease free, but not disease specific survival. CONCLUSIONS: In this cohort, 46% of patients had no histologic response to therapy. SRC histology, and possibly race, should be considered in determination of optimal multidisciplinary regimens and in amount of therapy to be given upfront, as patients with SRC histology and those of non-Asian race are less likely to respond to standard regimens.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Gastrectomia , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Docetaxel/uso terapêutico , Epirubicina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia
19.
Cancer Genomics Proteomics ; 18(2): 113-120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33608308

RESUMO

BACKGROUND/AIM: Cancers are selectively sensitive to methionine (MET) restriction (MR) due to their addiction to MET which is overused for elevated methylation reactions. MET addiction of cancer was discovered by us 45 years ago. MR of cancer results in depletion of S-adenosylmethionine (SAM) for transmethylation reactions, resulting in selective cancer-growth arrest in the late S/G2-phase of the cell cycle. The aim of the present study was to determine if blockade of the MET-methylation axis is a highly-effective strategy for cancer chemotherapy. MATERIALS AND METHODS: In the present study, we demonstrated the efficacy of MET-methylation-axis blockade using MR by oral-recombinant methioninase (o-rMETase) combined with decitabine (DAC), an inhibitor of DNA methylation, and an inhibitor of SAM synthesis, cycloleucine (CL). We determined a proof-of-concept of the efficacy of the MET-methylation-axis blockade on a recalcitrant undifferentiated/unclassified soft-tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) mouse model. RESULTS: The o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis. CONCLUSION: The new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.


Assuntos
Metionina/antagonistas & inibidores , Neoplasias/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Metilação , Camundongos , Camundongos Nus
20.
Anticancer Res ; 41(2): 641-643, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517268

RESUMO

BACKGROUND/AIM: Methionine addiction, a fundamental and general hallmark of cancer, is due to the excess use of methionine for transmethylation, and is described as the Hoffman-effect. Methionine-addicted cancer cells can revert at low frequency to methionine independence when selected under methionine-restriction. We report here that highly-malignant methionine-addicted H460 human lung-cancer cells, when selected for methionine independence, have greatly-reduced tumorigenic potential. MATERIALS AND METHODS: Methionine-addicted H460 parental cancer cells and methionine-independent revertant H460-R1 cells were injected in nude mice subcutaneously. RESULTS: When the parental H460 methionine-addicted cells were injected in nude mice at 2.5×105, 1×105 and 5×104, the cells could form tumors. In contrast, the H460-R1 methionine-independent revertant cells could not form tumors when the above-listed cell numbers were injected in nude mice. CONCLUSION: There is a tight linkage between methionine addiction and malignancy.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Metionina/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/patologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos Nus , Transdução de Sinais , Carga Tumoral
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