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1.
Anticancer Res ; 41(12): 5865-5871, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34848441

RESUMO

BACKGROUND/AIM: Recurrent osteosarcoma is recalcitrant with poor response rates to first-line chemotherapy due to heterogeneity and metastatic potential. This disease requires novel drug discovery and precision treatment. MATERIALS AND METHODS: The osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model mimics the clinical disease and has identified effective clinically-approved drugs and experimental agents, especially drug combinations, that hold much clinical promise. RESULTS: Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatinum, as combinations. CONCLUSION: The PDOX model can be used to improve the outcome of osteosarcoma patients, including individualized, precision therapy.

2.
Anticancer Res ; 41(12): 6191-6197, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34848473

RESUMO

BACKGROUND: Matrix-producing breast carcinoma (MPBC) is a very rare and usually aggressive triple-negative breast cancer. We successfully established a patient-derived orthotopic xenograft (PDOX) model from a patient with MPBC and used it to study tumor sensitivity to various agents. CASE REPORT: A 40-year-old woman was diagnosed with MPBC with a triple-negative phenotype. Due to axillary lymph-node metastases found during radical mastectomy, the patient was subsequently treated with epirubicin, cyclophosphamide and paclitaxel. In addition, radiotherapy was directed to the chest wall and subclavicular fossa. A portion of the cancer tissue from the mastectomy was used to establish a PDOX nude-mouse model. The PDOX model was resistant to paclitaxel, bevacizumab, vinorelbine, cisplatinum and olaparib, and sensitive to eribulin. Metastases in mediastinal lymph nodes and the right ovary were observed in the patient 14 months after mastectomy. Thoracoscopic mediastinal lymph-node biopsy and laparoscopic oophorectomy were performed, and both confirmed breast-cancer metastasis. The patient was then treated with paclitaxel and bevacizumab but no response was observed, which correlated with the inability of these drugs to arrest tumor growth in the PDOX models of the patient's tumor. The patient was then given eribulin based on the PDOX-model result, but treatment had to be stopped because of rapid progression of metastasis into the cervical lymph nodes and thyroid gland. The patient was subsequently treated with atezolizumab and nab-paclitaxel. Unfortunately, the patient died of her cancer 8 months after recurrence. CONCLUSION: The present study demonstrates that the PDOX model of a patient's triple-negative MPBC accurately predicted that paclitaxel and bevacizumab would not arrest the patient's tumor growth. Eribulin may have been effective if administered at an earlier stage of the patient's cancer course. Drug-screening results from PDOX models should be used as early as possible in order to improve patient outcome.

3.
Anticancer Res ; 41(11): 5507-5515, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732421

RESUMO

BACKGROUND/AIM: The aim of the present study was to correlate the survival response to regional arterial-perfusion chemotherapy (RAPC) with Borrmann classification in patients with gastric cancer. PATIENTS AND METHODS: The survival response of 270 patients with advanced gastric cancer treated with RAPC was analyzed and Borrmann classification of the tumors was retrospectively correlated to survival. RESULTS: The median survival time of RAPC-treated patients with Borrmann type I/II was 53 months compared with 19 and 12 months for those with Borrmann type III and IV, respectively (p<0.001). CONCLUSION: Borrmann classification is a potential indicator to predict prognosis of patients with advanced gastric cancer treated with RAPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Terapia Neoadjuvante , Neoplasias Gástricas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/mortalidade , Feminino , Gastrectomia , Humanos , Excisão de Linfonodo , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do Tratamento
4.
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.

5.
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
6.
Anticancer Res ; 41(10): 4761-4769, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593425

RESUMO

BACKGROUND/AIM: The early stage of atherosclerosis (AS) demonstrates a lipid-driven inflammatory cytokine increase. In the present study, we aimed to use ultrasound-targeted microbubble delivery (UTMD) therapy with the Endostar-loaded target microbubbles (MBs) to reduce AS-related inflammatory response. MATERIALS AND METHODS: Normal and lipopolysaccharide (LPS) induced human umbilical vein endothelial cells (HUVECs) were placed in a parallel-plate flow chamber. MBs were perfused through the parallel-plate flow chamber to mimic physiological blood flow. Five groups were set up: G1: Negative control (normal HUVECs); G2: LPS control (LPS induced HUVECs); G3: ICAM-1-loaded-MBs (MBi); G4: Endostar-loaded-MBs (MBe) and G5: Endostar-ICAM-1-loaded-MBs (MBei). mRNA expression of inflammatory factors and release of inflammatory cytokines were detected by RT-PCR and ELISA, respectively. RESULTS: After treatment with MBei, the mRNA expression of cell adhesion molecule-1 (CD31) (p=0.004), endothelin-1 (ET-1) (p=0.010), von willebrand factor (vWF) (p=0.018), extracellular regulated protein kinases (ERK) (p=0.046) and nuclear factor kappa B (NF-κB) (p=0.003) were significantly reduced compared to LPS-induced HUVECs. Release of inflammatory cytokines including tissue factor (TF) (p=0.033), tissue factor pathway inhibitor (TF-PI) (p=0.019), ET-1 (p=0.014), vWF (p=0.030) and blood-coagulation factor VIIα (FVIIα) (p=0.000) were also significantly reduced compared to LPS-induced HUVECs. CONCLUSION: UTMD therapy can inhibit the inflammatory response by reducing atherosclerotic-related inflammatory factors, suggesting a potential treatment at the early-stage of AS.


Assuntos
Anti-Inflamatórios/farmacologia , Fibrinolíticos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Microbolhas , Anti-Inflamatórios/química , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/terapia , Adesão Celular , Endostatinas/química , Endostatinas/farmacologia , Fibrinolíticos/química , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/toxicidade , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Ultrassom
7.
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
8.
In Vivo ; 35(6): 3107-3110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697141

RESUMO

BACKGROUND/AIM: Primary osteosarcoma of the mammary gland is a very rare disease, accounting for less than 1% of all mammary malignancies. There is no established first-line treatment and the prognosis is poor compared to normal breast cancer. We previously established the first patient tumor-derived animal model of this disease, grown subcutaneously in nude mice. In the present study, we established a patient derived orthotopic xenograft (PDOX) model of osteosarcoma of the breast and investigated the efficacy of cisplatinum (CDDP) and eribulin (ERB). MATERIALS AND METHODS: PDOX models of primary osteosarcoma of the breast were divided into 3 groups (5-6 mice per group): untreated control; CDDP treatment; ERB treatment. The tumor volume in the 3 groups was compared after 2 weeks. RESULTS: There were significant differences between control and CDDP, and control and ERB (p=0.036, 0.046, respectively). However, there was no significant difference between CDDP and ERB (p=0.964). CONCLUSION: CDDP and ERB are candidates for first-line clinical therapy of primary osteosarcoma of the breast.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Animais , Neoplasias Ósseas/tratamento farmacológico , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Furanos , Xenoenxertos , Humanos , Cetonas , Camundongos , Camundongos Nus , Osteossarcoma/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Adv Exp Med Biol ; 1329: 163-179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34664239

RESUMO

The tumor microenvironment (TME) contains stromal cells in a complex interaction with cancer cells. This relationship has become better understood with the use of fluorescent proteins for in vivo imaging, originally developed by our laboratories. Spectrally distinct fluorescent proteins can be used for color-coded imaging of the complex interaction of the tumor microenvironment in the living state using cancer cells expressing a fluorescent protein of one color and host mice expressing another color fluorescent protein. Cancer cells engineered in vitro to express a fluorescent protein were orthotopically implanted into transgenic mice expressing a fluorescent protein of a different color. Confocal microscopy was then used for color-coded imaging of the TME. Color-coded imaging of the TME has enabled us to discover that stromal cells are necessary for metastasis. Patient-derived orthotopic xenograft (PDOX) tumors were labeled by first passaging them orthotopically through transgenic nude mice expressing either green, red, or cyan fluorescent protein in order to label the stromal cells of the tumor. The colored stromal cells become stably associated with the PDOX tumors through multiple passages in transgenic colored nude mice or noncolored nude mice. The fluorescent protein-expressing stromal cells included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Using this model, specific cancer cell or stromal cell targeting by potential therapeutics can be visualized. Color-coded imaging enabled the visualization of apparent fusion of cancer and stromal cells. Color-coded imaging is a powerful tool visualizing the interaction of cancer and stromal cells during cancer progression and treatment.


Assuntos
Microambiente Tumoral , Animais , Xenoenxertos , Humanos , Proteínas Luminescentes/genética , Camundongos , Camundongos Nus , Microscopia Confocal
10.
Anticancer Res ; 41(10): 4985-4993, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593446

RESUMO

BACKGROUND/AIM: There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy. PATIENTS AND METHODS: This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy. RESULTS: Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS. CONCLUSION: Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.


Assuntos
Antibacterianos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Imunoterapia/métodos , Neoplasias Pulmonares/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
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.

12.
In Vivo ; 35(5): 2531-2534, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410939

RESUMO

BACKGROUND/AIM: The aim of the present study was to identify effective drugs for a highly-aggressive liver-metastasis of triple-negative breast cancer (TNBC) in a patient-derived orthotopic xenograft (PDOX) mouse model. Drugs tested were oral recombinant methioninase (o-rMETase), low-dose eribulin and their combination. MATERIALS AND METHODS: Patient-derived TNBC was implanted in the liver of nude mice by surgical hepatic implantation. Two weeks after transplantation, 32 mice were randomized (n=8 per group) into a phosphate-buffered saline vehicle-control group; o-rMETase-treatment group (100 units, o-rMETase, oral, daily for 2 weeks); eribulin-treatment group (0.05 mg/kg intraperitoneally once per week for 2 weeks); or combination-treatment group (100 units r-METase, oral, daily for 2 weeks + 0.05 mg/kg eribulin intraperitoneally once per week for 2 weeks). RESULTS: After 2 weeks, the three treatment groups exhibited significantly-inhibited TNBC growth in the liver compared to the vehicle-control group (p≤0.05). CONCLUSION: o-rMETase and low-dose eribulin monotherapy and their combination were efficacious against the highly-aggressive TNBC PDOX growing in the liver. The TNBC PDOX model can be used to identify highly-effective drugs for therapy of TNBC with liver metastasis.


Assuntos
Neoplasias Hepáticas , Neoplasias de Mama Triplo Negativas , Animais , Liases de Carbono-Enxofre , Furanos , Humanos , Cetonas , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Anticancer Res ; 41(8): 3867-3869, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281847

RESUMO

BACKGROUND: Ultrasonography (US) is widely used for pre-operative detection of liver tumors. However, US does not have high resolution and very small tumors, tumors located near the liver surface, or those in cirrhotic livers are often not detected. CASE REPORT: A 47-year-old woman with a previous surgery for sigmoid colon cancer (T3N1bM0 Stage3b) showed a liver tumor on the surface of segment 2 by contrast-enhanced computed tomography (CT) and gadoliniumethoxybenzyldiethlenetriaminepen-taacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI). However, preoperative US could not identify a tumor lesion at the same site. The most likely preoperative diagnosis was metastasis from her sigmoid colon cancer and laparoscopic liver resection was performed. Intraoperative ultrasonography (IOUS) did not identify the tumor, but it was visualized with indocyanine green (ICG) fluorescence at the surface of segment 2. Laparoscopic liver resection was performed under fluorescence guidance. Pathological examination showed a pseudotumor with negative margins. CONCLUSION: ICG fluorescence imaging can allow visualization of liver tumors that are undetectable on US.


Assuntos
Hepatectomia/métodos , Laparoscopia/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Cirurgia Assistida por Computador/métodos , Feminino , Corantes Fluorescentes , Humanos , Verde de Indocianina , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Ultrassonografia de Intervenção
15.
Front Oncol ; 11: 666549, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34195076

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a recalcitrant cancer. The Chinese herbal monomer fangchinoline (FCL) has been reported to have anti-tumor activity in several human cancer cell types. However, the therapeutic efficacy and underlying mechanism on ESCC remain to be elucidated. In the present study, for the first time, we demonstrated that FCL significantly suppressed the growth of ESCC both in vitro and in vivo. Mechanistic studies revealed that FCL-induced G1 phase cell-cycle arrest in ESCC which is dependent on p21 and p27. Moreover, we found that FCL coordinatively triggered Noxa-dependent intrinsic apoptosis and DR5-dependent extrinsic apoptosis by transactivating ATF4, which is a novel mechanism. Our findings elucidated the tumor-suppressive efficacy and mechanisms of FCL and demonstrated FCL is a potential anti-ESCC agent.

16.
Molecules ; 26(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204178

RESUMO

We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd~130 nM), receptor activation in the cell required the synthesis of dimeric versions of such agent (namely 135H12). This was expected given that the natural ephrin ligands also need to be dimerized or clustered to elicit agonistic activity in cell. In the present report we investigated whether the agonistic activity of 135H11 could be enhanced by biotin conjugation followed by complex formation with streptavidin. Therefore, we measured the agonistic EphA2 activity of 135H11-biotin (147B5) at various agent/streptavidin ratios, side by side with 135H12, and a scrambled version of 147B5 in pancreatic- and breast-cancer cell lines. The (147B5)n-streptavidin complexes (when n = 2, 3, 4, but not when n = 1) induced a strong receptor degradation effect in both cell lines compared to 135H12 or the (scrambled-147B5)4-streptavidin complex as a control, indicating that multimerization of the targeting agent resulted in an increased ability to cause receptor clustering and internalization. Subsequently, we prepared an Alexa-Fluor-streptavidin conjugate to demonstrate that (147B5)4-AF-streptavidin, but not the scrambled equivalent complex, concentrates in pancreatic and breast cancers in orthotopic nude-mouse models. Hence, we conclude that these novel targeting agents, with proper derivatization with imaging reagents or chemotherapy, can be used as diagnostics, and/or to deliver chemotherapy selectively to EphA2-expressing tumors.


Assuntos
Receptor EphA2/agonistas , Receptor EphA2/química , Animais , Sítios de Ligação/fisiologia , Biotina/química , Biotina/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Ligantes , Camundongos , Neoplasias Pancreáticas/metabolismo , Ligação Proteica/fisiologia , Receptor EphA2/metabolismo , Estreptavidina/química , Estreptavidina/metabolismo
17.
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
18.
Anticancer Res ; 41(7): 3287-3292, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230123

RESUMO

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cell Cycle ; 20(13): 1221-1230, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34148497

RESUMO

Hyperthermia has been used for cancer therapy for a long period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), a type of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of a novel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.Abbreviations: AMF: alternating magnetic field; DDW: double distilled water; DMEM: Dulbecco's Modified Eagle's; Medium; f: frequency; FBS: fetal bovine serum; FITC: Fluorescein isothiocyanate; GFP: green fluorescent protein; H: amplitude; Hsp: heat shock protein; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; PI: propidium iodide; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

20.
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
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