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6.
Int J Nanomedicine ; 16: 2443-2459, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814909

RESUMEN

Background: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab-valine-citrulline (vc)-doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells. Methods: Maleimidocaproyl-valine-citrulline-p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody-drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs. Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR-overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPs. Conclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.


Asunto(s)
Cetuximab/uso terapéutico , Citrulina/química , Neoplasias Colorrectales/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Receptores ErbB/metabolismo , Nanopartículas/química , Albúmina Sérica Bovina/química , Valina/química , Adsorción , Animales , Bovinos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Endocitosis/efectos de los fármacos , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Tamaño de la Partícula , Espectroscopía de Protones por Resonancia Magnética , Distribución Tisular/efectos de los fármacos
7.
Life Sci ; 276: 119390, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-33794252

RESUMEN

AIMS: Currently, the main problems with chemotherapy are its side effects, toxicity, and drug resistance. Propolis has biological activities, such as anti-inflammatory and anti-cancer properties. This study aims to examine the combined effects of 5-fluorouracil (5FU) and propolis on colorectal cancer (CRC) in mouse models. MATERIALS AND METHODS: The chemical composition of ethanolic extract of propolis was determined by gas chromatography-mass spectrometry (GC-MS). In this study, 49 male Balb/c mice (16-20 g) were divided in seven groups as a control group and experimental groups (treated and untreated CRC model [azoxymethane + dextran sodium sulfate]). This study was conducted in 8 weeks. To examine the anti-cancer effects of propolis, the number of aberrant crypt foci (ACF) was counted and the pathological lesions in the distal colonic epithelial tissue were diagnosed. In this study, the expression of beta-catenin (ß-catenin), induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins, which play a major role in the incidence and progression of cancer, were determined. KEY FINDINGS: GC-MS analysis of propolis showed the presence of hydrocarbons, alcohols, ketones, terpenes, phenols, and flavonoids. Administering propolis in combination with 5FU reduced the number of ACFs and pathological lesions in comparison with cancer control groups (p < 0.0001) and 5FU-alone treatment (p < 0.05). The propolis combined with 5FU reduced the expression of Cox-2, iNOS, and ß-catenin proteins. SIGNIFICANCE: The results showed that propolis increased the efficiency of 5FU and could be taken into account as the adjunct therapy for colorectal cancer.


Asunto(s)
Antiinfecciosos/farmacología , Antimetabolitos Antineoplásicos/farmacología , Azoximetano/toxicidad , Neoplasias Colorrectales/tratamiento farmacológico , Sulfato de Dextran/toxicidad , Fluorouracilo/farmacología , Própolis/farmacología , Animales , Carcinógenos/toxicidad , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/patología , Quimioterapia Combinada , Masculino , Ratones , Ratones Endogámicos BALB C
8.
Anticancer Res ; 41(4): 2157-2163, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813427

RESUMEN

BACKGROUND: This study assessed the efficacy and safety of biweekly trifluridine and tipiracil hydrochloride (TAS-102) with bevacizumab combination therapy for patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We included 19 patients with mCRC who received TAS-102 and bevacizumab combination therapy biweekly as third-line chemotherapy. The primary endpoint was progression-free survival. RESULTS: Patients had a median age of 73 years and most (73.4%) were men. The median progression-free and overall survival were 5.6 and 11.5 months, respectively. Five (26.3%) patients achieved a response and the disease control rate was 12/19 (63.1%). One patient (5.2%) experienced neutropenia grade 3 or more. The median time from baseline performance status 0/1 to worsening to 2 or more was 10.3 months. CONCLUSION: Biweekly TAS-102 plus bevacizumab facilitates tumor shrinkage by reducing the incidence of grade 3 or more neutropenia, improving survival, and maintaining performance status. This combination may represent a treatment option for patients with late-stage mCRC receiving third- or later-line therapy.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Neutropenia Febril Inducida por Quimioterapia/etiología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirrolidinas/efectos adversos , Análisis de Supervivencia , Timina/efectos adversos , Resultado del Tratamiento , Trifluridina/efectos adversos
9.
Anticancer Res ; 41(4): 2203-2207, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813435

RESUMEN

BACKGROUND/AIM: In later-line treatment of metastatic colorectal cancer (mCRC), trifluridine/tipiracil is often selected because regorafenib is difficult to use in patients with comorbidities such as thrombosis, hemorrhage, or cardiac events. However, the safety and efficacy of trifluridine/tipiracil in these patients is not clear. PATIENTS AND METHODS: The clinical outcomes of trifluridine/tipiracil were retrospectively investigated in patients who were ineligible for regorafenib because of comorbidities. RESULTS: Among the 27 patients who received trifluridine/tipiracil, many had comorbidities of deep venous thrombosis or hemorrhage. The median overall survival was 12.4 months, and the median progression-free survival was 2.8 months. The median overall survival was 7.7 months in 19 patients without subsequent regorafenib. Grade 3 or higher toxicities were found in 51% of patients. No treatment discontinuation because of comorbidities was observed. CONCLUSION: Trifluridine/tipiracil can be safely administered while maintaining efficacy in patients who were ineligible for regorafenib.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Timina/uso terapéutico , Trifluridina/uso terapéutico , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Adulto , Anciano , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Comorbilidad , Combinación de Medicamentos , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Selección de Paciente , Compuestos de Fenilurea/uso terapéutico , Supervivencia sin Progresión , Piridinas/uso terapéutico , Pirrolidinas/efectos adversos , Estudios Retrospectivos , Terapia Recuperativa , Análisis de Supervivencia , Timina/efectos adversos , Resultado del Tratamiento , Trifluridina/efectos adversos
10.
Gan To Kagaku Ryoho ; 48(3): 357-361, 2021 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-33790157

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of CAPOX plus bevacizumab as second-line chemotherapy for metastatic colorectal cancer. METHODS: In this multicenter phase Ⅱ study, the planned number of patients was 48, but owing to poor case accumulation, registration was discontinued for 20 patients. The primary endpoint was the response rate(RR). Secondary endpoints were progression-free survival(PFS), overall survival(OS), disease control rate(DCR), and safety. RESULTS: First-line treatment was combined with irinotecan in 14 cases and bevacizumab in 12 cases. The median number of second- line treatment courses was 7, and the median treatment period was 203 days. The reason for discontinuation of treatment was disease progression in 13 cases, adverse events in 4 cases, and other reasons in 3 cases. The best response was PR in 5 cases, SD in 8 cases, and NE in 4 cases. The RR was 25%, and the DCR was 65%. The median PFS was 7.2 months, and the median OS was 18.6 months. Grade≥3 adverse events were neutropenia in 3 cases and diarrhea and peripheral neuropathy in 2 cases each. There were no treatment-related deaths. CONCLUSION: CAPOX plus bevacizumab was a safe and effective second-line treatment option for metastatic colorectal cancer.


Asunto(s)
Neoplasias Colorrectales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Camptotecina/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Enfermedad , Fluorouracilo/uso terapéutico , Humanos , Oxaliplatino/uso terapéutico , Resultado del Tratamiento
11.
Gan To Kagaku Ryoho ; 48(3): 391-393, 2021 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-33790165

RESUMEN

There are few reports on laparoscopic stoma creation; we report here our experience with laparoscopic stoma creation. PATIENTS AND METHODS: Seven patients who underwent laparoscopic stoma creation between April 2019 and December 2019 were studied and their clinical outcome was evaluated retrospectively. Operation approach: We performed a colostomy in the transverse colon. At first, we insert a 12 mm first port into the site of stoma marking. And more, we insert three 5 mm ports on the opposite side of the first port. We remove the adhesions of the intestinal tract and create a colostomy. RESULT: We changed open method 2 cases out of 7 cases due to extensive adhesion. In laparoscopically, we had an operation time of 97 (42-130) minutes and a blood loss of 5(2-40) mL. We had no postoperative complications or stoma problems. CONCLUSION: Laparoscopic stoma creation was useful due to few postoperative complications and can be rapidly transferred to chemotherapy.


Asunto(s)
Neoplasias Colorrectales , Laparoscopía , Estomas Quirúrgicos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Colostomía , Humanos , Ileostomía , Estudios Retrospectivos
12.
Gan To Kagaku Ryoho ; 48(3): 416-418, 2021 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-33790173

RESUMEN

Conversion surgery for patients with initially unresectable colorectal liver metastases is increasingly being performed because of effective systemic chemotherapy. Additionally, many studies have reported the benefit of the liver-first approach for advanced liver metastasis. We report a case of an initially unresectable advanced colon cancer with multiple liver and lung metastases that was successfully treated with the liver-first approach following chemotherapy. The patient was a 36-year- old woman who was diagnosed with advanced rectal cancer, cT4aN2aM1b, cStage Ⅳb. After a temporary transverse colostomy, she was administered systemic chemotherapy for 9 months. The primary tumor and liver metastases showed partial response while the lung metastases showed complete response. Since it was considered that liver metastases were the main prognostic factors, we performed a right hemihepatectomy plus S3 partial hepatectomy, followed by laparoscopic high anterior resection. A partial pneumonectomy was also performed because of the regrowth of the lung metastases, and we succeeded in complete resection. The liver-first approach was a beneficial treatment option for this patient with unresectable colorectal liver metastases.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Neoplasias Pulmonares , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía
13.
Gan To Kagaku Ryoho ; 48(3): 419-421, 2021 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-33790174

RESUMEN

Trifluridine/tipiracil (TAS-102) is an important chemotherapeutic agent recommended by the Japanese guidelines as third- or fourth-line treatment for colorectal cancer. Some studies have reported that administration of TAS-102 concomitant with bevacizumab prolongs progression-free and overall survival in colorectal cancer. We describe 2 patients treated with a chemotherapeutic regimen comprising TAS-102 concomitant with bevacizumab for recurrent colorectal cancer. No adverse events ≥Grade 3(except for hematotoxicity)were observed in these patients. The patient received several courses of chemotherapy with adjustments of the dose and dosing intervals to prevent neutropenia. Combination therapy using TAS-102 and bevacizumab is a feasible Late-line chemotherapeutic regimen for colorectal cancer.


Asunto(s)
Neoplasias Colorrectales , Trifluridina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Combinación de Medicamentos , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirrolidinas , Timina , Trifluridina/uso terapéutico , Uracilo/uso terapéutico
14.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807620

RESUMEN

Glycyrrhizin (GL), an important active ingredient of licorice root, which weakens the proinflammatory effects of high-mobility group box 1 (HMGB1) by blocking HMGB1 signaling. In this study, we investigated whether GL could suppress inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer. ICR mice were divided into four groups (n = 5, each)-control group, GL group, colon cancer (CC) group, and GL-treated CC (CC + GL) group, and sacrificed after 20 weeks. Plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using an enzyme-linked immunosorbent assay. The colonic tissue samples were immunohistochemically stained with DNA damage markers (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxy-guanosine), inflammatory markers (COX-2 and HMGB1), and stem cell markers (YAP1 and SOX9). The average number of colonic tumors and the levels of IL-6 and TNF-α in the CC + GL group were significantly lower than those in the CC group. The levels of all inflammatory and cancer markers were significantly reduced in the CC + GL group. These results suggest that GL inhibits the inflammatory response by binding HMGB1, thereby inhibiting DNA damage and cancer stem cell proliferation and dedifferentiation. In conclusion, GL significantly attenuates the pathogenesis of AOM/DSS-induced colorectal cancer by inhibiting HMGB1-TLR4-NF-κB signaling.


Asunto(s)
Carcinogénesis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Ácido Glicirrínico/farmacología , Inflamación/tratamiento farmacológico , Animales , Azoximetano/farmacología , Colon/efectos de los fármacos , Colon/metabolismo , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína HMGB1/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos ICR , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
15.
BMC Surg ; 21(1): 188, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33836701

RESUMEN

BACKGROUND: Expansion of the indication for liver resection and new regimens for systemic chemotherapy have improved postoperative outcomes for synchronous colorectal liver metastases (CRLM). However, such cases can still have a high recurrence rate, even after curative resection. Therefore, there is a need for postoperative adjuvant chemotherapy (POAC) after liver resection in patients with CRLM. There are few studies of the efficacy of POAC with an oxaliplatin-based regimen after simultaneous resection for colorectal cancer and CRLM with curative intent. The goal of the study was to compare POAC with oxaliplatin-based and fluoropyrimidine regimens using propensity score (PS) matching analysis. METHODS: The subjects were 94 patients who received POAC after simultaneous resection for colorectal cancer and synchronous CRLM, and were enrolled retrospectively. The patients were placed in a L-OHP (+) group (POAC with an oxaliplatin-based regimen, n = 47) and a L-OHP (-) group (POAC with a fluoropyrimidine regimen, n = 47). Recurrence-free (RFS), cancer-specific (CSS), unresectable recurrence-free (URRFS), remnant liver recurrence-free (RLRFS), and extrahepatic recurrence-free (EHRFS) survival were analyzed. RESULTS: Before PS matching, the L-OHP (+) and (-) groups had no significant differences in RFS, CSS, URRFS, RLRFS, and EHRFS. Univariate analysis indicated significant differences in age, preoperative serum CEA (≤ 30.0 ng/mL/ > 30.0 ng/mL), differentiation of primary tumor (differentiated/undifferentiated), T classification (T1-3/T4), number of hepatic lesions and maximum diameter of the hepatic lesion between the L-OHP (+) and (-) groups. After PS matching using these confounders, RFS was significantly better among patients in the L-OHP (+) group compared with the L-OHP (-) group (HR 0.40, 95% CI 0.17-0.96, p = 0.04). In addition, there was a trend towards better RLRFS among patients in the L-OHP (+) group compared with the L-OHP (-) group (HR 0.42, 95% CI 0.17-1.02, p = 0.055). However, there were no significant differences in CSS, URRFS and EHRFS between the L-OHP (+) and (-) groups. CONCLUSIONS: PS matching analysis demonstrated the efficacy of POAC with an oxaliplatin-based regimen in RFS and RLRFS.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , Oxaliplatino , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/cirugía , Hepatectomía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Oxaliplatino/uso terapéutico , Cuidados Posoperatorios , Puntaje de Propensión , Estudios Retrospectivos , Resultado del Tratamiento
16.
Arq Gastroenterol ; 58(1): 26-31, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33909793

RESUMEN

BACKGROUND: Worldwide, colorectal cancer (CRC) and gastric cancer (GC) are the third and the fifth most prevalent, respectively. Diarrhea is a common symptom in patients on chemotherapy or radiotherapy treatment and can reduce treatment tolerance. Surgical resections and chemotherapy change the intestinal microbiota that can lead to lactose intolerance, small intestinal bacterial overgrowth (SIBO). OBJECTIVE: The aim of the study was to evaluate the frequency of diarrhea in patients with CRC and GC on chemotherapy with SIBO or intolerance of lactose. METHODS: This is a descriptive and observational study with patients of both sexes, over 18 years old, in treatment in the Gastro-Oncology outpatient clinic of the Federal University of São Paulo. Patients with a confirmed diagnosis of CRC or GC during chemotherapy treatment were included. To detect bacterial overgrowth and lactose intolerance, breath hydrogen test with lactulose and lactose was done. Number and aspects of the evacuations and toxicity degree were collected. For the nutritional assessment, weight and height were performed to calculate the BMI. and the Patient Generated Subjective Global Assessment (PG-SGA). RESULTS: A total of 33 patients were included, 29 with CRC and 3 with GC. Most of them were male (57.57%), mean age of 60.03±10.01 years and in chemotherapy with fluoropyrimidine and oxaliplatin (54.5%). Diarrhea was present in 57.6% and 30.3% had toxicity grade 2. According to the BMI, 78.9% were eutrophics, obese or overweight, but according to PG-SGA, 84.9% had moderate or severe nutritional risk grade. Between patients, 45% had lactose intolerance and 9% SIBO. Diarrhea grade 2-3 was observed in 66.6% of patients with SIBO and 66.7% of that with lactose intolerance. No statistical difference was observed between patients with SIBO or lactose intolerance and grade of diarrhea. CONCLUSION: Diarrhea was a frequent symptom in chemotherapy patients with gastric or colorectal cancer independent of the presence of SIBO or lactose intolerance. Surgery and chemotherapy treatment impacted in the intestinal habit of patients. Diagnosis of other causes of diarrhea may contribute to a better tolerance to treatment and quality of life.


Asunto(s)
Neoplasias Colorrectales , Intolerancia a la Lactosa , Neoplasias Gástricas , Adolescente , Anciano , Pruebas Respiratorias , Neoplasias Colorrectales/tratamiento farmacológico , Femenino , Humanos , Hidrógeno , Intestino Delgado , Lactosa , Intolerancia a la Lactosa/diagnóstico , Masculino , Persona de Mediana Edad , Calidad de Vida
17.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671292

RESUMEN

Anticancer drugs, such as fluorouracil (5-FU), oxaliplatin, and doxorubicin (Dox) are commonly used to treat colorectal cancer (CRC); however, owing to their low response rate and adverse effects, the development of efficient drug delivery systems (DDSs) is required. The cellular prion protein PrPC, which is a cell surface glycoprotein, has been demonstrated to be overexpressed in CRC, however, there has been no research on the development of PrPC-targeting DDSs for targeted drug delivery to CRC. In this study, PrPC aptamer (Apt)-conjugated gold nanoparticles (AuNPs) were synthesized for targeted delivery of Dox to CRC. Thiol-terminated PrPC-Apt was conjugated to AuNPs, followed by hybridization of its complementary DNA for drug loading. Finally, Dox was loaded onto the AuNPs to synthesize PrPC-Apt-functionalized doxorubicin-oligomer-AuNPs (PrPC-Apt DOA). The PrPC-Apt DOA were spherical nanoparticles with an average diameter of 20 nm. Treatment of CRC cells with PrPC-Apt DOA induced reactive oxygen species generation by decreasing catalase and superoxide dismutase activities. In addition, treatment with PrPC-Apt DOA inhibited mitochondrial functions by decreasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, complex 4 activity, and oxygen consumption rates. Compared to free Dox, PrPC-Apt DOA decreased proliferation and increased apoptosis of CRC cells to a greater degree. In this study, we demonstrated that PrPC-Apt DOA targeting could effectively deliver Dox to CRC cells. PrPC-Apt DOA can be used as a treatment for CRC, and have the potential to replace existing anticancer drugs, such as 5-FU, oxaliplatin, and Dox.


Asunto(s)
Aptámeros de Nucleótidos/química , Neoplasias Colorrectales/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos , Oro/química , Nanopartículas del Metal/química , Proteínas Priónicas/química , Apoptosis/efectos de los fármacos , Catalasa/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Superóxido Dismutasa/metabolismo
18.
Zhonghua Yi Xue Za Zhi ; 101(11): 759-765, 2021 Mar 23.
Artículo en Chino | MEDLINE | ID: mdl-33765714

RESUMEN

Objective: To investigate the influence of X-ray repair cross complementing 1 (XRCC1) gene polymorphism on the prognosis and safety of stage Ⅲ patients with colorectal cancer (CRC) who received oxaliplatin based adjuvant chemotherapy. Methods: A total of 218 stage Ⅲ patients with CRC after R0 resection and received oxaliplatin based adjuvant chemotherapy in the department of gastrointestinal surgery of the First Affiliated Hospital of Zhengzhou University from March 2012 to December 2019 were included and the baseline characteristics were collected. There were 125 male and 93 female patients, aged from 18 to 78 years. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimens of the colorectal cancer patients were preserved for genotyping of XRCC1 gene genetic variation and mRNA expression of XRCC1, respectively. The association between genotype status and prognosis was analyzed by Kaplan-Meier survival analysis. And the correlation between genotype status and adverse reactions was performed with χ2 test. Results: The median follow-up time were 4.9 (0.3-7.3) years. The median disease-free survival (DFS) of the 218 patients with CRC was 4.4 years and the median overall survival (OS) was 5.5 years. The prevalence of rs1799782 in XRCC1 gene among the 218 patients was: GG genotype 62.4% (136/218), GA genotype 33.0% (72/218) and AA genotype 4.6% (10/218), minor allele frequency was 0.21. And the distribution frequencies of the three genotypes were in accordance with the hardy-weinberg equilibrium (P=0.905). GA and AA genotypes were merged in the subsequent analysis. The median DFS [M (95%CI)] of GG genotype and GA/AA genotype was 5.2 (4.5-5.9) years and 3.8 (3.2-4.4) years, which was statistically significant (χ²=6.943, P=0.008). Furthermore, the median OS [M (95%CI)] of the two genotypes were 6.0 (5.3-6.7) years and 4.5 (3.9-5.1) years, which was statistically significant (χ²=5.538, P=0.010). The mRNA expression of XRCC1 in PBMC of the patients with GA/AA genotypes was 3.8±0.6,which was significantly higher than that of the GG genotype patients(2.8±0.7) (t=6.140, P<0.001). Conclusion: The prognosis of patients with CRC who received oxaliplatin based adjuvant chemotherapy may be influenced by XRCC1 rs1799782 through mediating the mRNA expression of XRCC1.


Asunto(s)
Neoplasias Colorrectales , Leucocitos Mononucleares , Anciano , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Femenino , Genotipo , Humanos , Masculino , Oxaliplatino/uso terapéutico , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Pronóstico , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética
19.
Cancer Treat Rev ; 95: 102174, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33721596

RESUMEN

In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Reparación de la Incompatibilidad de ADN/genética , Animales , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/secundario , Evaluación Preclínica de Medicamentos , Humanos , Inmunoterapia
20.
BMC Cancer ; 21(1): 217, 2021 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653301

RESUMEN

BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC). METHODS: A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis. RESULTS: Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival. CONCLUSIONS: According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival.


Asunto(s)
Neoplasias Colorrectales/genética , Daño del ADN , Mutación , Oxaliplatino/administración & dosificación , Proteína de la Poliposis Adenomatosa del Colon/genética , Anciano , Proteína BRCA2/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Filogenia , Proteínas Proto-Oncogénicas p21(ras)/genética
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