Efficacy and safety of neoadjuvant chemotherapy combined with PD-1 antibody for esophageal squamous cell carcinoma in the real world / 中华肿瘤杂志

Objective: To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with programmed death-1 (PD-1) antibody in operable, borderline or potentially resectable locally advanced esophageal squamous cell carcinoma(ESCC) in the real world. Methods: The study retrospectively analyzed 28 patients with operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from April 2020 to March 2021. According to the clinical TNM staging system of the 8th edition of the American Joint Committee on Cancer, there were 1, 15, 10, 1 and 1 case of stage Ⅱ, Ⅲ, ⅣA, ⅣB and unknown stage respectively. The treatment was two cycle of dual drug chemotherapy regimen including taxane plus platinum or fluorouracil combined with PD-1 antibody followed by tumor response assessment and surgery if the patient was eligible for resection. Results: Of the 28 patients, 1, 2, 3 and 4 cycles of chemotherapy combined with PD-1 antibody treatment completed in 1, 21, 5, and 1 patient, respectively. Objective response rate (ORR) was 71.4% (20/28), and disease control rate (DCR) was 100% (28/28). The incidence of adverse events exceeding grade 3 levels was 21.4% (6/28), including 3 neutropenia, 1 leukopenia, 1 thrombocytopenia and 1 immune hepatitis. There was no treatment-related death. Of the 23 patients underwent surgery, R0 resection rate was 87.0% (20/23), 13 patients had down staged to the T1-2N0M0 I stage, the pCR rate was 17.3% (4/23), and the pCR rate of primary tumor was 21.7% (5/23). Four patients received definitive chemoradiotherapy. One patient rejected surgery and other treatment after achieved PR response. Conclusion: Neoadjuvant chemotherapy combined PD-1 inhibitor is safe and has high efficacy in operable, borderline or potentially resectable locally advanced ESCC, and it is a promising regimen.

The application progress of tumor radiotherapy in combination with immune checkpoint blockade / 医学研究生学报

Nowadays, it has been widely reported that radiotherapy can synergize with immune checkpoint blockade to improve antitumor efficacy, which shows significant advantages in clinical practice. The value of radiotherapy combined with immune checkpoint blockade therapy mainly lies in three aspects: improved local tumor control, stimulation of systemic immune response to induce abscopal effect and the elimination of acquired immunological tolerance to fractionated radiotherapy. Further research shows that radiotherapy combined with multiple checkpoint blockade, costimulatory molecules agonist, checkpoint gene knockout will contribute to the improved antitumor effect of the combined treatment model. Thus, this article reviewed the immunoregulation characteristics of tumor radiotherapy as well as the application status and research progress of tumor radiotherapy in combination with immune checkpoint blockade.

Preparation of Juglone-loaded PLGA Nanoparticles and Its Anti-tumor Effect on Melanoma A375 Cells in Vitro / 中国实验方剂学杂志

Objective: To prepare Juglone-loaded poly lactic-co-glycolic acid nanoparticles (Jug-PLGA-NPs), and investigate their physicochemical properties, release characteristics in vitro and anti-tumor activities on A375 melanoma cells in vitro. Method: Jug-PLGA-NPs were prepared by emulsification-solvent evaporation method. Then the particle size, encapsulation efficiency, drug loading rate and in vitro release characteristics were investigated. Fluorescence microscopy was used to observe the uptake of PLGA-NPs in vitro. The distribution of PLGA-NPs in BALB/c nude mice after tail vein injection was observed by the small living animal imaging system. Their inhibition effect on proliferation of A375 cells was detected by thiazolyl blue tetrazolium bromide (MTT) assay. Apoptosis rate and cell cycle detection were performed by flow cytometry. Western blot was used to determine the protein kinase B (Akt), phosphorylated Akt (p-Akt) and cyclinD1. Result: The average particle size of the prepared Jug-PLGA-NPs was (149.6±21.5) nm, entrapment rate of (68.39±2.51)%, and drug-loading rate of (5.07±0.98)%, showing good sustained-release characteristics. PLGA-NPs showed good penetration and targeting properties in cellular uptake in vitro and in vivo imaging. Different concentrations of Jug-PLGA-NPs could significantly inhibit the proliferation and promote apoptosis of A375 cells in a time and concentration dependent manner (P1 expression (P0/G1 phase (PConclusion: The Jug-PLGA-NPs are easy to prepare and have good sustained-release characteristics, tumor targeting and anti-tumor ability, providing a new pharmaceutical dosage form for the future clinical application of Jug.

Evaluation for preparation and anticancer efficacy in vitro of drug-loaded nanoerythrosomes / 中国中药杂志

The objective of this study is to develop a new-type biodegradable, biocompatible curcumin-loaded nanoerythrosomes (Cur-RBC-NPs) by means of the sonication method. The size of Cur-RBC-NPs was optimized by varying drug loading parameters. The morphology, size distribution, stability, in vitro release pattern, cellular uptake of nanoparticles and in vitro anti-tumor effects were evaluated, respectively. The results showed the prepared Cur-RBC-NPs were nearly uniform spheres, with an average diameter of (245.7 ± 1.3) nm. Encapsulation efficiency (EE) and load efficiency (LE) of Cur-RBC-NPs were 50.65% ± 1.36% and 6.27% ± 0.29%. And the nanoparticles had a good sustained release property. According to the in vitro experiment, Cur-RBC-NPs were effectively taken in by tumor cells, and exhibited a significant anti-tumor effect. In conclusion, the method for preparing Cur-RBC-NPs is convenient, with a good sustained release behavior and anti-tumor efficacy, and so expected to be a new-type nano-drug delivery system in clinical practice.

Generation and comparison of two genetically engineered mouse models of ErbB2/Neu positive-PTEN deficient breast cancer / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To generate two genetically engineered mouse models of ErbB2/Neu positive-PTEN deficient breast cancer and to compare their biological properties.</p><p><b>METHODS</b>The genetically engineered mice previously developed with mouse mammary tumor virus (MMTV) promoter driven expression of activated ErbB2/Neu and recombinant Cre (FVB/N-MMTV-NIC) were interbred with Flox-PTEN mice; and FVB/N-ErbB2KI mice, harboring endogenous promoter driven activated ErbB2/Neu expression, FVB/N-MMTV-Cre mice and the flox-PTEN mice were interbred. Neu, Cre and PTEN genes were amplified by PCR for genotyping of the offsprings. ErbB2/Neu and PTEN expression in mammary tumors were detected by immunohistochemistry. Tumor formation time, tumor number, histopathology and lung metastasis were compared between two models, Ki-67 expression was detected by immunohistochemistry, and TUNEL staining of tumor tissues was performed.</p><p><b>RESULTS</b>Two genetically engineered mouse models of ErbB2/Neu positive-PTEN homozygous deficient breast cancer were generated. The models were confirmed by genotyping and immunohistochemistry. One model with exogenous MMTV promoter driven expression of activated ErbB2/Neu and Cre coupling PTEN disruption was designated as NIC/PTEN(-/-) mice, and the other with MMTV-Cre induced endogenous promoter driven expression of activated ErbB2/Neu with PTEN disruption was designated as ErbB2KI/PTEN(-/-) mice. The tumor formation time in NIC/PTEN(-/-) mice was significantly shorter than that of ErbB2KI/PTEN(-/-) mice (30 vs 368 d, P<0.01); the number of tumor and incidence of lung metastasis was also significantly higher in NIC/PTEN(-/-) mice (10 vs 1-2 and 75.0% vs 37.5%, respectively, Ps<0.01). The Two models displayed distinct histopathological morphology. NIC/PTEN(-/-) tumor showed more Ki-67 positive cells than ErbB2KI/PTEN(-/-) tumor did (86.9%±2.8% vs 37.4%±7.2%, P<0.01), while the amount of cell apoptosis in tumors was not significantly different between two models.</p><p><b>CONCLUSION</b>Two genetically engineered mouse models of ErbB2/Neu positive-PTEN homozygous deficient breast cancer with different phenotypes have been successfully generated, which may provide useful resource for further investigation of the initiation and progression of HER2/ErbB2 breast cancer, as well as for the development of novel prevention and treatment regimens of this malignance.</p>

Correlation between the methylation of SULF2 and WRN promoter and chemosensitivity to irinotecan in gastric cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the relationship between SULF2 and WRN promoter methylation and chemosensitivity to irinotecan, and also the clinicopathological features in patients with gastric cancer.</p><p><b>METHODS</b>The chemosensitivity to irinotecan was tested by MTT assay. The methylation of SULF2 and WRN promoter in the fresh gastric cancer tissues was detected by methylation specific PCR. The differences of chemosensitivity and clinicopathological features of the methylation group were compared with that of the non-methylation group. The tumor growth in nude mice bearing human gastric cancer xenografts treated with CPT-11was also observed.</p><p><b>RESULTS</b>The methylation rates of SULF2 and WRN were 28.4% (29/102) and 23.5% (24/102), respectively. There were no significant association between promoter methylation and clinicopathological features of patients including age, gender, histologic type, lymphatic invasion, and TNM Stage. In all the 102 cases, there were 30 cases of irrinotecan-sensitive group, and 72 cases of the irrinotecan-resistant group. The SULF2 methylation rate was 46.7% (14/30)in the sensitive group, and 20.8% (15/72) in the resistant group (P = 0.008),The WRN methylation rate was 33.3% (10/30) in the sensitive group, and 19.4% (14/72) in the resistant group (P = 0.214). Gastric cancer tissues were more sensitive to irrinotecan when both the genes were methylated. The nude mice bearing human gastric cancer xenografts with SULF2 methylation were more sensitive to irrinotecan.</p><p><b>CONCLUSIONS</b>The detection of SULF2 and WRN promoter methylation may provide evidence for screening and targeting the most sensitive gastric cancer subpopulation suitable for personalized irrinotecan chemotherapy.</p>

Relationship between BRCA1 mRNA expression in tumor cells from malignant effusions and chemosensitivity to cisplatin in patients with metastatic malignant effusions / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To explore the mRNA expression of breast cancer susceptibility gene 1 (BRCA1) in tumor cells isolated from malignant pleural and peritoneal effusions, and the predictive role of BRCA1 related to the efficacy of cisplatin-based chemotherapy.</p><p><b>METHODS</b>Tumor cells were isolated from malignant pleural and peritoneal effusions of 31 cancer patients. The response of these tumor cells to cisplatin was determined by CCK8 assay. Real time quantitative RT-PCR was used to examine the BRCA1 mRNA level in the primary culture cancer cells.</p><p><b>RESULTS</b>The expression level of BRCA1 mRNA was 0.618 (0.014 - 18.063) in primary culture tumor cells. The IC(50) of DDP was 2.809 µg/ml in the primary culture tumor cells (0.118 - 19.439 µg/ml). Both BRCA1 mRNA expression and the tumor cells IC(50) of DDP were not significantly related with patient age, gender, the type of primary tumor, whether to accept the chemotherapy and effusion type (P > 0.05). The level of BRCA1 mRNA was negatively correlated with the chemosensitivity in terms of IC(50) of cisplatin (P < 0.001).</p><p><b>CONCLUSION</b>Assessment of expression level of BRCA1 mRNA may be useful in predicting the efficacy of cisplatin-based chemotherapy in patients with metastatic malignant effusions.</p>

Anti-angiogenic effect of vinorelbine in combination with cetuximab in vitro and in vivo / 中华肿瘤杂志

<p><b>OBJECTIVE</b>This experiment aims to study the anti-angiogenic ability of vinorelbine combined with cetuximab in vitro and in vivo.</p><p><b>METHODS</b>Human lung adenocarcinoma A549 cells were used as control group. Proliferation of human umbilical vein endothelial cells (HUVEC) was assessed by MTT assay. Furthermore, we used Transwell chambers, capillary tube formation and flow cytometry to observe the effects of vinorelbine combined with cetuximab on HUVEC migration, tube formation and cell apoptosis, respectively. In addition, the anti-angiogenic ability of the drugs was checked using chicken chorioallantoic membrane (CAM) model.</p><p><b>RESULTS</b>The inhibitory rate of HUVEC growth was 25.8%, 39.2%, 54.0% for vinorelbine at the concentration of 0.1 ng/ml, 0.4 ng/ml, and 0.8 ng/ml, respectively; that of 0.25 microg/ml cetuximab was 19.7%, and that of 0.1 ng/ml vinorelbine + 0.25 microg/ml cetuximab, 0.4 ng/ml vinorelbine + 0.25 microg/ml cetuximab and 0.8 ng/ml vinorelbine + 0.25 microg/ml cetuximab was 29.5%, 46.4%, 64.6%, respectively. The inhibitory rates of the drugs at the above mentioned combinations of migration and tube formation of HUVEC were 51.9%, 68.2%, 95.0%, respectively. The inhibitory rate of 0.1 ng/ml + 0.25 microg/ml cetuximab and 0.4 ng/ml vinorelbine + 0.25 microg/ml cetuximab on tube formation of HUVEC was 38.8% and 57.7%, respectively, showing a sub-additive effect, and that of combination of 0.8 ng/ml vinorelbine + 0.25 microg/ml cetuximab was 78.9%, showing a synergistic effect. In addition, the apoptotic rate of HUVEC induced by 0.8 ng/ml vinorelbine + 0.25 microg/ml cetuximab was 59.9%, showing a synergistic effect. The in vivo experiment also showed that the combination of the two drugs had a synergistic anti-angiogenic effect.</p><p><b>CONCLUSION</b>Both low dose vinorelbine and cetuximab have an anti-angiogenic effect in vitro and in vivo, and the combination of the two drugs has sub-additive or synergistic inhibitory effect on angiogenesis.</p>

Prognostic significance of ERCC1 mRNA expression in patients with non-small cell lung cancer receiving platinum-based chemotherapy / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the correlation of the mRNA expression level of excision repair cross-complementing group 1 (ERCC1) gene with clinicopathological parameters and clinical outcome in patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy.</p><p><b>METHODS</b>The mRNA expression of ERCC1 in formalin-fixed paraffin-embedded primary tumor specimens was measured by real-time quantitative reverse transcriptase polymerase chain reaction. The association between ERCC1 expression levels and clinicopathological parameters in NSCLC patients was analyzed.</p><p><b>RESULTS</b>The median value of ERCC1 mRNA expression level compared with beta-actin in tumor specimens of 61 NSCLC patients was 0.48. There was no correlation between ERCC1 expression and clinicopathological parameters. Patients with low expression of ERCC1 mRNA (less than 0.35, 0.28, respectively) had a significantly longer median time to progression (TTP) (14.3 vs. 8.0 months, P = 0.028) and overall survival (OS) (28.4 vs. 12.9 months, P = 0.0064) than those with high expression. Multivariate analysis showed that a low ERCC1 mRNA expression was an independent factor for OS.</p><p><b>CONCLUSION</b>Our findings suggest that intratumoral ERCC1 mRNA expression level, although is uncorrelated with clinicopathological parameters, is an independent predictive marker for survival of the patients with NSCLC receiving platinum-based chemotherapy, and may provide critical information for personalized chemotherapy.</p>

Differential gene expression of the inhibitor of apoptosis proteins in docetaxel-resistant gastric cancer cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>Resistance to chemotherapy may indicate an unfavorable outcome for patients with gastric cancer. The purpose of this study was to examine whether docetaxel-resistance could be due in part to the expression of the inhibitor of apoptosis proteins (IAP).</p><p><b>METHODS</b>Docetaxel-resistant cells, BGC-823/R1, BGC-823/R2 and BGC-823/R3, were established from parent BGC-823 cells by stepwise increasing concentration of docetaxel. To characterize these cells, we examined the effects of docetaxel on cell growth and apoptosis by MTT assay and double staining with both annexin-V-FITC and PI, and analyzed the cross-resistance to various anticancer drugs. Expression of IAP compared with that in parental cells was evaluated by real-time quantitative PCR.</p><p><b>RESULTS</b>The BGC-823 resistant cells, BGC-823/R1, R2 and R3 cells, were 10.2-, 24.5-, 56.3-fold more resistant to docetaxel than parental cells, respectively, and this resistance was paralleled with reduced induction of apoptosis. BGC-823/R3 cells showed cross-resistance to paclitaxel, whereas exhibited weak or no cross-resistance against 5-fluorouracil, cisplatin and oxaliplatin. The expressions of survivin and XIAP were gradually increased with the extent of docetaxel resistance (r = 0.909, P < 0.001 and r = 0.892, P < 0.001, respectively).</p><p><b>CONCLUSION</b>IAP may make an important contribution to the resistance to the apoptotic effect of docetaxel in gastric cancer, and could be used as a potential therapeutic target.</p>

Inhibitory effect of oxaliplatin in combination with hyperthermia on angiogenesis / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the effect of oxaliplatin in combination with hyperthermia on angiogenesis in vitro and in vivo.</p><p><b>METHODS</b>MTT method was used to observe the influence of oxaliplatin on the proliferation of human umbilical vein endothelial cells (HUVEC) or human colon cancer cells (LOVO). The influence of oxaliplatin on HUVEC migration was evaluated by Transwell. Chick embryo chorioallantoic membrane (CAM) model was used to check whether the neovascularization of CAM could be suppressed in vivo.</p><p><b>RESULTS</b>The survival rate of HUVEC was 80.1% - 42.5% within a range of 0.5 - 16 microg/ml and was negatively correlated with the concentration (correlation coefficient was - 0. 943, P = 0.005). The survival rate of LOVO cells within those doses was more than that of HUVEC. There was a synergistic antiangiogenic effect when a combination of oxaliplatin (0.5 microg/ml, 1 microg/ml and 16 microg/ml) with hyperthermia was used while additional effect was shown by the combinatioin of oxaliplatin (2 microg/ml, 4 microg/ml and 8 microg/ml) and hyperthermia in vitro. Oxaliplatin inhibited migration of HUVEC in vitro at low doses (0.25 - 2 microg/ml), and also suppressed angiogenesis of CAM in vivo at doses of 1 -4 microg/ml.</p><p><b>CONCLUSION</b>The results of this experiment showed that low dose of oxaliplatin has anti-angiogenic effect in vitro, while in combination with hyperthermia has additional effect both in vivo and in vitro.</p>

Synergistic effect of Chinese materia medica and chemotherapeutic agents / 中国中西医结合杂志

Both in vitro and in vitro studies have proved that partial of Chinese materia medica including monomer or active ingredients have synergistic action with chemotherapeutic agents, the former could enhance the effect of the latter. Its mechanism may be correlated with the actions of Chinese materia medica in enhancing immune function, directly killing tumor cells, inducing tumor cell apoptosis, regulating cell cycle and reversing chemotherapeutic drug resistance, etc. The present article summarized the synergistic effect of Chinese materia medica, monomer or active ingredients, with various chemotherapeutic agents, and tried to provide a theoretical evidence for combined application of them in the procedure of clinical tumor treatment.

Distribution of hydroxycamptothecin after aerosol inhalation in rabbits / 药学学报

<p><b>AIM</b>To investigate the tissue distribution and pharmacokinetics of hydroxycamptothecin (HCPT) after aerosol inhalation in rabbits.</p><p><b>METHODS</b>RP-HPLC was used to determine the concentration of HCPT in different tissues and plasma of rabbits. The tissue distribution of HCPT after aerosol inhalation or iv administration was compared. The plasma concentrations at different time after aerosol inhalation were compared with iv injection.</p><p><b>RESULTS</b>The HCPT concentrations in lung after aerosol inhalation at 0.5, 1 and 2 h were 13.52, 27.81 and 20.82 times higher than that of iv administration group, respectively. At the same time, concentrations in other tissues were decreased obviously. The absolute bioavailability of HCPT after aerosol inhalation was 7.38%.</p><p><b>CONCLUSION</b>After aerosol inhalation, HCPT is retained mostly in lung. So this administration route can raise the therapeutic index and reduce adverse effects.</p>

Effect of arsenic trioxide on drug transporting molecules in acute promyelocytic leukemia cell line / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the effect of arsenic trioxide (As2O3) on expression of drug transporting molecules in APL MR2 cell line.</p><p><b>METHODS</b>MR2 resistant to all-trans retinoic acid (ATRA) and non-ATRA resistant APL cell line NB4 was used in this in vitro study. Expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) and lung resistance-related protein (LRP) was detected by immunocytochemical assay.</p><p><b>RESULTS</b>The expression of Pgp was significantly higher in MR2 (30%-40%) than in NB4 (10%-20%) (P < 0.001), and that of MRP was also higher in MR2 (56.9 +/- 3.4-21.2 +/- 1.1) than in NB4 (20.6 +/- 5.3-16.7 +/- 1.2) (P < 0.001). As2O3 at concentrations ranging from 0.5 approximately 2.0 micromol/L could significantly decrease the expression of Pgp and MRP, but not that of LRP. The decrease in the expression of Pgp and MRP in MR2 cell line was negatively correlated with the dose and duration of action of As2O3.</p><p><b>CONCLUSION</b>Pgp and MRP, but not LRP, may be the sensitive targets of As2O3 to overcome drug-resistance. ATRA might be the substrates of Pgp and MRP.</p>

Effects of four extracts of traditional Chinese medicinal materials on the proliferation of human lung cancer A549 cell line / 中国药理学通报

AIM: To study the influence of four extracts of traditional Chinese medicinal materials sodium cantharidinate, matrine, cinobufotain and sodium ferlate) on the proliferation of human lung cancer A549 cell line and breast cancer MCF7 cell line;the possible mechanism of sodium ferlate on the inhibition of A549 cells. METHODS: The inhibition of cell proliferation was determined by MTT assay and cell cycle was determined by flow cytometry. RESULTS: All four extracts of traditional Chinese medicinal materials showed growth inhibition to breast cancer MCF7 cells while only sodium ferlate showed inhibition to lung cancer A549 cells. Synergistic inhibition was found when sodium ferlate was combined with each of the three commonly-used chemotheraputic drugs. Sodium ferlate could induce A549 cell apoptosis. CONCULSION: The inhibition of cell proliferation induced is by sodium cantharidinate, matrine, and cinobufotain is quite different between different cancer cell lines. Sodium ferlate can inhibit cancer cell proliferation and show synergistic action while combined with chemotheraputic drugs. The mechanism of sodium ferlate on A549 cell proliferation seem to be related to the cell apoptosis.