Neoadjuvant Anlotinib and chemotherapy followed by minimally invasive esophagectomy in patients with locally advanced esophageal squamous cell carcinoma: Short-term results of an open-label, randomized, phase II trial.

Background: Clinical benefits of neoadjuvant Anlotinib for locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear. This study evaluated the efficacy and safety of neoadjuvant Anlotinib plus chemotherapy followed by minimally invasive esophagectomy (MIE) for the treatment of patients with locally advanced ESCC. Methods: Patients with locally advanced ESCC were randomly assigned to neoadjuvant Anlotinib combined with chemotherapy (Anlotinib group) or neoadjuvant chemoradiotherapy alone (nCRT group) with an allocation ratio of 1:1. The primary endpoint was the R0 surgical resection rate. Secondary endpoints included postoperative pathologic stage, complete response (CR) rate, and safety. Safety was assessed by adverse events (AEs) and postoperative complications. Results: From August 2019 to August 2021, 93 patients were assigned to the nCRT or Anlotinib group. Of the 93 patients, 79 underwent MIE and were finally included in the per-protocol set (nCRT group: n=39; Anlotinib group: n=40). The R0 resection rate was 97.4% for nCRT versus 100.0% for Anlotinib group (p>0.05). Compared with the nCRT group, patients in the Anlotinib group had shorter total operation duration (262.2 ± 39.0 vs. 200.7 ± 25.5 min, p=0.010) and less blood loss (161.3 ± 126.7 vs. 52.4 ± 39.3 mL, p<0.001). No significant differences were found in the postoperative pathologic stage between the Anlotinib group and nCRT group (all p>0.05). Besides, the incidences of AEs (80.0% vs. 92.3%) and postoperative complications (22.5% vs. 30.8%) were similar between the two groups (all p>0.05). Conclusions: Neoadjuvant Anlotinib plus chemotherapy had a similar safety profile and pathologic response, but better surgical outcomes than nCRT for locally advanced ESCC.

Satisfactory short-term outcome after anlotinib and docetaxel chemotherapy in tongue cancer with N3 cervical lymph node metastasis: A case report.

Patients with tongue squamous cell carcinoma (TSCC) and cervical lymph node metastasis are particularly difficult to treat. This is the first report of about anlotinib combined with docetaxel chemotherapy for chemotherapy-refractory TSCC with cervical lymph node metastasis, may provide a new, suitable therapeutic option for these patients.

MicroRNA-765 Enhances the Anti-Angiogenic Effect of CDDP via APE1 in Osteosarcoma.

Human osteosarcoma (HOS) is the most common malignancy in children and adolescents and has a heterogeneous presentation and high mortality. Previous studies have shown that microRNAs contribute to RNA silencing and post-transcriptional regulation of gene expression. Here, we showed that significantly increased expression of miR-765 with or without CDDP (Cisplatin) down-regulates APE1 expression and angiogenesis-related markers (VEGF, FGF2, TGFß, and CD34). Further investigation showed that miR-765 modulates osteosarcoma cell migration and angiogenesis following treatment with cisplatin in vitro and in vivo. MiR-765 increases the anti-angiogenic effect of CDDP in human osteosarcoma. Elucidation of the mechanism of the miR-765-APE1 axis in tumor progression of HOS will be beneficial in identifying biomarkers and therapeutic target of osteosarcoma.

Genetic polymorphism of DNA base-excision repair genes (APE1, OGG1 and XRCC1) and their correlation with risk of lung cancer in a Chinese population.

BACKGROUND AND AIMS: Reactive oxygen species (ROS) and numerous carcinogens may cause DNA damage including oxidative base lesions that contribute to the risk of lung cancer. The base excision repair (BER) pathway could effectively remove oxidative lesions in which 8-oxoguanine glycosylase-1 (OGG1), x-ray repair cross-complementing 1 (XRCC1), and apurinic/apyimidinic endonuclease 1 (APE1) play key roles. The aim of this study was to analyze the polymorphisms of DNA BER genes (OOG1, XRCC1 and APE1) and explore their associations, and the combined effects of these variants, with risk of lung cancer. METHODS: In a hospital-based, case-control study of 455 lung cancer cases and 443 cancer-free hospital controls, the SNPs of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), APE1 (Asp148Glu and -141T/G) were genotyped and analyzed for their correlation with the risk of lung cancer in multivariate logistic regression models. RESULTS: Individuals homozygous for the variants APE1 -141GG showed a protective effect for lung cancer overall (OR=0.62; 95% CI: 0.42-0.91; p=0.02) and for lung adenocarcinoma (OR=0.65; 95% CI, 0.44-0.96; p=0.03). When analyzing the combined effects of variant alleles, 84 patients and controls were identified who were homozygous for two or three of the potential protective alleles (i.e., OGG1 326Cys, XRCC1 399Gln and APE1 -141G). ORs were significantly reduced when all patients were analyzed (OR=0.62; 95% CI: 0.38-0.99; p=0.05). CONCLUSIONS: The combined effects of polymorphisms within BER genes may contribute to the tumorigenesis of lung cancer.

Californium-252 brachytherapy combined with external-beam radiotherapy for cervical cancer: long-term treatment results.

PURPOSE: To observe, by retrospective analysis, the curative effects and complications due to californium-252 (252Cf) neutron intracavitary brachytherapy (ICBT) combined with external-beam radiotherapy (EBRT) in the treatment of cervical cancer. METHODS AND MATERIALS: From February 1999 to December 2007, 696 patients with cervical cancer (Stages IB to IIIB) were treated with 252Cf-ICBT in combination of EBRT. Of all, 31 patients were at Stage IB, 104 at IIA, 363 at IIB, 64 at IIIA, and 134 at IIIB. Californium-252 ICBT was delivered at 7-12 Gy per insertion per week, with a total dose of 29-45 Gy to reference point A in three to five insertions. The whole pelvic cavity was treated with 8-MV X-ray external irradiation at 2 Gy per fraction, four times per week. After 16-38 Gy of external irradiation, the center of the whole pelvic field was blocked with a 4-cm-wide lead shield, with a total external irradiation dose of 44-56 Gy. The total treatment course was 5 to 6 weeks. RESULTS: Overall survival rate at 3 and 5 years for all patients was 76.0% and 64.9%, respectively. Disease-free 3- and 5-year survival rates of patients were 71.2% and 58.4%, respectively. Late complications included vaginal contracture and adhesion, radiation proctitis, radiation cystitis, and inflammatory bowel, which accounted for 5.8%, 7.1%, 6.2%, and 4.9%, respectively. Univariate analysis results showed significant correlation of stage, age, histopathologic grade, and lymph node status with overall survival. Cox multiple regression analysis showed that the independent variables were stage, histopathologic grade, tumor size, and lymphatic metastasis in all patients. CONCLUSION: Results of this series suggest that the combined use of 252Cf-ICBT with EBRT is an effective method for treatment of cervical cancer.

Microarray analysis of DNA damage repair gene expression profiles in cervical cancer cells radioresistant to 252Cf neutron and X-rays.

BACKGROUND: The aim of the study was to obtain stable radioresistant sub-lines from the human cervical cancer cell line HeLa by prolonged exposure to 252Cf neutron and X-rays. Radioresistance mechanisms were investigated in the resulting cells using microarray analysis of DNA damage repair genes. METHODS: HeLa cells were treated with fractionated 252Cf neutron and X-rays, with a cumulative dose of 75 Gy each, over 8 months, yielding the sub-lines HeLaNR and HeLaXR. Radioresistant characteristics were detected by clone formation assay, ultrastructural observations, cell doubling time, cell cycle distribution, and apoptosis assay. Gene expression patterns of the radioresistant sub-lines were studied through microarray analysis and verified by Western blotting and real-time PCR. RESULTS: The radioresistant sub-lines HeLaNR and HeLaXR were more radioresisitant to 252Cf neutron and X-rays than parental HeLa cells by detecting their radioresistant characteristics, respectively. Compared to HeLa cells, the expression of 24 genes was significantly altered by at least 2-fold in HeLaNR cells. Of these, 19 genes were up-regulated and 5 down-regulated. In HeLaXR cells, 41 genes were significantly altered by at least 2-fold; 38 genes were up-regulated and 3 down-regulated. CONCLUSIONS: Chronic exposure of cells to ionizing radiation induces adaptive responses that enhance tolerance of ionizing radiation and allow investigations of cellular radioresistance mechanisms. The insights gained into the molecular mechanisms activated by these "radioresistance" genes will lead to new therapeutic targets for cervical cancer.

APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells.

PURPOSE: Apurinic/apyrimidinic endonuclease (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with chemoresistance. In this study, we first investigated APE1 expression and its correlation with cisplatin resistance and prognosis in non-small cell lung cancer (NSCLC) patients. Then, we investigated the effect of chimeric adenoviral vector Ad5/F35 carrying human APE1 siRNA (Ad5/F35-APE1 siRNA) on the sensitivity of cisplatin in A549 human lung adenocarcinoma cells. METHODS: Tumor specimens from 103 patients with operable NSCLC were obtained from 1999 to 2001. Among these patients, 72 patients have been treated with at least three cycles of cisplatin-based chemotherapy. APE1 protein expression was examined by immunohistochemistry and Western blot on the tumor samples and a cultured A549 cell line, respectively. Cell survival and apoptosis were determined by MTT and TUNEL, respectively. RESULTS: 83.3% (20/24) cisplatin-resistant tumors showed high APE1 expression levels, while 8.3% (4/48) cisplatin-sensitive tumors showed high APE1 expression levels (p<0.01). Univariate analysis indicated that overall survival and disease-free survival were significantly better in NSCLC patients with low vs those with high APE1 expression levels (p<0.01). Treatment with cisplatin resulted in a dose-dependent increase in APE1 protein expression in A549 cells, and Ad5/F35-APE1 siRNA effectively inhibited APE1 expression. Ad5/F35-APE1 siRNA significantly enhanced sensitivity of A549 cells to cisplatin, associated with increased cell apoptosis. CONCLUSIONS: Our results indicate that APE1 is a new promising target for the combination of cisplatin-based chemotherapy in NCSLC patients.

Vector-based Ape1 small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo.

Osteosarcoma is a highly vascular and extremely destructive malignancy, and the survival of patients with osteosarcoma has not improved significantly in recent years. Antiangiogenic therapy currently holds great potential in conjunction with conventional treatment modalities for osteosarcoma. However, there are examples of gradual loss of response, and perhaps acquired resistance to antiangiogenic drugs. The acquired resistance of antiangiogenesis may be associated with a lot of hypoxia-response genes. The human apurinic/apyrimidinic endonuclease (Ape1) protein, a bifunctional redox factor and apurinic/apyrimidinic (AP) endonuclease, plays a crucial role in protecting against cell death due to hypoxia. We therefore hypothesized that Ape1 may contribute to the resistance of antiangiogenic therapy. To investigate the effect of Ape1 on the sensitivity of human osteosarcoma cells to endostatin, we constructed an Ape1 small interfering RNA expression vector, pSilenceApe1. Transfection of human osteosarcoma 9901 and HOS cells with pSilenceApe1 resulted in a dose-dependent loss of Ape1 protein. pSilenceApe1 also significantly suppressed the expression of vascular endothelial growth factor (VEGF) protein in the 9901 cells. Combined treatment with pSilenceApe1 and recombinant human endostatin (rhES) showed potent antiangiogenic effects in the transwell chamber invasion assay. Then, 20 nude mice bearing 9901 xenografts were divided into four groups: the phosphate-buffered saline treatment control group; the rhES treatment group (1.5 mg/kg, daily); the pSilenceApe1 treatment group (20 microg, once every 3 days); and the combination of rhES and pSilenceApe1 treatment group. pSilenceApe1 significantly suppressed the expression of Ape1 and VEGF protein in the 9901 xenografts. The tumor-inhibition rate of the pSilenceApe1, rhES, and combination of rhES and pSilenceApe1 treatment groups was 38.23, 35.29, and 62.18%, respectively. Furthermore, a significant decrease in microvessel density with an increase in apoptosis was observed following combined treatment with pSilenceApe1 and rhES, compared with control and either agent alone in 9901 xenografts. These results indicate that Ape1 small interfering RNA could enhance the sensitivity of osteosarcoma cells to endostatin.

[Effect of adenoviral N-methylpurine DNA glycosylase overexpression on chemosensitivity of human osteosarcoma cells].

OBJECTIVE: The overexpression of N-methylpurine DNA glycosylase (MPG) may imbalance the DNA base excision repair (BER) to sensitize tumor cells to current DNA damage chemotherapy. In an effort to improve the efficacy of cancer chemotherapy, we have constructed adenoviral vector of MPG, to study its ability to sensitize human osteosarcoma cell HOS to DNA damage agents. METHODS: The adenoviral infection and MPG expression, as well as enzyme activity were determined by flow cytometry, Western blot, and HEX labeled oligonucleotide-based assay respectively. The cell survival/proliferation was measured using MTS, SRB, and [(3)H] thymidine incorporation assay. Apoptosis cell death was assayed by flow cytometry after treatment using phycoerythin (PE)-conjugated Annexin V and 7-amino-actinomycin (7-AAD). RESULTS: A 10 MOI of recombinant nonreplicating adenovirus was found to infect more than 90% of HOS cells within 24 hours by EGFP fluorescence, in which the MPG overexpression and MPG enzyme activity were also detected. The MPG overexpression HOS cells were significantly more sensitive to the DNA damage agents, including MMS, MNNG, and TMZ, with changes in the IC50 of 6.0, 4.5, and 2.5 fold respectively. CONCLUSIONS: These data establish transient MPG overexpression as a potential therapeutic approach for increasing HOS cellular sensitivity to DNA damage agent chemotherapy.