Publications by authors named "Zetian Shen"

12 Publications

  • Page 1 of 1

Combined inhibition of AURKA and HSF1 suppresses proliferation and promotes apoptosis in hepatocellular carcinoma by activating endoplasmic reticulum stress.

Cell Oncol (Dordr) 2021 Jun 26. Epub 2021 Jun 26.

The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China.

Purpose: In this study we aimed to assess the anti-tumor effect of co-inhibition of Aurora kinase A (AURKA) and heat shock transcription factor 1 (HSF1) on hepatocellular carcinoma (HCC), as well as to explore the mechanism involved.

Methods: Expression of AURKA and HSF1 in primary HCC tissues and cell lines was detected by immunohistochemistry (IHC), qRT-PCR and Western blotting. AURKA was knocked down in HepG2 and BEL-7402 HCC cells using lentivirus-mediated RNA interference. Next, CCK-8, clone formation, transwell and flow cytometry assays were used to assess their viability, migration, invasion and apoptosis, respectively. The expression of proteins related to cell cycle progression, apoptosis and endoplasmic reticulum stress (ERS) was analyzed using Western blotting. In addition, in vivo tumor growth of HCC cells was assessed using a nude mouse xenograft model, and the resulting tumors were evaluated using HE staining and IHC.

Results: Both AURKA and HSF1 were highly expressed in HCC tissues and cells, while being negatively related to HCC prognosis. Knockdown of AURKA significantly inhibited the colony forming and migrating capacities of HCC cells. In addition, we found that treatment with an AURKA inhibitor (Danusertib) led to marked reductions in the proliferation and migration capacities of the HCC cells, and promoted their apoptosis. Notably, combined inhibition of AURKA and HSF1 induced HCC cell apoptosis, while increasing the expression of ERS-associated proteins, including p-eIF2α, ATF4 and CHOP. Finally, we found that co-inhibition of AURKA and HSF1 elicited an excellent in vivo antitumor effect in a HCC mouse model with a relatively low cytotoxicity.

Conclusions: Combined inhibition of AURKA and HSF1 shows an excellent anti-tumor effect on HCC cells in vitro and in vivo, which may be mediated by ERS. These findings suggest that both AURKA and HSF1 may serve as targets for HCC treatment.
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http://dx.doi.org/10.1007/s13402-021-00617-wDOI Listing
June 2021

Clinical Effects of Stereotactic Body Radiation Therapy Targeting the Primary Tumor of Liver-Only Oligometastatic Pancreatic Cancer.

Front Oncol 2021 27;11:659987. Epub 2021 May 27.

Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Nanjing Medical University, Nanjing, China.

Aim: To investigate the efficacy and safety of stereotactic body radiotherapy (SBRT) targeting the primary tumor for liver-only oligometastatic pancreatic cancer.

Methods: We compared the efficacy and safety of SBRT plus chemotherapy with chemotherapy alone in patients with liver-only oligometastatic pancreatic cancer. The populations were balanced by propensity score-weighted and propensity score-matched analyses based on baseline variables. The primary outcome was overall survival (OS). The secondary outcomes included progression free survival (PFS), local progression, metastatic progression and symptomatic local control.

Results: This is a retrospective study of 89 pancreatic cancer patients with liver-only oligometastasis. Overall, 34 (38.2%) and 55 (61.8%) patients received SBRT plus chemotherapy and chemotherapy alone, respectively. After propensity score matching, 1-year OS rate was 34.0% (95%CI, 17.8-65.1%) in the SBRT plus chemotherapy group and 16.5% (95%CI, 5.9-46.1%) in chemotherapy alone group (P=0.115). The 6-month PFS rate was 29.4% (95%CI, 15.4-56.1) in SBRT plus chemotherapy and 20.6% (95%CI, 8.8-48.6) in chemotherapy alone group (P=0.468), respectively. Further subgroup analysis indicated that the addition of SBRT improved OS in patients with primary tumor located in the head of pancreas (stratified HR, 0.28; 95% CI, 0.09 to 0.90) or good performance status (stratified HR, 0.24; 95% CI, 0.07 to 0.86). In terms of disease control, SBRT delayed local progression of pancreas (P=0.008), but not distant metastatic progression (P=0.56). Besides, SBRT offered significant abdominal/back pain relief (P=0.016) with acceptable toxicities.

Conclusions: The addition of SBRT to chemotherapy in patients with liver-only oligometastatic pancreatic cancer improves the OS of those with primary tumor located in the head of pancreas or good performance status. In addition, it is a safe and effective method for local progression control and local symptomatic palliation in patients with metastatic pancreatic cancer.
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http://dx.doi.org/10.3389/fonc.2021.659987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190391PMC
May 2021

Genetic analysis of rapidly progressing esophageal squamous cell carcinoma: A case report.

Medicine (Baltimore) 2021 Mar;100(9):e24462

Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Jiangsu, China.

Introduction: Numerous investigations have been performed to explore candidate biomarker proteins in esophageal squamous cell carcinoma (ESCC) patients, which could predict the response to chemoradiotherapy (CRT). Here we report a patient with unresectable ESCC who had unsatisfactory effects with radiotherapy, chemotherapy and immunotherapy. We performed genetic analysis in this patient to gain insights about the cause of the rapid progression.

Patient Concerns: A 65-year-old man presented with food obstruction, hoarse voice and choking on drinking water for 2 months, and pain behind the breastbone for 1 month.

Diagnosis: The patient was clinically diagnosed with ESCC and staged as T4N1M1 Stage IV.

Interventions: The patient was treated with CRT and immunotherapy. Mutational analyses through high throughput DNA sequencing methodology (next generation sequencing; NGS) was performed on the patient's blood sample.

Outcomes: The tumor progressed rapidly during the treatment period, and the patient passed away only 3 months from the onset of symptoms.

Conclusion: Although the role of TP53 gene and PIK3CA gene in the progression, treatment and sensitivity of esophageal cancer has been studied, the mechanism of their simultaneous appearance has not been demonstrated in relevant studies. We speculate that the reason for the rapid progression in this patient during active treatment might be related to this. Further studies are needed to validate our observations.
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http://dx.doi.org/10.1097/MD.0000000000024462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939201PMC
March 2021

Outcomes of Stereotactic Body Radiotherapy for Metastatic Colorectal Cancer With Oligometastases, Oligoprogression, or Local Control of Dominant Tumors.

Front Oncol 2020 29;10:595781. Epub 2021 Jan 29.

Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Nanjing Medical University, Nanjing, China.

Aim: To evaluate the clinical outcomes of metastatic colorectal cancer (mCRC) patients with oligometastases, oligoprogression, or local control of dominant tumors after stereotactic body radiotherapy (SBRT) and establish a nomogram model to predict the prognosis for these patients.

Methods And Materials: A cohort of 94 patients with 162 mCRC metastases was treated with SBRT at a single institution. Treatment indications were oligometastases, oligoprogression, and local control of dominant tumors. End points of this study were the outcome in terms of progression-free survival (PFS), overall survival (OS), local progression (LP), and cumulative incidence of starting or changing systemic therapy (SCST). In addition, univariate and multivariable analyses to assess variable associations were performed. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve.

Results: Median PFS were 12.6 months, 6.8 months, and 3.7 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. 0-1 performance status, < 10 ug/L pre-SBRT CEA, and ≤ 2 metastases were significant predictors of higher PFS on multivariate analysis. Median OS were 40.0 months, 26.1 months, and 6.5 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. In the multivariate analysis of the cohort, the independent factors for survival were indication, performance status, pre-SBRT CEA, and PTV, all of which were selected into the nomogram. The calibration curve for probability of survival showed the good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.848.

Conclusions: SBRT for metastases derived from colorectal cancer offered favorable survival and symptom palliation without significant complications. The proposed nomogram could provide individual prediction of OS for patients with mCRC after SBRT.
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http://dx.doi.org/10.3389/fonc.2020.595781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878536PMC
January 2021

Concurrent chemoradiotherapy with raltitrexed and nedaplatin regimen for esophageal squamous cell carcinoma.

Medicine (Baltimore) 2020 Jan;99(4):e18732

Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China.

Background: The aim of the study reported here was to evaluate the feasibility and safety of raltitrexed and nedaplatin with concurrent radiotherapy in patients with unresectable, locally advanced esophageal squamous cell carcinoma (ESCC).

Methods: Eligible patients were adults with newly diagnosed untreated, unresectable esophageal cancer in stages I to IV with lymph node metastases or cervical esophageal cancer. Patients received nedaplatin 25 mg/m per day on day 1-3, raltitrexed 3 mg/m on days 1 repeated every 21 days for 2 cycles, and combined concurrent radiotherapy (2 Gy/fraction, total dose of 60 Gy).

Result: Thirty patients were included with squamous cell carcinoma. The median follow-up duration was 24 months. The overall response rate was 90%. The 1-year and 2-year overall survival rates for all patients were 70.4% and 55.7% with a median survival time of 30 months, and the median progression free survival was 20 month. The major toxicities were leukopenia and thrombopenia, with grade 3 to 4 leukopenia and thrombopenia were 50% and 30% of patients.

Conclusion: Concurrent chemoradiotherapy with raltitrexed and nedaplatin agents frequently caused myelosuppression but was highly active and suggested to be a promising treatment option for locally advanced ESCC.
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http://dx.doi.org/10.1097/MD.0000000000018732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004679PMC
January 2020

Long non-coding RNA ROR promotes radioresistance in hepatocelluar carcinoma cells by acting as a ceRNA for microRNA-145 to regulate RAD18 expression.

Arch Biochem Biophys 2018 05 17;645:117-125. Epub 2018 Mar 17.

Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China; Department of Medical Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu 210002, China. Electronic address:

Radiotherapy plays a limited role in the treatment of hepatocellular carcinoma (HCC) due to the development of resistance. Therefore, further investigation of underlying mechanisms involved in HCC radioresistance is warranted. Increasing evidence shows that long non-coding RNAs (linc-RNAs) are involved in the pathology of various tumors, including HCC. Previously, we have shown that long noncoding RNA regulator of reprogramming (linc-ROR) promotes HCC metastasis via induction of epithelial-mesenchymal transition (EMT). However, the roles of linc-ROR in HCC radioresistance and its possible mechanisms are unclear. Here, we established two radioresistant HCC cell lines (HepG2-R and SMMC-7721-R) and found that linc-ROR was significantly upregulated in radioresistant HCC cells. Knockdown of linc-ROR reduces in vitro and in vivo radiosensitivity of parental HCC cells by reducing DNA repair capacity, while ectopic expression of linc-ROR enhances radiosensitivity of radioresistant HCC cells. Further mechanistic investigations revealed that lincRNA-ROR exerted its biological effects by acting as a competing endogenous RNA (ceRNA) for miR-145 to regulate RAD18 expression, thereby promoting DNA repair. Collectively, our findings demonstrate that linc-ROR promotes HCC radioresistance and targeting it will be a promising strategy for enhancing the efficacy of radiotherapies in HCC.
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http://dx.doi.org/10.1016/j.abb.2018.03.018DOI Listing
May 2018

CXCL14 and NOS1 expression in specimens from patients with stage I-IIIA nonsmall cell lung cancer after curative resection.

Medicine (Baltimore) 2018 Mar;97(10):e0101

Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu Province, China.

Many studies show that CXC chemokine ligand 14 (CXCL14) is highly expressed in tumor-associated stromal cells, promoting tumor cell growth, and invasion. Because of its unclear receptors, CXCL14-initiated intracellular signal cascades remain largely unknown. However, CXCL14 can regulate nitric oxide synthase 1 (NOS1) as its intracellular molecular target. In this paper, we investigated the expression of CXCL14 and NOS1 in specimens from patients with stage I-IIIA nonsmall cell lung cancer (NSCLC) after curative resection, and evaluated the prognostic significance of this gene expression in stromal fibroblasts and cancer cells.Immunohistochemistry was used to detect the expression of CXCL14 and NOS1 in 106 formalin fixed, paraffin-embedded specimens from patients with stage I-IIIA NSCLC. The chi-square test was performed to examine the correlation of CXCL14 and NOS1 expression level with clinicopathological features. The effects of the expression of CXCL14 or NOS1 on progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier and Cox hazard proportional model.The percentages of high CXCL14 expression in stromal fibroblasts and that in cancer cells were 46.2% (49/106) and 23.6% (25/106), respectively. The positive expression rates of NOS1 in cancer cells were 42.5% (45/106). The result indicated that there was a significant positive correlation between CXCL14 expression level in stromal fibroblasts and that in cancer cells (χ = 4.158, P = .041). In addition, the expression of CXCL14 in stromal fibroblasts was significantly correlated with NOS1 expression in cancer cells (χ = 16.156, P < .001). The 5-year PFS rates with low and high CXCL14 expression in stromal fibroblasts were 66.7% and 14.3% (χ = 44.008, P < .001), respectively, and the 5-year OS rates with those were 87.1% and 43.5% (χ = 21.531, P < .001), respectively. The 5-year PFS rates with negative and positive expression of NOS1 in cancer cells were 62.3% and 15.6% (χ = 33.756, P < .001), respectively, and the 5-year OS rates with those were 86.4% and 40.1% (χ = 24.430, P < 0.01), respectively.Both the high expression of CXCL14 in stromal fibroblasts and the positive expression of NOS1 in cancer cells are independent negative predictors of PFS and OS in patients with stage I-IIIA NSCLC after curative resection.
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http://dx.doi.org/10.1097/MD.0000000000010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882435PMC
March 2018

[Ionizing Radiation Reduces TKI Resistance Caused by T790M Mutation in NSCLC Cell Lines].

Zhongguo Fei Ai Za Zhi 2015 Aug;18(8):475-80

Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.

Background And Objective: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), which targets EGFR, plays an important role in non-small cell lung cancer (NSCLC) treatment. Patients with somatic activating mutations in the EGFR gene exhibit significant initial response but eventually develop resistance to TKI. The second mutation (T790M) of the EGFR gene is the possible main cause of drug resistance. The aim of this study is to investigate the effect of ionizing radiation on EGFR-TKI resistance caused by T790M mutation in NSCLC cell lines.

Methods: We selected H1975 and H3255 as research subjects and tested the mutation states by real-time PCR analysis. Radiosensitivity was determined by clone-forming test, and drug resistance was detected in different groups by MTT assay.

Results: H1975 is an EGFR double mutant (L858R plus T790M), whereas H3255 is an EGFR single mutant (L858R). The cell survival fractions of H1975 and H3255 did not vary in different treatment groups (P=0.952). Thus, T790M mutation did not affect the radiosensitivity of NSCLC cell lines. The IC50 of H1975 in the 2.5 Gy group [(0.678; 2±0.373) μmol/L] was statistically significant compared with that in the 0 Gy normal control group [(3.520±0.821) μmol/L] (P=0.008). The drug tolerance of the H1975 cell line by 89.5 dropped to 39.2 times.

Conclusions: Ionizing radiation can reduce TKI resistance caused by T790M mutation in NSCLC cell lines. Our results provide a research basis for future in vivo and clinical studies. Radiotherapy combined with EGFR-TKI treatment can be a promising strategy to overcome T790M-mediated drug resistance.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2015.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000229PMC
August 2015

Effect of miR-18a overexpression on the radiosensitivity of non-small cell lung cancer.

Int J Clin Exp Pathol 2015 1;8(1):643-8. Epub 2015 Jan 1.

Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University Nanjing 210002, Jiangsu Province, China.

The aim of the present study is to investigate whether there is a relationship between miR-18a expression and radiosensitization of non-small-cell lung caner (NSCLC). The relationship between miR-18a expression and clinicopathological characteristics was investigated. To determine whether the miR-18a expression levels were associated with radiotherapeutic efficacy, therapeutic response was evaluated by radiologic Response Evaluation Criteria in Solid Tumors (RECIST). To determine whether miR-18a was required for lung cancer cell radioresistance, A549 cells were treated with different doses of ionizing radiation, following transfection with inhibitor miR-18a or inhibitor NC. We found that the level of miR-18a in NSCLC was strongly correlated with tumor differentiation (P = 0.026), regional lymph node metastasis (P = 0.013) and clinical TNM stage (P = 0.005). According to RECIST, miR-18a expression level was significantly associated with therapeutic response, exhibiting higher expression level in non-responsive patients. Furthermore, the depletion of miR-18a increased A549 cell radiosensitivity. In conclusion, we provide the evidence that down-regulation of miR-18a sensitizes NSCLC to radiation treatment, and it may help to develop a new approach to sensitizing radioresistant lung cancer cells by targeting miR-18a.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348909PMC
December 2015

Treating adrenal tumors in 26 patients with CyberKnife: a mono-institutional experience.

PLoS One 2013 20;8(11):e80654. Epub 2013 Nov 20.

Jinling Hospital, Department of Radiotherapy Center, Nanjing University School of Medicine, Nanjing, China.

Background: CyberKnife (CK) is a novel stereotactic radiosurgery system for treating tumors in any part of the body. It is a non-invasive or minimally invasive tumor treatment modality that can deliver high doses of spatially precise radiation and minimize exposure to neighboring healthy tissues or vital organs. The purpose of this study was to investigate the safety and efficacy of CK in the treatment of adrenal tumors.

Methods And Results: We performed a retrospective analysis of 26 patients with adrenal tumors who had been treated with CK in the radiotherapy center of our hospital between March 2009 and March 2012. Eight patients had primary adrenal tumors and 18 patients had metastatic adrenal tumors. In addition to CK, 4 patients received chemotherapy and 2 patients received immunotherapy. The average tumor volume was 72.1 cm(3) and the prescribed radiation dosage ranged from 30 to 50 Gy and was fractionated 3 to 5 times with a 58% to 80% isodose line. Abdominal CT was performed between 1 to 3 months after the CK treatment to evaluate the short-term efficacy with follow-up examinations once every 3 months. Three patients had complete remission, 12 patients had partial remission, 5 patients had stable disease, and 6 patients had progressive illness. The effective rate of pain relief was 93.8% and the disease control rate was 77% with a median overall survival of 17 months and a median progression-free survival of 14 months. Treatment Related toxicity was well-tolerated, but preventative measure need to be taken for radiation enteritis.

Conclusions: CK is safe and effective for treating adrenal tumors with few adverse reactions. Nonetheless, its long-term effects requires further follow-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835566PMC
December 2014

[Preliminary effect of Cyberknife radiosurgery in the treatment of 31 patients with advanced non-small cell lung cancer].

Zhongguo Fei Ai Za Zhi 2011 Apr;14(4):329-34

Department of Respiratory Disease, Nanjing Clinical school of Southern Medical University, Nanjing General Hospital Of Nanjing Military Command, Nanjing, China.

Background And Objective: Recently, Cyberknife is a new flame-less stereotactic radiation therapy technology, which has several advantages, such as large dose, high precision and minimizing exposure to the surrounding normal tissue or adjacent vital structures, so it is successful in the treatment of non-small cell lung cancer (NSCLC). The aim of this study is to determine the effectiveness and safety of robotic stereotactic radiotherapy-Cyberknife with image guidance and realtime respiratory tracking against clinical stage III-IV peripheral NSCLC.

Methods: A review of treatment details and outcomes for 31 patients, with 34 tumors with histologically proven cancers treated by Cyberknife at the CyberKnife Center of Nanjing general hospital of Nanjing military command between March 2009 and March 2010 is presented. Of the 31 patients, 15 were adenocarcinoma and 12 were squamous cell cancer. Twenty-eight patients received other forms of antineoplastic therapy such as chemotherapy. A total dose of 36 Gy-60 Gy was prescribed to the 65%-85% isodose line and given in two to five fractions in less than 1 week using the CyberKnife radiosurgery system. CT scans were performed after one-two months, then patients were followed every 3 months.

Results: Two patients had complete radiographic responses, 16 patients showed PRs, 7 patients showed SDs. Two patients showed PRs (reduction in tumor size), but developed distant metastases. Response rate was 58% and disease control rate was 81%. All patients tolerated the radiosurgery well, fatigue being the main side effect. No grade 4 or above toxicity was encountered.

Conclusions: In this small cohort of patients with advanced peripheral NSCLC, Cyberknife seems to be a safe and has good therapeutic effects with slight adverse reaction, but long time follow-up is necessary to evaluate the survival data and late toxicity.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2011.04.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999721PMC
April 2011

Enhanced efficiency of thermally targeted taxanes delivery in a human xenograft model of gastric cancer.

J Pharm Sci 2008 Aug;97(8):3170-81

Department of Oncology, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, P.R. China.

Since successful chemotherapy with taxanes requires an improvement in their therapeutic index, especially by the reduction in unwanted systemic toxicity of either drug or adjuvants, we have investigated and are reporting results from an investigation of the use of a novel polymeric thermosensitive micellar delivery system for docetaxel and paclitaxel. Here we reported a novel metastable thermosensitive polymeric micelle for docetaxel and paclitaxel delivery [poly(N-isopropylacrylamide-co-acrylamide)-b-poly(DL-lactide), Poly(IPAAm-co-AAm)-b-PDLLA]. Previous in vitro efficacy studies indicated that, with hyperthermia, docetaxel-loaded micelles showed stronger cytotoxicity to different tumor cell lines than conventional docetaxel formulation while exhibiting slighter toxicity to normal cells. Present in vivo studies indicated that at the same dose level of docetaxel (paclitaxel), hyperthermia greatly enhanced the antitumor effect of micellar docetaxel (paclitaxel) in human gastric BGC mouse xenograft model by showing an extraordinary tumor volume and weight growth percentage inhibition of more than 80%. Meanwhile, acute toxicity tests features the lower LD(50) of the combination of hyperthermia and micellar docetaxel (paclitaxel) compared to that of the control group. The present results suggest that poly(IPAAm-co-AAm)-b-PDLLA micelles could be a clinically useful chemotherapeutic formulation and merit further research to evaluate the feasibility of clinical application.
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http://dx.doi.org/10.1002/jps.21194DOI Listing
August 2008
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