• Toxicological Research
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• 제35권2호
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• pp.201-207
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• 2019

Nanoxel-$PM^{TM}$ (Nanoxel) is a docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA). This newly developed and marketed nanoformulation exhibits an improved pharmacokinetic profile, efficacy, and safety. Although the safety of Nanoxel to docetaxel as well as its bioequivalence must be clinically confirmed, all biological activities have not been examined in in vitro or in vivo studies. Here, the toxicity in a cultured cell system and the effects on blood cells were tested with Nanoxel and docetaxel. The in vitro cytotoxicity of Nanoxel was found to be comparable to or slightly lower than that of docetaxel depending on the concentrations tested or the cell types. Neither docetaxel nor Nanoxel induced erythrocytes hemolysis and produced reactive oxygen species up to $100{\mu}M$. However, Nanoxel was able to enhance the aggregatory response of platelets to collagen, whereas docetaxel attenuated such aggregation in a range of $50-100{\mu}M$, while thrombin-induced aggregation was not affected by either of them. Docetaxel or Nanoxel did not alter basal level of $Ca^{2+}$ and 5-hydroxytryptamine-evoked $Ca^{2+}$ transient in vascular smooth muscle cells. These results suggest that the mPEG-PDLLA micellar formulation alters the toxicological properties of docetaxel, and that extra cautions are needed when evaluating the safety of nanomedicine.

• Journal of Chest Surgery
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• 제39권9호
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• pp.668-673
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• 2006

Taxene 계 화학요법제로서 항암치료에 사용되고 있는 docetaxel 은 폐암을 포함한 다양한 종양에서 효과적인 항암 치료제로 사용되고 있다. Docetaxel 에 의한 폐암세포의 사멸 유도 기전은 정확히 알려져 있지 않으며, 기전을 연구하기 위해 docetaxel로 처리한 NCI-H1703 세포의 세포주기 및 형태적 변화를 유세포측정기, 형광현미경, western blot 분석법을 통하여 확인하였다. 그 결과 docetaxel 은 의미 있게 S기를 감소시키고 G2기를 증가시킴으로써 NCI-H1703 세포의 사멸을 증가시켰다. Docetaxel에 노출되었을 때 caspase-3와 caspase-9의 활성이 증가되었다. 이들 결과를 종합해볼때, docetaxel 은 H1703 의 세포사멸 유도 시 caspase-3 의존성 미토콘드리아 관련 세포사멸기전으로 apoptosis를 일으키는 것으로 생각한다.

• Journal of Pharmaceutical Investigation
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• 제40권2호
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• pp.85-90
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• 2010

Docetaxel-loaded liposomes were prepared by emulsion-solvent evaporation method, then coated with chitosan at room temperature and lyophilized. This system was designed in order to improve solubility and stability of docetaxel in the GI tract for oral drug delivery. The solubilizing effect of some frequently used solubilizers and/or liposome was determined. Among the results docetaxel-loaded liposomes prepared with 0.5% TPGS as a solubilizer showed 100-fold higher solubility than docetaxel. In a stability test, mean particle size of different liposome formulations was measured by a particle size analyzer in simulated gastric fluid (SGF) and in simulated intestinal fluid (SIF). The particle size of uncoated liposomes was significantly increased compared with that of chitosan-coated liposomes in SGF, however, there was no significant difference between coated and uncoated liposome in SIF. It is evident that chitosan-coated liposomes were more stable in GI conditions. The release characteristics of docetaxel-loaded liposomes were also investigated in three buffer solutions (pH 1.2, 4.0, 6.8). Docetaxel release did not occur in pH 1.2 for 4 hrs. However, in pH 4.0 and 6.8 conditions, docetaxel was gradually released over 24 hrs as a sustained release. It seems that aggregation and precipitation of particles by electrostatic interaction might protect docetaxel from being released. In Conclusion, the results from this study show that the chitosan-coated liposomes may be useful in enhancing solubility and GI stability of docetaxel.

• Journal of Pharmaceutical Investigation
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• 제39권1호
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• pp.13-18
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• 2009

Docetaxel is an anticancer agent with low aqueous solubility. More extensive clinical use of this drug is somewhat delayed due to lack of appropriate delivery vehicles. An attempt was made to adopt an o/w emulsion as the drug carrier which incorporated docetaxel in the propyleneglycerol stabilized by a mixed-emulsifier system. A suitable formulation was found in this study: 10 mg/mL docetaxel, 10% (w/v) oil blend, 4% (w/v) PG, 3% (w/v) Solutol HS 15 in 2.25% (w/v) glycerol solution. The formulated emulsion has very good stability when stored at $40^{\cird}C$, and the docetaxel containment efficiency can be maintained above 95% and the mean emulsion diameter around $10{\mu}m$ for at least 3 months. The formulated emulsion is a promising carrier for docetaxel and other lipophilic drugs.

• Tuberculosis and Respiratory Diseases
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• 제66권5호
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• pp.380-384
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• 2009

비소세포폐암의 일차치료로 사용되고 있는 항암치료제인 docetaxel은 세포주기 정체를 통한 세포자멸을 야기하는 약제로 이로 인한 누클리오좀 유리가 약제유발 홍반루푸스의 원인으로 추정되고 있으나 실제 docetaxel로 야기된 아급성 피부 홍반루푸스의 증례는 지금까지 전세계적으로 4명의 증례 보고만이 있을 뿐이며 국내에서는 아직까지 보고된 바가 없다. 저자들은 비소세포폐암 환자에서 docetaxel과 cisplatin 병합 항암 화학요법 도중 발생한 아급성 피부 홍반루푸스 1예를 경험하였기에 이를 보고하는 바이다.

• Asian Pacific Journal of Cancer Prevention
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• 제17권2호
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• pp.697-702
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• 2016

Background: The Asia-Pacific Breast Initiatives (APBI) I and II registries were established to collect safety data for patients with early stage breast cancer receiving adjuvant docetaxel-based regimens in the Asia-Pacific region. Materials and Methods: Data from the two registries were combined to perform a safety analysis. Participants in the registry were women with early stage operable breast cancer with an intermediate or high risk of recurrence. These women received adjuvant chemotherapy that included docetaxel between 2006 and 2011. Adverse events (AEs) were recorded and analyzed. Results: Data were collected from 3,224 patients from 13 countries. The mean dose intensity of docetaxel was 24.1, 22.7, $25.1mg/m^2/week$ among patients receiving docetaxel-based monotherapy, combination therapy and sequential therapy, respectively. Granulocyte colony-stimulating factor (G-CSF) was given with docetaxel to 41.8% of women and 20.6% of women receiving prophylactic antibiotics. Adverse events were reported in 86% of patients (anthracycline-containing regimens vs. non-anthracycline regimens; 87% vs. 80%). The most common adverse events were alopecia, nausea, neutropenia, vomiting, and myalgia. Adverse events NCI CTCAE ${\geq}$Grade 3 were reported in 45.4% of patients. Serious adverse events were reported in 13% of patients, of which 2.5% led to study discontinuation. Forty-six deaths (1.4%) were reported, with no significant difference between regimens. Conclusions: The safety parameters of adjuvant docetaxel therapy used to treat sequential Asian women were comparable to those reported in clinical trials evaluating the role of adjuvant docetaxel. No unusual adverse events linked to Asia-Pacific region patients were observed.

• Asian Pacific Journal of Cancer Prevention
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• 제16권17호
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• pp.7859-7863
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• 2015

Purpose: To compare the efficacy and toxicity of gemcitabine versus docetaxel in a second-line setting of nonsmall cell lung cancer (NSCLC) patients previously treated with platin-based combination chemotherapy. Materials and Methods: We retrospectively evaluated the medical records of 57 patients treated with single agent gemcitabine or docetaxel in second-line setting of advanced NSCLC who received one prior platinum-based therapy. Results: The mean age was $56.7{\pm}8.39$ years with 55 (96.5%) males and two (3.5%) females. Forty of them received docetaxel and 17 gemcitabine. The mean number of chemotherapy cycles was $6.8{\pm}4.0$ in the gemcitabine group, while it was $4.6{\pm}3.0$ in the docetaxel group. Overall response rates were 8% and 12% (P=0.02) for gemcitabine and docetaxel, respectively. The median survival time was 22 versus 21 months for gemcitabine and docetaxel, respectively. The median times to progression were 8 and 5 months. There was no difference between the two groups in terms of incidence of adverse affects (40% vs 47.1%). All of the hematological side effects were grade 1/2. No major toxicity was encountered necessitating stopping the drug for either group. Conclusions: Treatment with gemcitabine demonstrated clinically equivalent efficacy with a significantly improved safety profile compared with those receiving docetaxel in the second-line setting for advanced NSCLC in this study. Based on these results, treatment with gemcitabine should be considered a standard treatment option for second-line NSCLC.

• Annals of Surgical Treatment and Research
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• 제95권5호
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• pp.240-248
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• 2018

Purpose: This study aimed to validate the synergistic effect of ABT-737 on docetaxel using MDA-MB-231, a triple negative breast cancer (TNBC) cell line overexpressing B-cell lymphoma-2 (Bcl-2). Methods: Western blot analysis was performed to assess expression levels of Bcl-2 family proteins and caspase-related molecules. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution was determined by flow cytometry analysis. Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (z-VAD-fmk) was used for pretreatment to assess the role of caspases. Results: Cell viability of MDA-MB-231 after combination treatment with ABT-737 and docetaxel was significantly lower than that after docetaxel or ABT-737 monotherapy based on MTT assay (both P < 0.001), with a combination index of 0.41. The proportion of sub-G1 population after combination treatment was significantly higher than that after docetaxel or ABT-737 monotherapy (P = 0.001, P = 0.003, respectively). Pretreatment with z-VAD-fmk completely restored cell viability of MDA-MB-231 from apoptotic cell death induced by combination therapy (P = 0.001). Although pro-caspase-8 or Bid did not show significant change in expression level, pro-casepase-9 showed significantly decreased expression after combination treatment. Cleaved caspase-3 showed increased expression while poly (ADP-ribose) polymerase cleavage was induced after combination treatment. However, hypoxia-inducible factor 1-alpha and aldehyde dehydrogenase 1 totally lost their expression after combination treatment. Conclusion: Combination of ABT-737 with docetaxel elicits synergistic therapeutic effect on MDA-MB-231, a TNBC cell line overexpressing Bcl-2, mainly by activating the intrinsic pathway of apoptosis. Therefore, adjunct of ABT-737 to docetaxel might be a new therapeutic option to overcome docetaxel resistance of TNBCs overexpressing Bcl-2.

• Tuberculosis and Respiratory Diseases
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• 제75권2호
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• pp.59-66
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• 2013

Background: This study was conducted in order to elucidate the effects of docetaxel on the growth of peroxiredoxin 1 (Prx1) knockdown A549 xenograft tumors and further tested the role of Prx1 as a predictor for how a patient would respond to docetaxel treatment. Methods: Effects of docetaxel on the growth of scrambled- and shPrx1-infected A549 xenograft tumors in nude mice were measured. Moreover, immunohistochemical expression of Prx1 was evaluated in paraffin-embedded tissues from 24 non-small cell lung cancer patients who had received docetaxel-cisplatin regimens as a first-line treatment. Results: Docetaxel treatment in Prx1 knockdown xenograft tumor resulted in reduced tumors growth compared with other groups. Prx1 knockdown increased the production of cleaved caspases-8 and -9 in the control itself compared to scramble tumors. Moreover, docetaxel treatment in Prx1 knockdown tissue led to an increased protein band. Phosphorylated Akt was found in Prx1 scramble tissues. Phosphorylated FOXO1 was detected in the docetaxel treatment group. On the other hand, Prx1 knockdown completely suppressed the Akt-FOXO1 axis. The median progression-free survival (PFS) of patients with low Prx1 expression was 7 months (95% confidence interval [CI], 6.0-7.7), whereas the median progression-free survival of patients with high Prx1 expression was 4 months (95% CI, 4.0-5.0). However, high Prx1 expression was not associated with decreased PFS (p=0.114). Conclusion: Our findings suggest that elevated Prx1 provides resistance to docetaxel treatment through suppression of FOXO1-induced apoptosis in A549 xenograft tumors, but may not be related with the predictive significance for response to docetaxel treatment.

• Tuberculosis and Respiratory Diseases
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• 제82권3호
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• pp.211-216
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• 2019

Background: Docetaxel is one of the standard treatments for advanced non-small cell lung cancer. Docetaxel is usually administered in a 3-week schedule, but there is significant toxicity. In this phase II clinical study, we investigated the efficacy and safety of a 4-weekly schedule of docetaxel monotherapy, as first-line chemotherapy for advanced squamous cell carcinoma in elderly lung cancer patients. Methods: Patients with stage IIIB/ IV lung squamous-cell carcinoma age 70 or older, that had not undergone cytotoxic chemotherapy were enrolled. Patients received docetaxel $25mg/m^2$ on days 1, 8, and 15, every 4 weeks. Primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profiles. Results: A total of 19 patients were enrolled. Among 19 patients, 17 were for evaluated efficacy and safety. In the intent-to-treat population, ORR and disease control rate (DCR) were 11.8% and 47.1%, respectively. In the response evaluable population, ORR was 16.7% and DCR was 66.7%. Median PFS and OS were 3.1 months and 3.3 months, respectively. There were three adverse grade 3/4 events. Grade 1 neutropenia was reported in one patient. Conclusion: Our data failed to demonstrate efficacy of a 4-weekly docetaxel regimen, in elderly patients with a poor performance status. However, incidence of side effects, including neutropenia, was lower than with a 3-week docetaxel regimen, as previously reported.