Targeted therapy of Apt-siRNA combining with docetaxel for PSMA-positive prostate cancer and monitoring imaging of 99Tc m-Apt-siRNA / 中华核医学与分子影像杂志

Objective:Apt-A10-3.2 (aptamer of prostate specific membrane antigen (PSMA)) can be used as a specific ligand for early diagnosis and targeted treatment of prostate cancer. Mouse double minute 2 homolog (MDM2) is closely related to the malignancy of prostate cancer, and MDM2 small interfering RNA (siRNA) can silence MDM2 gene through RNA interference. To design a novel chimera of PSMA Apt-MDM2 siRNA and combine it with docetaxel (DTX) to explore a new diagnosis and treatment model combining targeted therapy of PSMA-positive prostate cancer with 99Tc m-chimera imaging monitoring. Methods:Apt-siRNA were obtained by covalent connection of PSMA Apt-A10-3.2 and MDM2 siRNA, which was combined with DTX to treat PSMA-positive prostate cancer cell lines (22RV1 and LNCaP). Cell lines were treated with Apt-siRNA alone or in combination with DTX. The levels of MDM2 and apoptosis-related proteins (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), poly ADP-ribose polymerase (PARP), caspase-3) were detected by Western blot, which were used to evaluate the therapeutic effect. Fifteen BALB/c mice bearing 22RV1 xenografts were treated with PBS, DTX+ Apt-siRNA (200 pmol) and DTX+ Apt-siRNA (400 pmol), respectively. Tumor volume and MDM2 level were observed, and 99Tc m-Apt-siRNA SPECT imaging was performed to obtain the tumor/muscle (T/M) ratio. One-way analysis of variance, Tukey′s test and linear regression analysis were used for data analysis. Results:The levels of MDM2 protein were significantly decreased by Apt-siRNA (0.25±0.02, F=183.40, P<0.001; 0.56±0.03, F=37.15, P<0.001) in 22RV1 and LNCaP cells. After the treatment of Apt-siRNA+ DTX, the levels of Bcl-2 were significantly decreased, and the levels of Bax, PARP and caspase-3 were significantly increased. MDM2 protein level (400 pmol: 0.59±0.12; F=49.99, P=0.023) and tumor volume (400 pmol: (0.22±0.07) cm 3;F=71.30, P=0.039) were significantly inhibited by Apt-siRNA+ DTX in mice bearing 22RV1 xenografts. As for 99Tc m-Apt-siRNA SPECT imaging in vivo, T/M ratio of treatment group was significantly decreased (400 pmol: 2.07±0.22; F=34.99, P=0.022), and there was a linear regression relationship between T/M ratio and the expression level of MDM2 ( R2=0.875, P<0.001). Conclusion:Apt-siRNA combined with DTX can effectively inhibit the progression of prostate cancer, and realize visual targeted diagnosis and treatment of PSMA-positive prostate cancer by coupling radionuclide technetium.

Taxane-induced scleroderma: report of two cases / Esclerodermia inducida por taxanos: informe de dos casos

ABSTRACT Taxanes are a class of chemotherapeutic agents with common associated dermatologic adverse events, such as skin hyperpigmentation, hand-foot skin syndrome, paronychia and onycholysis. Taxane-induced scleroderma is rare. Few cases with skin findings resembling systemic sclerosis, have been reported after the administration of these agents. We report two cases with stage IV breast cancer, aged 66 and 71 years, who developed sclerodermic skin lesions in their extremities after starting treatment with placlitaxel and nabplaclitaxel respectively.

Los taxanos son agentes quimioterapéuticos cuyo uso se asocia a problemas dermatológicos tales como hiperpigmentación, síndrome manos-pies, paroniquia y onicolisis. La esclerodermia inducida por taxanos es rara, con pocos casos informados en la literatura. Informamos los casos de dos pacientes con cáncer de mama en estado IV, de 66 y 71 años, que desarrollaron lesiones esclerodérmicas en las extremidades después de ser tratadas con placlitaxel y nabplaclitaxel, respectivamente.

Prediction of Acquired Taxane Resistance Using a Personalized Pathway-Based Machine Learning Method / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to develop and validate an individualized prediction model for automated detection of acquired taxane resistance (ATR). MATERIALS AND METHODS: Penalized regression, combinedwith an individualized pathway score algorithm,was applied to construct a predictive model using publically available genomic cohorts of ATR and intrinsic taxane resistance (ITR). To develop a model with enhanced generalizability, we merged multiple ATR studies then updated the learning parameter via robust cross-study validation. RESULTS: For internal cross-study validation, the ATR model produced a perfect performance with an overall area under the receiver operating curve (AUROC) of 1.000 with an area under the precision-recall curve (AUPRC) of 1.000, a Brier score of 0.007, a sensitivity and a specificity of 100%. The model showed an excellent performance on two independent blind ATR cohorts (overall AUROC of 0.940, AUPRC of 0.940, a Brier score of 0.127). When we applied our algorithm to two large-scale pharmacogenomic resources for ITR, the Cancer Genome Project (CGP) and the Cancer Cell Line Encyclopedia (CCLE), an overall ITR cross-study AUROC was 0.70, which is a far better accuracy than an almost random level reported by previous studies. Furthermore, this model had a high transferability on blind ATR cohorts with an AUROC of 0.69, suggesting that general predictive features may be at work across both ITR and ATR. CONCLUSION: We successfully constructed a multi-study–derived personalized prediction model for ATR with excellent accuracy, generalizability, and transferability.

The sensitivity change and its mechanism of cervical cancer cells transfected with miR-200b analogues to paclitaxel / 中国医师杂志

Objective To explore the effect of miR-200b on chemosensitivity of cervical cancer HeLa cells to paclitaxel and its mechanism.Methods A recombinant miR-200b mimics was transfected into cultured HeLa cells,which were divided into observation group,negative group,and blank control group.Each group was treated with different concentrations of paclitaxel.Methyl thiazolyl tetrazolium (MTF) assay was performed to evalate the proliferative ability of these treated cells to paclitaxel.AnnexinVFITC/PI method was used to detect the apoptosis rate of Hela cells.The protein level of vascular endothelial growth factor (VEGF) was detected by Western blot.Results MTT assay showed that the OD values of three groups were totally different;and compared to the other two groups,the OD value of the transfected HeLa cells was significantly lower (P ＜ 0.05).Compared to the negative group and the blank control group,there was no statistical difference (P ＞ 0.05).AnnexinV-FITC/PI results demonstrated that the apoptotic index of the transfected HeLa cells was significantly higher than that in the other two groups (P ＜0.05).Western blot assay showed that expression of VEGF protein in three groups of relative quantity was 0.403 ± 0.046,0.882 ± 0.094,and 0.901 0.102,respectively.There was significant difference among there groups (P ＜ 0.05).Conclusions miR-200b mimics can increase the sensitivity of cervical cancer HeLa cells to paclitaxel,and targeted regulation of VEGF may be the cause of increasing in drug sensitivity.

Cep70 drives taxol drug resistance through regulating the acetylation α-tubulin to reduce microtubule stability / 中国医师杂志

Objective To explore the Cep70 by adjusting the stability of acetylated alpha tubulin,participate in breast cancer drug resistance mechanisms.Methods (1) In order to induce taxol drug resistance cell line Michigan cancer foundation-7 (MCF-7)/pac,high-dose shock treatments taxol MCF-7 was used for 6 months,until the cells can grow in 3.5 μmol/L of paclitaxel.(2) The 3-(4,5-dimenthylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) method was used to detect inhibition rate by taxol to MCF-7 and MCF-7/pac cell.(3) Immunofluorescence and Western blot were used to test acetylated alpha-tubulin and Cep70 expression levels in MCF-7 and MCF-7/pac cells.(4) Chemical intervention was used to acetylate apha-tubulin expression,Western blot and polymerase chain reaction (PCR) were used to detect the change of acetylated alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac groups.Flow cytometry and Western blot were used to detect the change of cell cycle.Results (1) IC50 of MCF-7 and MCF-7/pac was 22.47 μ mol/L and 31.38 μmol/L,respectively.(2) Immunofluorescence and Western blot results showed that the expression of acetylation of alpha-tubulin in resistant MCF-7 cell/pac was obviously decreased.(3) Real time polymerase chain reaction (RT-PCR) and Western blot showed Cep70 expression was consistent of acetylation of alpha-tubulin.(4) After incubation with paclitaxel for 24 hours,the expressions of acetylation of alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac were increased,but the extent of MCF-7 cell was much higher.Instead,incubation with nocodazole after 24 hours,the acetylation of alpha-tubulin and Cep70 in MCF-7 and MCF-7/pac cells were obviously lowered.(5) After paclitaxel intervention,compared to the same group MCF-7 cells,the G2 phase ratio in MCF-7/pac cells was lower.In addition,given nocodazole after the intervention,compared to the same group MCF-7 cells,the ratio of G2 phase in MCF-7 cell/pac was significantly decreased.Conclusions Cep70 decreased the expression of the acetylated alpha-tubulin,reduced the stability of microtubules,which could be an important mechanism of taxol drug resistance.

Influence of hyperthermic intraperitoneal perfusion chemotherapy on cellular immune function in esophagogastric junction adenocarcinoma after radical resection / 中华普通外科杂志

Objective To evaluate T lymphocyte changes in esophagogastric junction adenocarcinoma (AEGJ) patients receiving early hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) after radical resection.Methods 98 AEGJ cases were randomized into postoperative early paclitaxel HIPEC group (50 cases) and surgery only group (48 cases).The changes in TLC,CD3 +,CD4 +,CD8 + and CD4 + CD25 + were examined by using flow cytometry on the preoperaive d1,and on the postoperative d 9.Results There were significant differences in cellular ratios of TLC,CD3 +,CD4 +,CD8 + and CD4 + CD25 + between the two groups on postoperative d 9 [(1.85 ± 0.36) × 109/L,(1.28 ± 0.28) ×109/L,t=8.727,P＜0.001;76％ ±6％,65％ ±6％,t =8.680,P＜0.001;57％ ±8％,41％ ± 7％,t =10.246,P ＜0.001:20％ ±7％,25％ ±6％,t =4.037,P ＜0.001;4.2％ ±1.8％;6.7％ ± 2.0％,t =6.548,P ＜ 0.001].Conclusion Postoperative early HIPEC using paclitaxel improves the celluar immune activity of T cell subsets in advanced AEGJ patients.

The therapeutic efficacy of thymidylate synthase on pemetrexed treatment of lung adenocarcinoma / 中国医师杂志

Objective To investigate thymidylate synthase on pemetrexed treatment of lung adenocarcinoma effect relationship.Methods The 60 patients with lung adenocarcinoma in our hospital from January 2014 to January 2016 were selected as the research subjects.They were treated with pemetrexed.According to the clinical efficacy,they were divided into the effective group (n =27) and ineffective group (n =33) after 3 courses of treatment.The levels of thymidylate synthase (thymidylate synthase,TS),TS mRNA expression,and the expression of TS protein in the tumor tissues of two groups were analyzed by enzyme-linked immunoadsorbent assay (ELISA),fluorescence quantitative polymerase chain reaction (PCR),and immunohistochemistry.The relationship between TS level and pemetrexed in the treatment of lung adenocarcinoma was investigated.Results The level of ST in peripheral blood of the effective group was significantly lower than ineffective group.The objective response rate and protein of ST gene low expression were significantly higher than high expression of ST.Conclusions The level of thymidylate synthase in patients with adenocarcinoma of the lung is related to the therapeutic effect of pemetrexed in the treatment of adenocarcinoma of the lung.It can be used as a molecular marker to evaluate the clinical efficacy of pemetrexed in the treatment of patients with lung adenocarcinoma.

Taxane resistance in metastatic breast cancer and novel microtubule-targeting agents / 国际肿瘤学杂志

The development of primary or acquired taxane resistance inevitably becomes to be the main problem.Ixabepilone is effective in metastatic breast cancer (MBC) patients including those heavily pretreated or resistant to taxanes.Eribulin has been used for the treatment of MBC patients who have received at least two prior chemotherapy regimens.New microtubule-targeting agents are promising to be effective options for patients progressing after standard taxane-containing chemotherapy.

Clinical curative effect on non-small cell lung cancer patients by cinobufacini injection combined first-line chemotherapy / 国际肿瘤学杂志

Objective To explore the clinical curative effect on non-small cell lung cancer (NSCLC) patients by cinobufacini injection combined with first-line chemotherapy.Methods Eighty patients with NSCLC from January 2013 to January 2015 in our hospital were selected as the research objects.Then they were divided into the observation group (n =40)and the control group (n =40)by random number tables.The patients in control group accepted docetaxel and cisplatin combination chemotherapy regimens (TP).While the observation group accepted cinobufacini injection on the basis of the control group.Then the local control, adverse reactions and prognosis of the two groups were compared.Results The local control of observation group was 77.5%,while the control group was 62.5%,the local control of observation group was obviously higher than that of the control group (χ2 =5.36,P =0.03).Leucopenia incidence of the observation group was 27.5%,the control group was 50.0%,and the incidence of the observation group was obviously lower than that of the control group (χ2 =4.27,P =0.04).There was no statistically significant difference between the two groups in diarrhea,stomachache,vomiting,tinnitus (17.5% vs.27.5%,χ2 =1.15,P =0.28;25.0% vs.45.0%,χ2 =3.52,P =0.06;5.0% vs.7.5%,χ2 =0.34,P =0.56;7.5% vs.10.0%,χ2 =0.16,P =0.69).There was statistically significant difference between the two groups in median survival time (97 d vs.45 d,HR =8.934,χ2 =9.928,P <0.05).Conclusion The cinobufacini injection combined with docetaxel can effectively reduce the incidence of myelosuppression,and improve survival and local control with high safety,and the clinical effect is remarkable and can improve the prognosis of patients.

Persistent docetaxel-induced supravenous erythematous eruption

AbstractTaxanes are drugs used to treat many types of cancer, including breast and lung cancer. The most common side effects of these drugs are neutropenia and mucositis. Signs of skin toxicity are observed in about 65% of cases and include alopecia, hypersensitivity reactions, persistent supravenous erythematous eruption, nail changes, scleroderma reactions and others. We report two cases of skin reaction to docetaxel and warn that it is not necessary to interrupt the treatment in these cases.

Effect of propofol on docetaxel-induced toxicity to cervical cancer Hela cells transfected with Cx32 plasmid / 中华麻醉学杂志

Objective To evaluate the effect of propofol on docetaxel-induced toxicity to cervical cancer Hela cells transfected with Cx32 plasmid.Methods Cervical cancer Hela cells transfected with Cx32 plasmid were seeded at two different densities and induced to express Cx32 by incubation with doxycycline for 48 h.The cells at high density were seeded at 1 × 105 cells/ml such that the cells would be confluent at the time of docetaxel exposure.The cells at low density were seeded at 500 cells/ml and the cells did not attach at the density.Each type of cells obtained was randomly divided into 5 groups (n =8 each):control group (group C),docetaxel group (group D),docetaxel + intralipid group (group D + I),docetaxel + 18-α-GA group (D + 18-α-GA),and docetaxel +propofol group (group D + P).Groups D,D + I,D + 18-α-GA and D + P were exposed to 5 nmol/L docetaxel,5 nmol/L docetaxel + 10μg/ml intralipid,5 nmol/L docetaxel + 10 μmol/L 18-α-GA,and 5 nmol/L docetaxel +2.8 μg/ml propofol,respectively.18-α-GA,intralipid and propofol were added prior to docetaxel,and the action time for 18-α-GA alone was 1 h and for intralipid or propofol alone 2 h.The time for coaction between the three drugs and docetaxel was 2 h.Cell survival was determined by a standard colony-forming assay.Results The colony formation rate of the cells seeded at high density in group D was significantly lower than that of the cells seeded at low density in group D (P ＜ 0.05).For the cells seeded at high density,the colony formation rate was significantly decreased in the other groups when compared with group C (P ＜ 0.05).The colony formation rate was significantly higher in groups D + 18-α-GA and D + P than in groups D and D + I (P ＜ 0.05).There was no significant difference in the colony formation rate between groups D and D + I (P ＞ 0.05).For the cells seeded at low density,the colony formation rate was significantly decreased in the other groups when compared with group C (P ＜ 0.05) and there was no significant difference in the colony formation rate between D,D + I,D + 18-α-GA and D + P groups (P ＞ 0.05).Conclusion Propofol can attenuate docetaxel-induced toxicity to Hela cells transfected with Cx32 plasmid and inhibition of gap junction function is involved in the mechanism.

Microtubule-Associated Protein Tau, alpha-Tubulin and betaIII-Tubulin Expression in Breast Cancer

BACKGROUND: The microtubule-associated protein Tau binds to both inner and outer surfaces of microtubules, leading to tubulin assembly and microtubule stabilization. The aim of this study was to evaluate the significance of Tau, alpha-tubulin, and betaIII-tubulin expression in breast carcinoma and to assess their relationships with disease progression in the context of taxane treatment. METHODS: Immunohistochemical expressions of Tau, alpha-tubulin, and betaIII-tubulin were assessed in 183 breast cancer cases. Expression was correlated with clinicopathologic parameters, disease progression and overall survival. RESULTS: Tau expression was correlated with lymph node metastasis and estrogen receptor (ER) positivity (p=.003 and p<.001, respectively). Loss of alpha-tubulin was significantly correlated with distant metastasis (p=.034). Loss of betaIII-tubulin was correlated with lymph node metastasis and ER positivity (p=.004 and p<.001, respectively). In taxane-treated cases, Tau expression and loss of alpha-tubulin and betaIII-tubulin expression were related to disease progression (p=.001, p=.028, and p=.030, respectively). Tau expression was associated with a worse survival rate in taxane-treated patients (p=.049). CONCLUSIONS: Tau expression and loss of alpha-tubulin and betaIII-tubulin expression were correlated with aggressive behavior in taxane-treated breast cancer. Further evaluation of Tau, alpha-tubulin and betaIII-tubulin may be useful in predicting clinical behavior and seeking therapeutic measures in taxane-based chemotherapy for breast cancer.

Efeitos colaterais cutâneos de quimioterapia com taxanos: O ponto de vista do dermatologista / Cutaneous adverse reactions to chemotherapy with taxanes: The dermatologist's point of view

Taxanos são drogas quimioterápicas cada vez mais utilizadas no tratamento adjuvante de um grande número de cânceres, principalmente câncer de mama e de pulmão. Os efeitos colaterais não cutâneos mais importantes e limitantes do uso destas drogas são neutropenia e mucosite. Os efeitos colaterais cutäneos, além de muito frequente, interfere de forma importante na qualidade de vida dos doentes. Não existem tratamentos totalmente eficazes, mas algumas orientações podem diminuir os sintomas e prevenir recidivas em novas sessões de quimioterapia.

Chemotherapy with taxanes has recently become part of the treatment for many advanced neoplastic diseases, specially breast and lung cancer. Their main noncutaneous adverse reactions include neutropenia and mucositis, which eventually lead to drug discontinuation. Cutaneous adverse reactions are frequent and significantly interfere with the patient's quality of life. Treatments are poorly effective, but special recommendations may improve symptoms and prevent relapses requiring drug rechallenge.

Thrombospondin-1 and taxol resistance / 国际肿瘤学杂志

Thrombospondin-1 is known as its anti-angjogenic and proapoptotic activities in oncogenesis. In current research, it has a intimate relationship with taxol resistance. Sensitivity of tumor cells to taxol will descend when the expression:of TSP1 is downregulated,and TSP1 downregulation is mediated by a new gene of taxol-resistance gene 1, the discovery provids a new trend to solve taxol resistance.

Biodistribution of samarium-153-EDTMP in rats treated with docetaxel / Biodistribuição de EDTMP-153-samário em ratos tratados com docetaxel

PURPOSE: Many patients with metastatic bone disease have to use radiopharmaceuticals associated with chemotherapy to relieve bone pain. The aim of this study was to assess the influence of docetaxel on the biodistribution of samarium-153-EDTMP in bones and other organs of rats. METHODS: Wistar male rats were randomly allocated into 2 groups of 6 rats each. The DS (docetaxel/samarium) group received docetaxel (15 mg/kg) intraperitoneally in two cycles 11 days apart. The S (samarium/control) group rats were not treated with docetaxel. Nine days after chemotherapy, all the rats were injected with 0.1ml of samarium-153-EDTMP via orbital plexus (25µCi). After 2 hours, the animals were killed and samples of the brain, thyroid, lung, heart, stomach, colon, liver, kidney and both femurs were removed. The percentage radioactivity of each sample ( percent ATI/g) was determined in an automatic gamma-counter (Wizard-1470, Perkin-Elmer, Finland). RESULTS: On the 9th day after the administration of the 2nd chemotherapy cycle, the rats had a significant weight loss (314.50±22.09g) compared (p<0.5) to pre-treatment weight (353.66± 22.8). The percent ATI/g in the samples of rats treated with samarium-153-EDTMP had a significant reduction in the right femur, left femur, kidney, liver and lungs of animals treated with docetaxel, compared to the control rats. CONCLUSION: The combination of docetaxel and samarium-153-EDTMP was associated with a lower response rate in the biodistribution of the radiopharmaceutical to targeted tissues. Further investigation into the impact of docetaxel on biodistribution of samarium-153-EDTMP would complement the findings of this study.

OBJETIVO: Muitos pacientes com metástases ósseas são tratados com radiofármacos associados com quimioterapia para alívio da dor óssea. O objetivo do trabalho foi estudar a influência do docetaxel na biodistribuição do EDTMP-153-samário nos ossos e outros órgãos de ratos. MÉTODOS: Ratos Wistar foram aleatoriamente alocados em 2 grupos de 6 animais cada. O grupo DS (docetaxel/samário) recebeu docetaxel (15 mg/kg) intraperitoneal em dois ciclos com 11 dias de intervalo. Os ratos do grupo S (samário/controle) não foram tratados com docetaxel. Nove dias após a quimioterapia, todos os animais receberam 0,1ml de EDTMP-153-samário via plexo orbital (25µCi). Após 2 horas, os animais foram mortos e feitas biópsias de cérebro, tireóide, pulmão, coração, estômago, cólon, fígado, rim e fêmures. O percentual de radioatividade por grama ( por centoATI/g) de tecido de cada biópsia foi determinado em contador gama automático (Wizard-1470, Perkin-Elmer, Finland). RESULTADOS: No 9º após 2º ciclo de docetaxel os ratos tiveram perda de peso significante, passando de 353,66± 22,8g (controle/pré-tratamento) para 314,50±22,09g (p<0,5). Os por cento ATI/g nos órgãos dos ratos tratados com EDTMP-153-samário e docataxel tiveram redução significante nos fêmures direito e esquerdo, rim, fígado e pulmão, quando comparados com os não tratados com docetaxel. CONCLUSÃO: A combinação de docetaxel com EDTMP-153-samário foi associada com resposta mais baixa na biodistribuição do radiofármaco em órgãos alvo. Futuras investigações sobre o impacto do docetaxel na biodistribuição do EDTMP-153-samário poderão complementar os achados teste estudo.

Research progress on mechanism and premedication regimen of taxanes hypersensitivity reactions / 国际肿瘤学杂志

Hypersensitivity reactions ( HSRs) are the serious problems of taxanes in the clinical appli- cation. These reactions range in severity from mild flushing and itching to bronchospasm, dyspnea and signifi-cant alterations in blood pressure with loss of consciousness or not, and death in some rare cases. Nevertheless, HSRs are often reported only sporadically in clinical trials or as case reports. The vague or inconsistent termi-nology used to describe these reactions may reflect our poor understanding of their pathophysiology. This article will reviews the advancement of taxanes HSRs.