Productions of Taxol and Related Taxanes by Cell Suspension Cultures of Taxus yunnanensis

A high taxol yield cell line of Taxus yunnanensis Cheng et L. K. Fu keeps a high taxol_producing level after successive subcultures for more than eight years. In this study, eight taxanes were isolated from the suspension cell cultures of this cell line. Based on NMR and MS analyses, and comparison with literature data and standards, their structures were determined to be 2α,5α,10β_triacetoxy_14β_propionyloxy_4(20),11_taxadiene (1), 2α,5α,10β_triacetoxy_14β_(2′_methyl)_butyryloxy_4(20),11_taxadiene (2), 2α,5α,10β_14β_tetra_acetoxy_4 (20),11_taxadiene (3, taxuyunnanine C), 2α,5α,10β_triacetoxy_14β_(2′_methyl_3′_hydroxy)_butyryloxy_4(20),11_taxadiene (4, yunnanxane) and its 3′_epimer (5), baccatin Ⅳ (6), baccatin Ⅲ (7) and taxol (8), respectively. Among those compounds, 3, 5, 6 and 7 were reported to be isolated from the suspension cell cultures of T. yunnanensis for the first time. TLC and HPLC analyses indicated that the chemical constituents of the culture solution were similar to those of cultured cells. Moreover, the highest taxol content of this cell line reached 0.3% and the cell line could be applied for a large_scale culture.

Role of taxanes in pancreatic cancer

Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.

NEW TAXANES FROM TAXUS CHINENSIS.2

Tow new taxane diterpenes were isolated from the leaves and stems of Taxus chinensis.Thcir structures were established as 2-deacctyl-5-decinnamatetaxagifine and taxagifinc Ⅲ on the basis of spectroscopic analysis.

YUNNANXOL AND YUNNANXAHINE——TWO NEW TETRACYCLIC TAXANE DITERPENOIDS FROM TAXUS YUNNANENSIS

Two new tetracyclic taxane diterpenoids----yunnanxol(1) and yunnanxamine(2)have been isolated from the bark of Taxus yunnanensis Cheng et L.K.Fu.Their structures have been established from the spectral data,mainly from MS,highfield ~1H NMR,~1H-~1H COSY, ^(13)C NMR,^(13)C-~1H COSY and ^(13)C-~1H COLOC spectroscopies.

TAXAYUNTIN A,B,C AND D----FOUR NEW TETRACYCLIC TAXANES FROM TAXUS YUNNANENSIS

Four new taxane diterpenoids were isolated from the bark of Taxus yunnanensis.Their structures were elucidated as the new skeleton with 5/7/6/4 membered rings by spectral analysis and 2D NMR shift correlation experiments.

TAXAYUNTIN,A NEW TETRACYCLIC TAXANE FROM THE LEAVES OF TAXUS YUNNANENSIS

A new skeleton taxane diterpene,taxayuntin,was isolated from the leaves and stems of Taxus yunnanensis.Its structure was determined by spectroscopic methods(MS,~1H NMR,^(13)C NMR, ~1H-~1H COSY,~1H-^(13)C COSY and ^(13)C-~1H COLOC)and X-ray diffraction.

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer:Intraperitoneal chemotherapy with taxanes

The effect of chemotherapy on peritoneal carcinomatosis(PC) of gastric cancer remains unclear.Recently,the intraperitoneal(IP) administration of taxanes [e.g.,paclitaxel(PTX) and docetaxel(DOC)] during the perioperative period has shown promising results.Herein,we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results.IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h.The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects,making it ideal for IP chemotherapy.There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy(SPIC).In SPIC,patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery(CRS) until disease progression.Usually,a taxane dissolved in 500-1000 m L of saline at ordinary temperature is administered through an IP access port on an outpatient basis.According to phase Ⅰ?studies,the recommended doses(RD) are as follows: IP DOC,45-60 mg/m2; IP PTX [without intravenous(IV) PTX],80 mg/m2; and IP PTX(with IV PTX),20 mg/m2.Phase Ⅱ studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%.A phase Ⅲ study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011.The prognosis of patients who underwent CRS was better than that of those who did not; however,this was partly due to selection bias.Although several phase Ⅱ studies have shown promising results,a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.

Unfavorable Pathological Complete Response Rate of Neoadjuvant Chemotherapy Epirubicin plus Taxanes for Locally Advanced Triple-negative Breast Cancer

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer （TNBC）. Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m^2 plus paclitaxel 175 mg/m^2 or docetaxel 75 mg/m^2 every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response （pCR）, which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival （RFS） and overall survival （OS） were secondary endpoints. Thirty-nine （90.7%） patients were at clinical stages II B-IIIC. Thirty-seven （86%） completed 4-6 cycles of preop- erative chemotherapy, and objective response rate （ORR） was 81.4% （35/43）. Forty-two patients un- derwent radical surgery subsequently. The pCR rate was 14.3% （6/42）. The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting （88.4%, 38/43） and neutropenia （88.4%）. After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally ad- vanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

A Highly Regioselective Deacetylation of Taxanes

A highly regioselective O-deacetylation of taxanes at C-5 position was accomplished by treatment with t-BuOK and a possible mechanism was proposed.

A New Deoxygenation Method for Taxanes Using Hypophosphorous Acid

An efficient and practical radical chain deoxygenation method by phosphorus centered radicals generated from hypophosphorous acid was developed in the synthesis of analogues of paclitaxel.

Clinical Implications of HER-2 and P53 in Taxane-Based and Anthracycline-Based Neoadjuvant Chemotherapy in Breast Cancer

OBJECTIVE To evaluate the predictive value of humanepidermal growth factor receptor-2 (HER-2) and P53 in taxane-based and anthracycline-based neoadjuvant chemotherapy (NAC)in breast cancer.METHODSSixty-two patients with breast cancer wereincluded in this study.Twenty-two patients were treated withtaxane-based (taxane group) and 40 with anthracycline-based(anthracycline group).ER,PR,c-erbB2 and P53 were detected byimmunohistochemistry staining before NAC,and FluorescenceIn Situ Hybridization(FISH) was used to detect the HER-2 geneamplification for the cases with the expression of c-erbB2 proteinas (++) or (+++).The efficacy of the regimens was evaluated afterNAC.RESULTS In the anthracycline group,objective response (OR)was observed in 30 out of 40 patients (75%),whereas no response(NR) was observed in 10 patients (25%).In the taxane group,ORwas observed in 15 patients out of 22 patients (68.2%),whereasNR was observed in 7 patients (31.8%).HER-2-negative status wascorrelated with a high OR in both taxane-based and anthracycline-based NAC (P = 0.023 and P = 0.029),whereas P53-negative statuswas correlated with high OR rate in anthracycline-based NAC (P= 0.041).The significant difference of the CR rates was observedbetween the patients took<4 cycles and>4 cycles NAC (4.65% vs.21.05%,P<0.05).CONCLUSION The patients with HER-2 gene non-amplicationmay be sensitive to both taxane-based and anthracycline-basedchemotherapy;the patients without P53 overexpression maysuitable to select anthracycline-based chemotherapy;and properincreased NAC cycles may increase CR rates.

Weekly taxane-anthracycline combination regimen versus tri-weekly anthracycline-based regimen for the treatment of locally advanced breast cancer:a randomized controlled trial

Background:Extensive studies have confirmed the efficacy of taxanes in combination with anthracycline-based chemotherapy on breast cancer.However,few studies have assessed the efficacy of weekly taxane-anthracycline regimens on locally advanced breast cancer.This study was to compare the efficacy and safety of a weekly taxaneanthracycline regimen with those of tri-weekly anthracycline-based regimen in patients with locally advanced breast cancer.Methods:Patients with locally advanced breast cancer were randomized to receive 4-6 cycles of neoadjuvant chemotherapy with tri-weekly 5-fluorouracil-epirubicin-cyclophosphamide(FEC) regimen or weekly paclitaxel-epirubicin(PE) regimen.The primary endpoint was the pathologic complete response(pCR) rate.Other endpoints included the clinical tumor response,breast-conserving surgery rate,and adverse events.Results:Between March 2010 and September 2013,293 patients were randomized to the FEC(n=151) and PE(n=142) arms.The overall clinical response rate was significantly higher in the PE arm than in the FEC arm(76.06%vs.59.95%,P=0.001).Consistently,the post-chemotherapy pathologic T and N stages were significantly lower in the PE arm than in the FEC arm(P<0.001).However,the pCR rate was similar in the two arms(10.61%vs.12.31%,P=0.665).Overall,36(27.27%) patients in the FEC arm and 6(35.28%) in the PE arm were qualified for breast-conserving surgery.Most adverse events were comparable in both arms,with more severe neutropenia in the PE arm than in the FEC arm(11.97%vs.5.96%,P=0.031).Conclusions:In patients with locally advanced breast cancer,weekly PE was not superior to FEC in terms of pCR.However,weekly PE has a higher response rate and superior down-staging effects.On this account,the PE regimen may be considered an alternative option for locally advanced breast cancer.Long-term follow-up data are needed to confirm the efficacy of this regimen on locally advanced breast cancer.Trial registration Chinese clinical trial registry,ChiCTR-TRC-10001043,September 21。

An Unusual Formation of Cyclic Sulfite at C-4 and C-5 Positions of Taxane

An unusual formation of cyclic sulfite at C-4 and C-5 positions of taxane was accomplished by treatment of compound 1 with excess MeSO2Cl/Et3N and a possible mechanism was proposed.

New Taxane Diterpenoids from Taxus yunnanensis

Three hitherto unknown taxane diterpenoids,namely baccatin Ⅷ(1),baccatin Ⅸ(2),and baccatin Ⅹ(3),along with 10 known analogues were isolated from an ethanolic extract of the twigs and leaves of Taxus yunnanensis.The new structures were characterized based on extensive spectroscopic analysis.Compounds 1 and 2 were tested for their in vitro cytotoxicity against five human tumor cell lines,and 1 exhibited inhibitory effects on HL-60 and MCF-7,with IC_(50) values of 3.44 and 9.67 μM,respectively.

Optic Nerve Metastasis from Breast Carcinoma after Treatment with Taxanes

Introduction: The incidence of ocular metastasis from Breast Carcinoma is only between 5% - 30%, mainly located in choroid, but the location in optic nerve is even more infrequent. We present a rare case that combined both locations sequentially in the same eye. Methods: Case report. Results: A 58-year-old woman with advanced breast cancer was referred with a choroidal metastasis in her right eye which responded well to systemic Taxol and Avastin. Afterwards, she developed an optic nerve metastasis in the same eye when she was under the treatment, so it was changed to Docetaxel. Unfortunately the patient didn’t respond to this treatment and died. Conclusions: Choroidal metastasis secondary to breast cancer generally responds well to radiotherapy. Even so, in cases that a great deterioration of visual acuity is expected after radiation, chemotherapy like taxanes is an alternative to preserve vision with complete tumor regression. Nevertheless, the presentation of a second metastasis in optic nerve can be indicative of inadequate treatment of metastatic disease or complication of the treatment, or both.

Two New Taxane Diterpenoids from Taxus Chinensis

Two new taxane diterpenoids, 2-deacetoxy-7,9-dideacetyltaxinine J (1) and 2-deacetoxytaxinine B (3), were isolated from the barks of Taxus chinensis. Their structures were elucidated by spectroscopic methods.

Pseudocirrhosis after the Use of Taxanes and Bevacizumab in Metastatic Breast Cancer： Case Reports

Currently, multiple lines of cytotoxic chemotherapy for treatment of metastatic breast cancer are available, and Taxanes, used as monotherapy or in combination with anti-angiogenic drugs, such as Bevacizumab, are one of the most used schemes in clinical practice. These drugs have different side effects and the liver is one of the most affected organs. The objective of this paper is to report three cases of metastatic breast cancer with positive expression of hormone receptors and without amplification of HER-2 protein that were treated with Taxane and Bevacizumab, developed pseudocirrosis probably caused by these drugs and died due to liver failure. It can be drawn from the study that liver failure, as a pseudocirrhosis evolution, is an unusual but lethal event that may occur during the treatment of metastatic breast cancer with Taxanes and Bevacizumab. This warns the importance of diagnostic suspicion of this pathology.

Methylated PLK2 is a prognostic biomarker in taxane-treated breast cancers

Background:In search of potential biomarkers of drug responsiveness the tumour suppressor PLK2 has been identified as a mediator of taxane sensitivity in some tumour types,based on its role of G2M checkpoint regulation.Objective:The current study set out to evaluate PLK2 methylation in breast cancer treated with neo-adjuvant chemotherapy including a taxane,as a biomarker of disease progression.Methods:Silencing of PLK2 in MCF-7 cells followed by taxane treatment was assessed using apoptotic readout for proof of principle.DNA was extracted from 64 cases of diagnostic surgical FFPE sections.Using pyrosequencing,levels of PLK2 promoter methylation were measured.Results:Silencing of PLK2 resulted in a significantly reduced apoptotic response following paclitaxel treatment(compared with scramble transfected controls).An association with higher levels of CpG island promoter methylation was seen for those cases with a progression-free survival(PFS)of less than 12 months.Kaplan-Meier analysis showed there was an association between overall survival(OS)and level of methylation(p=.06).Conclusions:Thus,based on data obtained from this pilot study,further larger studies evaluating the utility of PLK2 methylation as a potential predictive biomarker in breast cancer are warranted.

Adjuvant Taxanes in Breast Cancer: A Critical Re-appraisal

Purpose: Several studies have reported a positive impact for taxanes in adjuvant breast cancer (BC) treatment in terms of reduced recurrence and mortality. However the impact of the magnitude on overall survival (OS) remains partially controversial. Methods: We examined the impact of taxane-containing adjuvant therapy for patients with early BC on OS, based on the number of deaths and on the calculated number of patients who need to be treated with taxanes to avoid one death (NNT). We classified patients in three different groups according to whether taxanes were administered concurrently or sequentially, and whether all treatment arms had the same or different duration. Results: 1) Taxanes in combination therapy: 8258 patients (4373 with taxanes and 3885 without taxanes), with 723 OS events. Overall survival for taxane-treated patients was 92.7% versus 89.6% for patients not receiving taxanes. NNT was 33. 2) Sequential treatment of unequal duration in the treatment arms: 14,228 patients (7970 with taxanes and 6256 without). Overall survival in taxane-treated patients was 86% compared with 83.2% for patients not receiving taxanes. NNT was 44. 3) Sequential treatment and similar duration in treatment arms: 9511 women (5093 with taxanes and 4418 without). Overall survival in patients treated with taxanes was 87% versus 85% in patients not receiving taxanes. NNT was 50. When the results of all these trials were considered together, the NNT stands at 43 patients. Conclusion: Taxanes afford a modest increase in overall survival in BC patients regardless of how they are given. Translational trials may well help to improve patient selection in the future.

Concurrent chemoradiotherapy comparison of taxanes and platinum versus 5-fluorouracil and platinum in nasopharyngeal carcinoma treatment

Background Nasopharyngeal carcinoma （NPC） is a squamous-cell carcinoma especially prevailing among the natives of southern China.The regimen of concurrent chemoradiotherapy （CCRT） that include platinum and 5-fluorouracil （5-FU）is considered to be the standard treatment for NPC.However,its clinical use is limited by its toxicity.Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment.Methods Medline,the Cochrane library,and the Chinese medical literature database were searched for eligible studies.Meta-analysis was performed using Review Manager （Version 5.2）.Results Six random controlled trials （RCTs） including 514 patients met our criteria.Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission （CR） and less incidence rate in adverse reactions such as gastrointestinal impairment grades Ⅲll-Ⅳ,liver and kidney impairment grades Ⅰ-Ⅱ,and radiodermatitis grades Ⅲ-Ⅳ versus the conventional regimen of CCRT with 5-FU and platinum,while the long-term effectiveness rate of overall survival,Iocoregional failure-free survival,or distant metastasis failure-free survival between the two groups was therapeutic equivalence.Conclusions The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT.However,we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare,analyze,and confirm the findings.