Advances in influential factor and drug treatment studies for taxane-induced peripheral neuropathy / 中国药房

There are millions of patients with taxane-induced peripheral neuropathy （TIPN）， and there is no effective treatment or prevention measure in clinical practice. The occurrence of TIPN may be related to the dosage form of paclitaxel drugs， genetic and molecular markers， drug dosage and chemotherapy cycle， patient factors， etc. At present， drugs for treating TIPN mainly include those that inhibit axonal degeneration （such as dosazosin， tamsulosin）， prevent mitochondrial dysfunction （such as glutathione trisulfides， antioxidants α -lipoic acid）， improve calcium imbalance in the internal environment （Shaoyao gancao decoction， N-type voltage-gated calcium channel inhibitor IPPQ）， and inhibit neuroinflammation （such as chemokine inhibitors and selective interleukin-8 receptor inhibitors DF2726A）. Further exploration of drug treatment strategies targeting different induction mechanisms is expected to become a new direction for precise clinical prevention and personalized treatment of TIPN.

Probing the new strategy for the oral formulations of taxanes: changing the method with the situation / 中国天然药物

The first-generation taxanes (including paclitaxel and docetaxel) are widely used for the treatment of various cancers in clinical settings. In the past decade, a series of new-generation taxanes have been developed which are effective in the inhibition of tumor resistance. However, intravenous (i.v.) infusion is still the only route of administration, and may result in serious adverse reactions with respect to the utilization of Cremophor EL or Tween-80 as solvent. Besides, the dosing schedule is also limited. Therefore, oral administration of taxanes is urgently needed to avoid the adverse reactionss and increase dosing frequency. In this review, we first outlined the discovery and development of taxane-based anticancer agents. Furthermore, we summarized the research progress on the oral formulations of taxanes and proposed some thoughts on the future development of oral taxane formulations.

Cáncer de mama Triple Negativo / Triple Negative Breast Cancer

El cáncer de mama Triple Negativo ha sido estudiado a lo largo de los años principalmente por ser uno de los de peor pronóstico y, además, por carecer de terapia blanco. El debut de esta patología se puede dar de diversas formas, y es en función de esto que el especialista optará entre distintas medidas: ya sea instaurará tratamiento adyuvante o neoadyuvante o enfrentará directamente la enfermedad metastásica. Si bien muchas veces las terapias a utilizar no se encuentran bien establecidas, las drogas quimioterápicas no difieren de las de los otros subtipos. Pero, al ser tumores que se asocian con mayor frecuencia a mutaciones en el brca, se han investigado tratamientos que apuntan más hacia el defecto de reparación del adn mediante la recombinación homóloga, como son los platinos y los inhibidores del parp. Por otro lado, no se debe dejar de mencionar las terapias dirigidas hacia los distintos subtipos tumorales como, por ejemplo, los antagonistas androgénicos que aún se encuentran en estudio. Sabemos que el cáncer de mama Triple Negativo es una patología extremadamente difícil de tratar, pero todavía quedan en el tintero investigaciones para esclarecer y enfocar las terapias blanco según cada subtipo dentro de estos tumores

Over the years, Triple Negative breast cancers have been studied, mainly because of its poor prognosis but also because it lacks a target therapy. Its debut may occur in different ways, therefore specialists can choose between different measures for treatment. The choices lay between adjuvant or neoadjuvant therapies or to directly face metastatic disease. Although these therapies are not fully established, chemotherapeutic drugs do not differ from other breast cancer subtypes. The association between these tumors and brca mutations is so high, target treatments have been focusing in dna defect repair, through homologous recombination, such as platinum-based chemotherapy and parp inhibitors. Other target therapies should be taken into account, such as androgenic antagonists, which are still being studied. Considering the nature of such an heterogeneous disease, which is extremely difficult to treat, we should acknowledge research in this subject is yet to be clarified to be able to provide new target therapies for each subtype within the triple negative tumors

Advances in strategies of improving solubility and permeability of taxanes / 药学学报

As a new generation of anti-tumor drugs, taxanes has a good clinical efficacy in the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, head and neck cancer. However, low bioavailability of oral administration from low water solubility and low permeability significantly limited the development of their oral applications. Currently, the marketed preparations were non-oral drug preparations, and the injection contained a large number of surfactants (cremophor EL or Tween 80) and organic solvents (ethanol), which could result in fluid retention, hypersensitivity and other side effects, as well as poor compliance. Oral preparation will be an ideal form for development of taxanes medicines. According to the research by our and other groups in recent years, we investigate the technical strategies enhancing the water solubility and absorptive permeability to improve their oral bioavailability. Among them, we emphasize the application prospects of crystallography technology, and provide a theoretical basis to guide future research in the development of oral preparations for taxanes.

Genetic polymorphisms of autophagy-related gene 5 (ATG5) rs473543 predict different disease-free survivals of triple-negative breast cancer patients receiving anthracycline- and/or taxane-based adjuvant chemotherapy / 癌症

BACKGROUND@#Autophagy plays a crucial role in chemotherapy resistance of triple-negative breast cancer (TNBC). Hence, autophagy-related gene 5 (ATG5), an essential molecule involved in autophagy regulation, is presumably associated with recurrence of TNBC. This study was aimed to investigate the potential influence of single-nucleotide polymorphisms in ATG5 on the disease-free survival (DFS) of early-stage TNBC patients treated with anthracycline- and/or taxane-based chemotherapy.@*METHODS@#We genotyped ATG5 SNP rs473543 in a cohort of 316 TNBC patients treated with anthracycline- and/or taxane-based chemotherapy using the sequenom's MassARRAY system. Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to analyze the association between ATG5 rs473543 genotypes and the clinical outcome of TNBC patients.@*RESULTS@#Three genotypes, AA, GA, and GG, were detected in the rs473543 of ATG5 gene. The distribution of ATG5 rs473543 genotypes was significantly different between patients with and without recurrence (P = 0.024). Kaplan-Meier survival analysis showed that patients carrying A allele of ATG5 rs473543 had an increased risk of recurrence and shorter DFS compared with those carrying the variant genotype GG in rs473543 (P = 0.034). In addition, after adjusting for clinical factors, multivariate Cox regression analyses revealed that the AA/GA genotype of rs473543 was an independent predictor for DFS (hazard risk [HR], 1.73; 95% confidence interval [CI], 1.04-2.87; P = 0.034). In addition, DFS was shorter in node-negative patients with the presence of A allele (AA/GA) than in those with the absence of A allele (P = 0.027).@*CONCLUSION@#ATG5 rs473543 genotypes may serve as a potential marker for predicting recurrence of early-stage TNBC patients who received anthracycline-and/or taxane-based regimens as adjuvant chemotherapy.

Comparative analysis on contents of 10-deacetyl-bacratin III, cephalomannine, taxol of Taxus madia from different habitats and growth years / 中草药

Objective To analysis and compare the content differences of three effective components of taxanes of Taxus madia Rehd. from five different habitats and growth years by High Performance Liquid Chromatography (HPLC). Methods The mixed liquor of CH3OH and CHCl3 was used for the ultrasonic extraction of 10-deacetyl-bacratin III (10-DAB III), cephalomannine and taxol before being dissolved by CH3OH to obtain sample solution. By HPLC, the contents of three effective components were performed and compared. Results There were extremely significantly differences (P SM3 > SM2, ZL3 > HK4 > ZL4, ZL3 > SM2 > HK4, HK4 > ZL3 > ZL6, respectively. Except for the contents of 10-DAB III and cephalomannine, there were significant positive correlations among the contents of other components (P < 0.01). The contents of taxol would rise or decline when the total contents of three kinds of taxanes rised or declined among different habitats and growth years. The clustering analysis results showed that the contents of taxol have certain peculiarity. In Fuzhou of Fujian, while the total contents of three kinds of taxanes were different from others in Kaifen of Henan. Conclusion Habitants and growth years have a significant impact on the contents change of three effective components of taxanes from Taxus madia Rehd.. Therefore, regulation and control of biosynthetic pathway by choosing habitat conditions and harvest years should be considered, in order to obtain more crude drug of taxol in T. madia.

Treatment of patients with aortic atherosclerotic disease with paclitaxel-associated lipid nanoparticles

OBJECTIVE: The toxicity of anti-cancer chemotherapeutic agents can be reduced by associating these compounds, such as the anti-proliferative agent paclitaxel, with a cholesterol-rich nanoemulsion (LDE) that mimics the lipid composition of low-density lipoprotein (LDL). When injected into circulation, the LDE concentrates the carried drugs in neoplastic tissues and atherosclerotic lesions. In rabbits, atherosclerotic lesion size was reduced by 65% following LDE-paclitaxel treatment. The current study aimed to test the effectiveness of LDE-paclitaxel on inpatients with aortic atherosclerosis. METHODS: This study tested a 175 mg/m2 body surface area dose of LDE-paclitaxel (intravenous administration, 3/3 weeks for 6 cycles) in patients with aortic atherosclerosis who were aged between 69 and 86 yrs. A control group of 9 untreated patients with aortic atherosclerosis (72-83 yrs) was also observed. RESULTS: The LDE-paclitaxel treatment elicited no important clinical or laboratory toxicities. Images were acquired via multiple detector computer tomography angiography (64-slice scanner) before treatment and at 1-2 months after treatment. The images showed that the mean plaque volume in the aortic artery wall was reduced in 4 of the 8 patients, while in 3 patients it remained unchanged and in one patient it increased. In the control group, images were acquired twice with an interval of 6-8 months. None of the patients in this group exhibited a reduction in plaque volume; in contrast, the plaque volume increased in three patients and remained stable in four patients. During the study period, one death unrelated to the treatment occurred in the LDE-paclitaxel group and one death occurred in the control group. CONCLUSION: Treatment with LDE-paclitaxel was tolerated by patients with cardiovascular disease and showed the potential to reduce atherosclerotic lesion size.

Review on taxanes-induced peripheral neuropathy / 中国生化药物杂志

As a tubulin stabilizer, taxanes are widely used in the treatment of breast cancer, ovarian cancer, non-small-cell lung cancer (NSCLC),and part of head and neck malignant tumors, and were confirmed to be significantly effective.However, taxanes-induced peripheral neuropathy(TIPN) still affects the quality of life and psychological status of patients to varying degrees, severe cases can lead to dose reduction, and even chemotherapy interruption.In this paper, we summarize the pathogenesis, risk factors, clinical assessment, the progress of prevention and treatment of TIPN, to provide the basis for the prediction and early prevention of TIPN in the clinical administration, thus we can improve patients’ quality of life while extending their survival.

Plant derived anticancer agents: A review.

Cancer is a major public health burden in both developed and developing countries. Plant-derived compounds have been an important source of several clinically useful anti-cancer agents including taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, and etoposide derived from epipodophyllotoxin are in clinical use all over the world. About 30 plant derived compounds have been isolated so far and are currently under clinical trials. Cancer chemopreventive agents, many of which are natural products, are capable of preventing or inhibiting the process of carcinogenesis. As with other pharmaceutical agents useful for disease prevention, a pharmacoeconomic analysis of a cancer chemopreventive formulation would need to be considered, and the composition of the formulation should improve over time. A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol, roscovitine, combretastatin A-4 phosphate , betulinic acid and silvestrol are in clinical or preclinical development.

Chemical constituents from seeds of Taxus yunnanensis / 中草药

Objective: To study the chemical constituents from the seeds of Taxus yunnanensis. Methods: The chemical constituents in the seeds of T. yunnanensis were isolated by chromatography and identified by a comprehensive analysis on the spectral data. Results: Twelve taxanes were isolated from the seeds of T. yunnanensis and identified as 7-epi-10-deacetyltaxol (1), 2-deacetoxytaxuspine C (2), 9α-hydroxy-2α, 7α, 10β-triacetoxy-5α-cinnamoyloxy-3, 11-cyclotaxa-4(20)-en-13-one (3), 2α-acetoxy-5α-cinnamoyloxy-9α, 10β-dihydroxy-taxa-4 (20), 11-diene-13-one (4), dantaxusin C (5), taxezopidine H (6), 9-deacetyltaxinine A (7), 5α-decinnamoyltaxagifine (8), taxumairol B (9), 2α, 5α, 13α-trihydroxy-7β, 9α, 10β-triacetoxy-taxa-4(20), 11-diene (10), 7, 9, 10, 13-tetra-O-deacetylabeobaccatin VI (11), and taxacustin (12). Conclusion: Compounds 2, 3, and 7-12 are isolated from T. yunnanensis for the first time.

Clinical study on neoadjuvant chemotherapy for phase II B breast cancer / 中华内分泌外科杂志

Objective To investigate clinical effects of neoadjuvant chemotherapy(NAC)for phase II B breast cancer.Methods From Jan.2002 to Nov.2004,330 female patients with phase II B unilateral breast cancer were enrolled in the study and they were randomly divided into 2 groups.Group A was NAC group and 152 cased were enrolled in this group,among whom 78 cases had left-side cancer and 74 cases had right-side cancer.The mean age of group A was 42.6 years(ranging from 32 to 73 years).Group A were given beth taxane-and anthracycline- based chemotherapy,according to the protocol of group A.After 4 cycles of chemotherapy,patients in group A underwent conservative breast surgery or radical mastectomy according to the result of chemotherapy.Group B,the non-NAC group,had 178 cases in it,among whom 98 had left-side cancer and 80 had rightside cancer.The mean age of group B was 41.4 years(ranging from 31 to 72 years).Group B also underwent conservative breast surgery or radical mastectomy according to tumor size and axillary node status.According to standards of International Union against Cancer(UICC),the primary focus and axillary node status in NAC group were analyzed before and after chemotherapy.Results Group A had a total effective rate of 91.45%.Breast conservation rate in group A and group B was 44.70%and 21.90%respectively.The overall 3 and 5 year survival rate in group A was 96.05%and 75.00%respectively.which was significantly higher than that in group B.Conclusion NAC is effective in reducing clinical stage of phase II B breast cancer,which increases breast conservation rate and postoperative survival rate.

Effect of gemcitabine plus cisplatin in advanced breast cancer with anthracycines and /or taxanes resistance / 中国癌症杂志

Background and purpose:Ever since the use of anthracycine and /or taxanes-based regimen for the adjuvant and/or neoadjuvnat chemotherapy of breast cancer,there have few sensitive agents for advanced breast cancer(ABC)when it occurs drug resistance to anthracycine and /or taxanes.The aim of this study is to evaluate the effect of gemcitabine plus cicplatin in advanced breast cancer after the failure of treatment with anthracycines and /or taxanes.Methods:From May,2005 to Jan 2007,34 ABC cases with anthracycine and/or taxanes resistance were treated with GEM(1000 mg/m2.day1,day8)and DDP(30 mg/m2,day 1 to day 3)every 3 weeks.A median of 5 cycles(2-6 cycles)of the treatment was delivered.All cases were followed up more than 6 months.Results:3 cases(8.8%)had complete response(CR),13 cases(38.2%)had partial response(PR),while 12 cases(35.3%)had stable disease(SD)and progressive disease(PD)was 6 cases(17.7%);the overall response rate was 47.0%.The median time to progression(TTP)was 6.5 months,grade 3/4 diarrhoea and thrombocytopenia were main side effects.Conclusions:GEM plus DDP are effective in the treatment of advanced breast cancer with anthracycine and/or taxanes resistance.

Research development on drug-resistance mechanism of taxanes / 医学研究生学报

Drug resistance is the main restriction factor for clinical usage of taxanes.This review concentrates on drug-resistance mechanisms of taxanes that include drug target change,avidity change between drug-target interaction,decrease of cellular effective drug concentration,downstream cellular responses to a drug target molecular lesion,and cell cycle regulation-mediated drug resistance.