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Introduction: Breast cancer (BC) is the most diagnosed tumor among women worldwide. The aim of this study was to investigate the incidence and causes of low relative dose intensity (RDI) < 85% for taxane-based chemotherapy regimens used in the treatment of BC in Sultan Qaboos University Hospital (SQUH). Methods: This was a retrospective study that included 303 BC patients, treated with taxane-based chemotherapy protocols at SQUH. RDI was calculated for each chemotherapy regimen and causes and predictors of low RDI < 85% were identified. Prophylactic and therapeutic supportive measures for certain toxicities were studied. Results: 50.8% of the patients had neoadjuvant chemotherapy, 38% had adjuvant chemotherapy, and 11.2% of patients were given palliative treatment. AC-T and AC-THP were the most used regimens (40.3% and 17.2%). Mean RDI of used taxane-based chemotherapy regimens was 93.4%. Dose delays, dose reductions, and treatment discontinuation occurred in 36.6%, 14.8%, and 11.5%, respectively. Thirty-eight patients (12.5%) had low RDI < 85% which was reduced to 9.9% after the use of an alternative taxane. Age and chemotherapy intent were significant risk factors. 83.8% received primary granulocyte colony stimulating factor. Conclusion: An optimal RDI greater than 85% was achieved in most cases. Furthermore, prophylactic and therapeutic supportive measures were widely used. [ABSTRACT FROM AUTHOR]

Aim: To present the characteristics of drug hypersensitivity reactions (DHRs) among taxane recipients with non-small cell lung carcinoma (NSCLC), and to describe the results of rapid drug desensitization (RDD). Methods: A retrospective cross-sectional study included 45 patients who were treated with taxane for NSCLC and were found to be hypersensitive to taxane. All patients were administered the standard 3-bag, 12-step RDD protocol following the development of DHR. RDD success was evaluated separately for each cycle, and successful RDD was defined as the completion of the cycle with application of 12 steps of the desensitization protocol and the absence of early and/or late reactions afterwards. Results: Among 45 patients hypersensitive to taxane 43 (95.6%) successfully received taxane cycles with desensitization. Failed RDD occurred in only 2 (4.4%) patients. The total number of desensitization cycles was 183, of which 181 (98.9%) were successful. The mean age of patients with successful desensitization was 59.42 ± 10.48 years and 37 (86.0%) of them were male. Conclusion: RDD is a reliable procedure that enables effective administration and completion of first-line taxane treatments in taxane-sensitive patients. [ABSTRACT FROM AUTHOR]

Taxanes are one of the most widely used classes of breast cancer (BC) therapeutics. Despite the long history of clinical usage, the molecular mechanisms of their action and cancer resistance are still not fully understood. Here we aimed to identify gene expression and molecular pathway activation biomarkers of BC sensitivity to taxane drugs paclitaxel and docetaxel. We used to our knowledge the biggest collection of clinically annotated publicly available literature BC gene expression data (12 datasets, n = 1250) and the experimental clinical BC cohort (n = 12). Seven literature datasets were used for biomarker discovery (n = 914), and the remaining five literature plus one experimental datasets (n = 336) – for the validation. We totally found 34 genes and 29 molecular pathways which could strongly discriminate good and poor responders to taxane treatments. The biomarker genes and pathways were associated with molecular processes related to formation of mitotic spindle and centromeres, and with the spindle assembly mitotic checkpoint. Furthermore, we created gene expression and pathway activation signatures predicting BC response to taxanes. These signatures were tested on the validation BC cohort and demonstrated strong biomarker potential reflected by mean AUC values of 0.76 and 0.77, respectively, which outperforms previously reported analogs. Taken together, these findings can deepen our understanding of mechanism of action of taxanes and potentially improve personalization of treatment in BC. [ABSTRACT FROM AUTHOR]

Purpose: Taxanes are widely used chemotherapeutic agents that frequently cause nail changes and have a significant impact on patients’ quality of life. Despite the prevalence of taxane-induced nail toxicity, limited data are available regarding evidence-based management strategies for the prevention or treatment of taxane-induced nail changes. Therefore, we aimed to gain insights into the prevention, treatment, and evaluation of nail changes in patients with cancer in Japan by conducting a questionnaire survey of physicians, pharmacists, and nurses involved in oncology treatment. Methods: The questions addressed prophylactic methods, evaluation practices, and treatment approaches for various nail disorders. The questionnaires were distributed on March 1, 2022, with a response deadline of December 1, 2022. Results: Of the 120 questionnaires distributed, 88 (73.3%) were returned, and all of them were analyzed. The respondents included 69 physicians (32 oncologists, 26 breast surgeons, 6 dermatologists, 3 obstetricians/gynecologists, 1 gastroenterological surgeon, and 1 urologist), 9 pharmacists, and 10 nurses. Prophylactic measures included moisturizing (58.0%), protection (42.0%), cooling therapy (37.5%), and cleanliness (33.0%). Approximately 70% of the respondents used the Common Criteria for Adverse Events (CTCAE), while approximately 30% did not use a specific evaluation method. Opinions regarding treatment with antimicrobial or corticosteroid ointments varied; however, all severe cases were referred by dermatologists. Conclusion: Our survey revealed that the management of chemotherapy-induced nail changes varies in clinical practice in Japan. These findings emphasize the need for standardized management strategies and further research. [ABSTRACT FROM AUTHOR]

Drug resistance used in chemotherapy is a common challenge in cancer treatment. The present review of resistance-modulating molecules in cancer recapitulates in vitro, in vivo, and in silico studies of flavonoids, lactones, taxanes, curcuminoids, catechins, and chalcones stand out among others. The main mechanisms of action involve inhibiting the overexpression and function of efflux proteins and altering signaling pathways related to resistance. For their part, the discussed in silico studies identified key interactions between modulating molecules and multidrug resistance (MDR) transporters. This information supports research on synthetic modifications to create new scaffolds for reversing MDR and minimizing toxicity. [ABSTRACT FROM AUTHOR]

Taxanes are kinds of diterpenoids with important bioactivities, such as paclitaxel (taxol®) is an excellent natural broad-spectrum anticancer drug. Attempts to biosynthesize taxanes have made with limited success, mainly due to the bottleneck of the low efficiency catalytic elements. In this study, we developed an artificial synthetic system to produce taxanes from mevalonate (MVA) by coupling biological and chemical methods, which comprises in vitro multi-enzyme catalytic module, chemical catalytic module and yeast cell catalytic module. Through optimizing in vitro multienzyme catalytic system, the yield of taxadiene was increased to 946.7 mg/L from MVA within 8 h and the productivity was 14.2-fold higher than microbial fermentation. By incorporating palladium catalysis, the conversion rate of Taxa-4(20),11(12)-dien-5α-yl acetate (T5α-AC) reached 48 %, effectively addressing the product promiscuity and the low yield rate of T5αOH. Finally, we optimized the expression of T10βOH in yeast resulting in the biosynthesis of Taxa-4(20),11(12)-dien-5α-acetoxy-10β-ol(T5α-AC-10β-ol) at a production of 15.8 mg/L, which displayed more than 2000-fold higher than that produced by co-culture fermentation strategy. These technologies offered a promising new approach for efficient synthesis of taxanes.

Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan–Meier method. Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC.

Background: The management of advanced prostate cancer continues to evolve rapidly, particularly with the earlier use of survival-prolonging therapies in metastatic castration-sensitive prostate cancer (mCSPC). Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, there is little evidence determining the outcomes of taxane chemotherapies as the first subsequent taxane (FST) in mCRPC pts who received docetaxel intensification (DI) in mCSPC. The purpose of this study is to compare outcomes between the survival-prolonging taxanes, docetaxel and cabazitaxel as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 December 2020 were retrospectively reviewed. Pts were considered eligible if they received DI for mCSPC and then received either docetaxel or cabazitaxel in mCRPC. Variables of interest were collected from electronic medical records. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from the FST start date. PSA responses were compared using the chi-squared test, and time-based endpoints were compared using the Kaplan–Meier method. Results: In total, 34 pts were identified: docetaxel = 22 and cabazitaxel = 12 as FST. 91.2% of pts (docetaxel 95.5% vs. cabazitaxel 83.3%) received FST in 2nd line mCRPC. The median age at diagnosis (63.1 vs. 67.1 yrs, p = 0.236) and the median time to CRPC (18.6 vs. 14.2 mos, p = 0.079) were similar for docetaxel and cabazitaxel, respectively. The median time to FST (24.1 vs. 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs. 52.7 mos, p = 0.002) were significantly shorter for pts receiving cabazitaxel vs. docetaxel. PSA responses occurred in 40.9% of pts treated with docetaxel compared to 25.0% treated with cabazitaxel (p = 0.645). There was no significant difference in median PFS (2.7 vs. 3.5 mos, p = 0.727) or median OS (11.4 vs. 8.1 mos, p = 0.132) from the time of FST for pts treated with docetaxel vs. cabazitaxel, respectively. Conclusions: Both docetaxel and cabazitaxel demonstrated activity as FST after DI in mCSPC. Pts who received cabazitaxel had a shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for cabazitaxel in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with docetaxel compared to cabazitaxel. While limited by its retrospective nature and small sample size, this study suggests that docetaxel is active as FST despite treatment with DI in mCSPC. [ABSTRACT FROM AUTHOR]

Introduction: Taxus species contain the anticancer alkaloid paclitaxel, as well as other taxanes similar in structure and potentially in effect to paclitaxel. Tissue-specific distribution patterns and seasonal variations of taxanes in some Taxus species have been reported; however, it is still under-presented for the taxanes in Taxus cuspidata. Methods: The radial distributions of eight taxanes in the transverse surface of freeze-fixed T. cuspidata stems from the late summer and the spring seasons were investigated by cryo-time-of-flight secondary ion mass spectrometry and scanning electron microscopy (cryo-TOF-SIMS/SEM) visualization and liquid chromatography-mass spectrometry (LC-MS) quantitative analysis. By optical microscopic observation, seasonal differences in the amounts and distribution patterns of target taxanes were further characterized in specific tissues. Results and Discussion: The overall amount of taxanes was higher in the late summer than in the spring. Also, taxanes' radial distribution was generally found at higher concentration in the phloem, the cambium and lower level in the periderm, the latest-forming xylem, with different taxanes showing several patterns with distinction between seasons, which were considered related to seasonal plant physiological behaviors. In addition, the distribution of baccatin III (BAC) was investigated at the cellular level, which was regarded in specific cells suggesting its transport in the radial and axial directions in the T. cuspidata stem. Characterizing the microscopic distribution of taxanes in the T. cuspidata stem is expected to play a role in the further study of their biosynthesis and in planta behaviors. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the anticancer taxane profiles of edible and non-edible parts of seven Turkish hazelnut (Corylus avellana L.) genotypes. Hazelnut is one of the healthy foods rich in nutrients and antioxidants. Its regular consumption is associated with a reduced risk of coronary heart disease and cancer. Hazelnut has been described as a plant source that produces taxanes which are widely used in many cancers. Türkiye is a homeland of hazelnut culture and has its own cultivars. Investigation of anticancer taxane profiles in different parts of Turkish hazelnut genotypes is important to show the potential and value of this plant from the perspective of the pharmaceutical and food industries. Materials and Methods: In this study, green leafy covers (GLCs) and hard shells (HSs) (non-edible parts), skinless kernels (SKs), brown-skins (BSs), and brown-skinned kernels (BSKs) (edible parts) of Çakıldak, Sivri, Tombul, Palaz, and Kalınkara as standard and Ham and Sivri Yağlı as local genotypes were used. The five parts of each genotype were ground to powder and eliminated to a size of less than 80 mesh. Each part was extracted using hexane and methanol for 10-deacetylbaccatin III (10-DAB III), baccatin III (BAC III), cephalomannine, and paclitaxel analyses in three replicates. Samples and standards were analyzed by acetonitrile: water gradient method on NOVA Spher 100 Phenyl-Hexyl C18 column inhigh-performance liquid chromatography reverse phase system with 228 nm ultraviolet detector and 1.0 mL/min flow rate. Microsoft Office Excel, 2016, and analysis of variance Jamovi Version 2.3 were used for statistical and data analysis, consecutively. Results: Hazelnut parts differed to a very high degree from each other in terms of the highest amount of 10- DAB III (Ham HSs, 9,15 μg/g), BAC III (Kalınkara BSs, 7.24 μg/g), cephalomannine (Sivri Yağlı BSs, 6.37 μg/g), and paclitaxel (Ham BSKs, 4.36 μg/g) they contained. While HSs, BSKs, and BSs were rich in taxanes in all of the analyzed genotypes, SKs, and GLCs remain limited for anticancer taxanes. Conclusion: This is the first report that revealed the differences in taxane contents of Turkish hazelnuts including previously untested standard and local genotypes and their parts. Significant differences between genotype and hazelnut parts are expected to highlight the health benefits of consuming raw Turkish hazelnut with BSs and their possible use as a functional food. These results add more information to elucidate the bioactive potential of Turkish hazelnuts and their by-products and provide a promising resource for the food and pharmaceutical industry with an anticancer perspective. [ABSTRACT FROM AUTHOR]

Background: Cancer is a critical disease characterized by unhampered progress and metastasis of atypical aberrant cells. In India, cancer is a leading cause of increased mortality, and it is also the cause of 3 million deaths per year. Most of the anti-cancer medications originated from plants, and despite the promising anti-cancer effects of natural medications, researchers have encountered various adverse drug reactions (ADR) related to the drug. Aims and Objectives: The aims and objectives of the study are to analyze the ADR profile of cancer patients treated with microtubule-damaging anti-neoplastic and assess the preventability, severity, and causality of the documented ADR. Materials and Methods: All the cancer patients on treatment regimens containing taxanes undergoing treatment in the medical oncology department were included in this study. All the study participants were monitored for adverse effects, and any ADR reported by the patients that were diagnosed and documented in the case sheet form was recorded in the adverse reaction reporting form. The mean ± standard deviation was performed for continuous variables. Categorical variables were stated in numbers and percentages. Results: A total of sixty study participants with ADR to microtubule-damaging anticancer drugs were registered for the study and among them, 10% were males and 90% were females. The majority of adverse reactions developed in patients between 51 and 60 years of age with female dominance. A total of 114 adverse reactions were reported by the sixty study participants registered in this study, and nevertheless, more than one ADR was noticed in a greater number of patients. Conclusion: Early observation of ADR may help in either modifying the dose or changing the drug that produces adverse reactions so that damage to the organ system can be prevented. [ABSTRACT FROM AUTHOR]

Background: Inetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated. Methods: This prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results: Forty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusion: Neoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment. Trial registration: NCT05749016 (registration date: Nov 01, 2021). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the correlation of ABCB1 gene polymorphism and myelosuppression with taxanes application in breast cancer patients. METHODS: From Oct. 2019 to Dec. 2022, a total of 160 patients diagnosed with breast cancer in Affiliated Taian Central Hospital of Qingdao University were retrospectively analyzed. All patients were treated with a taxanes drug-based regimen. Univariate and Logistic regression were used to analyze the correlation with myelosuppression such as ABCB1 genotype. The correlation was analyzed by using gene stratification. Linkage disequilibrium effect of ABCB1 genotype was analyzed by SHEsis online software. RESULTS: Body mass index, ABCB1 G2677T genotype and molecular subtype had an effect on myelosuppression with significant difference (P< 0. 05). Compared with patients receiving taxanes for injection (albumin-bound), the incidences of moderate-to-severe myelosuppression (P = 0. 03), moderate-to-severe leukopenia(P = 0. 01) and moderate-to-severe neutrophilia (P<0. 05) were lower in liposomes of taxanes for injection; the incidence of myelosuppression in patients with ABCB1 2677TT genotype was higher than those with GT and GG genotypes (P < 0. 05), with statistically significant differences. There was linkage disequilibrium in ABCB1 loci, yet the difference between ABCB1 haplotypes and the occurrence of myelosuppressive in patients was not statistically significant (P> 0. 05). CONCLUSIONS: In patients with breast cancer, clinical assessment of adverse drug reactions of taxanes requires a comprehensive consideration of the patients' genotype and gene-gene interactions, in addition to body mass index, molecular subtype, and type of taxanes. [ABSTRACT FROM AUTHOR]

Purpose: The study investigates cryotherapy's efficacy in mitigating Chemotherapy-induced peripheral neuropathy (CIPN), an adverse effect of chemotherapy that often leads to dosage reduction or treatment discontinuation. Method: The study was registered with PROSPERO (CRD42023428936). A literature search was conducted using the PubMed, Embase, and Cochrane Library databases. Randomized and nonrandomized controlled trials that investigated the effects of cryotherapy on CIPN were included for systematic review and meta-analysis. The primary outcome for prevention was the incidence of CIPN. Results: We identified 17 trials involving 2,851 patients. In total, 11 trials compared the incidence of CIPN between cryotherapy and control groups. Significant differences in the incidence of CIPN at the midpoint and end of chemotherapy were observed, with risk ratios (RRs) of 0.23 (95% confidence interval [CI] = 0.13 to 0.43) and 0.54 (95% CI = 0.33 to 0.88), respectively. Cryotherapy also significantly reduced the incidence of sensory CIPN, with an RR of 0.67 (95% CI = 0.49 to 0.92). Additionally, cryotherapy demonstrated a significant reduction in the incidence of CIPN in patients with gynecological cancers (RR = 0.24, 95% CI = 0.14 to 0.41). Significantly favorable global quality of life scores following chemotherapy (standardized mean difference = 1.43; 95% CI = 0.50 to 2.36) and relieved neuropathic symptoms were found with cryotherapy. Conclusions: Cryotherapy demonstrates a pronounced preventive effect against the development of CIPN, providing substantial symptomatic relief and quality of life improvements for patients undergoing chemotherapy. The administration of cryotherapy through the use of frozen gloves and socks, or continuous-flow cooling systems, optimally initiated 15 min prior to and concluded 15 min following chemotherapy, is recommended for achieving maximum therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background: The mechanisms by which SLC2A1 enhances chemo-resistance of taxanes to non-small cell lung cancer (NSCLC) remains enigmatic. Methods: An investigation into the SLC2A1 expression pattern and prognosis across diverse datasets, as well as our internally collected samples, was undertaken. Additionally, the biological function of SLC2A1 was further delved into through in vitro experiments. The study also examined the chemo-resistance of NSCLC to taxanes using CCK-8, Annexin-V, and caspase-3 assays. Furthermore, the impact of taxanes on SLC2A1 expression was determined via western blot analysis. The effects of SLC2A1 on the formation of CSCs was examined via flow cytometry and metabolomics techniques. Finally, the impact of SLC2A1 on the tumor microenvironment was analyzed using single-cell sequencing and cellchat. Results: In the present investigation, it was observed that there was an elevated expression of SLC2A1 in NSCLC tumor tissues, which exhibited a significant association with a poorer prognosis. SLC2A1 overexpression in vitro promoted NSCLC cell proliferation, invasion, migration, chemo-resistance, and the formation of CD90+ and EpCAM+ CSCs. NSCLC cells were categorized based on SLC2A1 and EpCAM expression. SLC2A1highEpCAM+ CSCs were more chemo-resistance to taxanes. NSCLC patients with high SLC2A1 and EpCAM expression had poorer prognosis. Mechanically, SLC2A1 promoted the formation of CD90+ and EpCAM+ CSCs via activating glycolysis. Finally, SLC2A1low tumor cells promoted CD8+ T cell function via HLA-A, B, C, and suppressed NK cell function via HLA-E. Conclusion: Together, SLC2A1 plays an important role in enhancing chemo-resistance of taxanes to NSCLC.

Abstract Alternaria alternata fungus is a potent paclitaxel producer isolated from Corylus avellana. The major challenge is the lack of optimized media for endophytic fungi productivity. In the effort to maximize the production of taxoids by A. alternata, several fermentation conditions, including pH (pH 4.0–7.0), different types and concentrations of carbon (fructose, glucose, sucrose, mannitol, sorbitol, and malt extract), and nitrogen (urea, ammonium nitrate, potassium nitrate, ammonium phosphate, and ammonium sulfate) were applied step by step. Based on the results, A. alternata in a medium containing sucrose 5% (w/v) and ammonium phosphate 2.5 mM at pH 6.0 showed a rapid and sustainable growth rate, the highest paclitaxel yield (94.8 µg gFW−1 vs 2.8 µg gFW−1 in controls), and the maximum content of amino acids. Additionally, the effect of pectin was evaluated on fungus, and mycelia harvested. Pectin significantly enhanced the growth and taxoid yield on day 21 (respectively 171% and 116% of their corresponding on day 7). The results were checked out by mathematical modeling as well. Accordingly, these findings suggest a low-cost, eco-friendly, and easy-to-produce approach with excellent biotechnological potential for the industrial manufacture of taxoids.

Abstract The variability in response to conventional prostate cancer (PC) therapies, coupled with the emergent issue of drug resistance, underscores the critical need for innovative treatment strategies. Aerobic physical exercise reduced incidence of several cancers, but the mechanism underlying these effects associated the nanoemulsion not fully understood. The application of a lipid nanoemulsion (LDE) delivery system for docetaxel (DTX), showing marked enhancement in therapeutic efficacy when combined with aerobic physical exercise. This novel intervention potentiates the antitumor activity of LDE-delivered DTX by augmenting nanoparticle internalization and inducing cell cycle arrest. Our findings reveal that this synergistic treatment not only significantly reduces prostate weight and mitigates adenocarcinoma proliferation but also attenuates anti-apoptotic BCL-2 protein expression. Concurrently, it elevates pro-apoptotic proteins and diminishes inflammatory markers. Metabolic profiling of the combined therapy group disclosed additional benefits, such as reduced lipid and plasma glucose levels. Collectively, our data illuminate the profound impact of integrating LDE-mediated DTX delivery with structured physical exercise, which together spearhead a dual-front assault on PC. This multimodal approach heralds a new paradigm in PC management, accentuating the promise of combined pharmacological and non-pharmacological interventions to elevate tumor suppressor protein activity and refine patient outcomes.

Background: Adenocarcinoma of the lung is the most common type of lung cancer. Platinum agents in combination with other chemotherapy are currently the cornerstone for chemotherapy of advanced cases with metastasis. Objective: To compare the response rate of pemetrexed doublets versus taxanes doublets in patients with metastatic lung adenocarcinoma. Patients and Methods: This a prospective study that included 60 patients with pulmonary adenocarcinoma. Those patients received a platinum based doublet chemotherapy with additional treatment protocol; combined with either pemetrexed or taxanes (paclitaxel or docetaxel) with 30 patients in each arm. Tumor size, response rate and side effects of chemotherapy were evaluated in both arms. Results: The median reduction in tumor size in pemetrexed and taxan arms were 4.72 cm2 and 6.53 cm2 respectively. Nausea, fatigue, constipation and anorexia were more common in pemetrexed arm, while leukopenia, arthralgia and peripheral neuropathy were more common in taxan arm. Conclusion: Serious side effects such as leukopenia, and peripheral neuropathy were more common in taxan than pemetrexed arm. Pemetrexed is preferable to use as a fist line treatment for patients with metastatic adenocarcinoma of the lung. [ABSTRACT FROM AUTHOR]

Background: Squamous-cell carcinoma (SCC) of the lung is a kind of non-small-cell lung carcinoma. Cytotoxic chemotherapy has been found to deliver benefits to patients in advanced disease settings. Objective: To compare response rate and side effects between first-line chemotherapies vinorelbine, gemcitabine, and taxanes in patients with metastatic SCC of the lung. Patients and Methods: This is a retrospective study including 45 patients with metastatic lung SCC. All patients had received platinum-based doublet chemotherapy for 4-6 cycles. Patients were allocated into three groups based on the additional treatment protocol, with fifteen patients per group. A reduction in tumor size was assessed from tumor measurements for patients who had at least two evaluable assessments with computed tomography. The side effects of each drug were evaluated. Results: The reduction in tumor size in the gemcitabine, taxan, and vinorelbine arms was -5.59±35.62 cm3, 1.3±39.98 cm3 and -10.55±14.62 cm3, respectively, with no significant differences. The response rates in the taxan, gemcitabine, and vinorelbine arms were 73.33%, 80%, and 86.67%, respectively, with no significant differences. The side effects, including nausea, alopecia, diarrhea, arthralgia, and peripheral neuropathy, were, in particular, more common in patients in the taxan arm than in other arms, with significant differences. Conclusion: The three therapeutic arms, vinorelbine, gemcitabine, and taxanes, had similar efficiency based on response rate, with a mild preponderance of vinorelbine. [ABSTRACT FROM AUTHOR]

The treatment landscape of non-small cell lung cancer (NSCLC) has seen significant advancements in recent years, marked by a shift toward target agents and immune checkpoint inhibitors (ICIs). However, chemotherapy remains a cornerstone of treatment, alone or in combination. Microtubule-targeting agents, such as taxanes and vinca alkaloids, play a crucial role in clinical practice in both early and advanced settings in NSCLC. This review outlines the mechanisms of action, present significance, and prospective advancements of microtubule-targeting agents (MTAs), with a special highlight on new combinations in phase 3 trials. The online databases PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'Microtubule-targeting agents' and 'non-small cell lung cancer' or synonyms, with a special focus over the last 5 years of publications. Despite the emergence of immunotherapy, MTA remains crucial, often used alongside or after immunotherapy, especially in squamous cell lung cancer. Next-generation sequencing expands treatment options, but reliable biomarkers for immunotherapy are lacking. While antibody-drug conjugates (ADCs) show promise, managing toxicities remain vital. In the early stages, MTAs, possibly with ICIs, are standard, while ADCs may replace traditional chemotherapy in the advanced stages. Nevertheless, MTAs remain essential in subsequent lines or for patients with contraindications. [ABSTRACT FROM AUTHOR]

Background: This prospective real‐world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China. Patients and Methods: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo−/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m2) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression‐free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed. Results: One hundred and thirty‐four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3–15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first‐ or second‐line treatment was significantly better than those who received eribulin as ≥3‐line treatment (6.9 months [95% CI: 3.2–8.8] vs. 4.0 months [95% CI: 3.4–4.6], p = 0.006). The mPFS of patients with triple‐negative, HER2‐positive, and HER2(−)/HR(+) was 3.4 (95% CI: 2.7–4.1), 6.2 (95% CI: 2.3–10.1) and 5.0 months (95% CI: 4.1–5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6–6.3] vs. 4.0 months [95% CI: 3.3–4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non‐TNBC receiving eribulin as ≤2‐line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment‐related adverse events. Conclusion: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real‐world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials. [ABSTRACT FROM AUTHOR]

A taxane 2‐O‐benzoyltransferase (mTBT, derived from Accession: AF297618) biocatalyzed the dearoylation and rearoylation of next‐generation taxane precursors of drugs effective against multidrug‐resistant cancer cells. Various taxanes bearing an acyl, hydroxyl, or oxo group at C13 were screened to assess their turnover by mTBT catalysis. The 13‐oxotaxanes were the most productive, where 2‐O‐debenzoylation of 13‐oxobaccatin III was turned over faster compared to 13‐oxo‐10‐O‐(n‐propanoyl)‐10‐O‐deacetylbaccatin III and 13‐oxo‐10‐O‐(cyclopropane carbonyl)‐10‐O‐deacetylbaccatin III, yielding ~20 mg of each. mTBT catalysis was likely affected by an intramolecular hydrogen bond with the C13−hydroxyl. Oxidation to the 13‐oxo recovered catalysis. The experimental data for the debenzoylation reaction was supported by Gaussian‐accelerated molecular dynamics simulations that evaluated the conformational changes caused by different functional groups at C13 of the substrate. These findings also helped postulate where the 2‐O‐benzoylation reaction occurs on the paclitaxel pathway in nature. mTBT rearoylated the debenzoylated 13‐oxobaccatin III acceptors fastest with a non‐natural 3‐fluorobenzoyl CoA among the other aroyl CoA thioesters evaluated, yielding ~10 mg of each with excellent regioselectivity at laboratory scale. Reducing the 13‐oxo group to a hydroxyl yielded key modified baccatin III precursors (~10 mg at laboratory scale) of new‐generation taxoids. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets. [ABSTRACT FROM AUTHOR]

Purpose: Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies. Methods: This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays. Results: Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC50 profile of ABT-751 was higher than the taxanes docetaxel and paclitaxel in the melanoma cell line panel, but fell within clinically achievable parameters. ABT-751 IC50 was not impacted by P-gp-overexpression in DKLP-A cells, which display strong resistance to the P-gp substrate taxanes compared to DLKP parental controls. The addition of ABT-751 to paclitaxel treatment significantly decreased cell proliferation, suggesting some reversal of MDR. ATPase activity assays suggest that ABT-751 is a potential BCRP substrate, with the ability to inhibit P-gp ATPase activity. Conclusion: Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma. [ABSTRACT FROM AUTHOR]

The variability in response to conventional prostate cancer (PC) therapies, coupled with the emergent issue of drug resistance, underscores the critical need for innovative treatment strategies. Aerobic physical exercise reduced incidence of several cancers, but the mechanism underlying these effects associated the nanoemulsion not fully understood. The application of a lipid nanoemulsion (LDE) delivery system for docetaxel (DTX), showing marked enhancement in therapeutic efficacy when combined with aerobic physical exercise. This novel intervention potentiates the antitumor activity of LDE-delivered DTX by augmenting nanoparticle internalization and inducing cell cycle arrest. Our findings reveal that this synergistic treatment not only significantly reduces prostate weight and mitigates adenocarcinoma proliferation but also attenuates anti-apoptotic BCL-2 protein expression. Concurrently, it elevates pro-apoptotic proteins and diminishes inflammatory markers. Metabolic profiling of the combined therapy group disclosed additional benefits, such as reduced lipid and plasma glucose levels. Collectively, our data illuminate the profound impact of integrating LDE-mediated DTX delivery with structured physical exercise, which together spearhead a dual-front assault on PC. This multimodal approach heralds a new paradigm in PC management, accentuating the promise of combined pharmacological and non-pharmacological interventions to elevate tumor suppressor protein activity and refine patient outcomes. [ABSTRACT FROM AUTHOR]

The efficacy of taxane-containing regimens has been demonstrated for various cancers, particularly ovarian, endometrial, breast, lung, and prostate cancers. However, extensive taxane-induced toxicities limit their use. Prediction and management of many toxic complications in cancer patients have evolved significantly over the last decade. Peripheral neuropathy is the most typical non-hematological taxane-related complication, and it has a multifactorial pathogenesis. It is often dose-dependent and progressive during therapy and sometimes even after treatment. Unfortunately, the prediction of these common adverse events remains unclear. In the past few years, several polymorphisms of candidate genes with a possible role in the development of this consequence were studied. This minireview aims to highlight the critical yet underappreciated roles of genetic predictors that may increase susceptibility to taxane-induced peripheral neuropathy in cancer patients (Ref. 40). [ABSTRACT FROM AUTHOR]

The advent of taxane-based chemotherapy has revolutionized breast cancer care. This advance has helped improve the response to downstaging tumors that might otherwise be inoperable. It has also helped in rendering clinically (cN+) positive lymph nodes (LNs) pathologically negative (ypN0). The standard of care for cN+ patients included post-mastectomy radiotherapy (PMRT), regardless of the response to neoadjuvant chemotherapy. However, PMRT in patients with 1-3 positive LNs still lacks definitive guidelines. Numerous retrospective results have been inconclusive about the benefit of PMRT on survival in patients with 1-3 positive LNs. This pooled analysis attempts to reach a consensus. The PubMed database was searched through October 2023. The search yielded 27 papers, of which 11 satisfied the inclusion criteria. The locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) for each study were tabulated when given, and two groups were created, the PMRT and NO PMRT, respectively. The results were then pooled for analysis. The total number of patients was 8340, 4136 in the PMRT group, and 4204 in the NO PMRT group, respectively. The LRRFS, DFS, and OS were 96.9%, 82.1%, and 87.3% for the PMRT group and 93.2%, 79.6%, and 84.8% for the NO PMRT group, respectively. There was no statistical significance in LRRFS, DFS, or OS between the two groups (p = 0.61, p = 0.61, and p = 0.38, respectively). PMRT does not seem to confer survival benefits in patients with pN1 rendered ypN0 for stages T1-3. This pooled analysis's findings should be confirmed prospectively with a longer period of follow-up. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the course of arm swelling caused by the use of taxanes and to identify valid predictors of persistent swelling. Methods and Results: A total of 15 patients with unilateral arm swelling that developed during the course, or within 3 months after termination, of postoperative taxane-based chemotherapy were included in the present study. The patients attended follow-up appointments every 3–6 months for 24 months after their initial visit. Their arm circumference was measured at each follow-up appointment, while ultrasonography of the skin and subcutaneous tissues was performed at the 0-, 6-, 12-, and 24-month follow-ups. Of the 15 patients, 12 (80%) saw their taxane-induced arm swelling resolved within a median of 12 months (range, 3–29 months) after their final taxane administration. Of the 12 patients whose swelling resolved, 9 did not use compression sleeves; however, their course of resolution did not differ from the other 3 patients who regularly used compression sleeves. In the three patients with persistent swelling, the excess subcutaneous thickness in the medial upper arm (median, 283%) was significantly greater than that in the patients whose swelling resolved (120%; p < 0.05) during their initial visits. Conclusions: Of the 15 patients included in the present study, 80% saw their taxane-induced arm swelling resolve within a median of 12 months after their final taxane administration, independent of the use of compression therapy. Persistent swelling may be predicted during the initial visit based on subcutaneous thickening of the medial upper arm. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is a lethal gynecologic cancer in industrialized countries. Treatments for OC include the surgical removal and chemotherapy. In the last decades, improvements have been made in the surgery technologies, drug combinations and administration protocols, and in diagnosis. However, mortality from OC is still high owing to recurrences and insurgence of drug resistance. Accordingly, it is urgent the development of novel agents capable to effectively target OC. In this respect, tyrosine kinase inhibitors (TKIs) may play an important role. Most of TKIs developed and tested so far are organic. However, owing to their chemical versatility, also metals can be exploited to design selective and potent TKIs. We provide a short and easy-to-read overview on the main organic TKIs with a summary of those that entered clinical trials. Additionally, we describe the potential of metal-based TKIs, focusing on this overlooked family of compounds that may significantly contribute towards the concept of precision-medicine. [ABSTRACT FROM AUTHOR]

IntroductionTaxus species contain the anticancer alkaloid paclitaxel, as well as other taxanes similar in structure and potentially in effect to paclitaxel. Tissue-specific distribution patterns and seasonal variations of taxanes in some Taxus species have been reported; however, it is still under-presented for the taxanes in Taxus cuspidata.MethodsThe radial distributions of eight taxanes in the transverse surface of freeze-fixed T. cuspidata stems from the late summer and the spring seasons were investigated by cryo-time-of-flight secondary ion mass spectrometry and scanning electron microscopy (cryo-TOF-SIMS/SEM) visualization and liquid chromatography-mass spectrometry (LC-MS) quantitative analysis. By optical microscopic observation, seasonal differences in the amounts and distribution patterns of target taxanes were further characterized in specific tissues.Results and DiscussionThe overall amount of taxanes was higher in the late summer than in the spring. Also, taxanes’ radial distribution was generally found at higher concentration in the phloem, the cambium and lower level in the periderm, the latest-forming xylem, with different taxanes showing several patterns with distinction between seasons, which were considered related to seasonal plant physiological behaviors. In addition, the distribution of baccatin III (BAC) was investigated at the cellular level, which was regarded in specific cells suggesting its transport in the radial and axial directions in the T. cuspidata stem. Characterizing the microscopic distribution of taxanes in the T. cuspidata stem is expected to play a role in the further study of their biosynthesis and in planta behaviors.

Abstract Background Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) – the most aggressive BC form – is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients’ response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. Methods Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. Results This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. Conclusions Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles’ heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.

Abstract Background Breast cancer patients are commonly treated with sequential administrations of epirubicin–cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. Methods Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. Results Decrease in muscle fibres cross‐sectional area was only observed post‐EC (−25%; P

Abstract Background The use of taxanes following the first trimester of pregnancy is endorsed by current clinical guidelines. However, evidence regarding their safety in terms of obstetric and neonatal outcomes is limited. Methods A comprehensive literature search was performed using the MEDLINE, CENTRAL and Web of Sciences databases from their inception up to 12/16/2022. Eligibility criteria included gestational taxane use, presentation of original findings, and individual case data presented. A descriptive statistical analysis was undertaken. Results A total of 159 patients treated with taxane-containing regimens during pregnancy were identified, resulting in 162 fetuses exposed in utero. The majority of patients had breast cancer (n = 88; 55.3%) or cervical cancer (n = 45; 28.3%). The most commonly employed taxane was paclitaxel (n = 131; 82.4%). A total of 111 (69.8%) patients were also treated with other cytotoxic drugs during pregnancy, including platinum salts (n = 70; 63.0%) and doxorubicin/cyclophosphamide (n = 20; 18.0%). While most patients received taxanes during the second trimester of pregnancy (n = 79; 70.0%), two were exposed to taxanes in the first trimester. Obstetric outcomes were reported in 105 (66.0%) cases, with the most frequent adverse events being preterm contractions or premature rupture of membranes (n = 12; 11.4%), pre-eclampsia/HELLP syndrome (n = 6; 5.7%), and oligohydramnios/anhydramnios (n = 6; 5.7%). All cases with pregnancy outcome available resulted in live births (n = 132). Overall, 72 (54.5%) neonates were delivered preterm, 40 (30.3%) were classified as small for gestational age (SGA), and 2 (1.5%) had an Apgar score of

Currently, clinical biomarkers are urgently needed to improve patient management to guide personal therapy for cancer. In this study, we investigate the deregulation of Zeb-1 in prostate cancer (PC) Tunisian patients. Expression patterns of the Zeb-1 were investigated in prostate adenocarcinoma and benign prostate biopsies using quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt method. Statistical analysis was used to identify differences across groups depending on gene expression level. Furthermore, we exploited a follow-up over 15 years to correlate Zeb-1 deregulation and clinical outcomes in PC patients. Based on ROC curve analyses, the AUC was found in discriminating PC patients from controls (AUC = 0.757; p < 0.001). In addition, the higher expression level was significantly associated with PSA, Digital Rectal Examination, Gleason score, tumor stage, and distant lymph node metastases. Moreover, Zeb-1 overexpression was correlated with shorter overall survival (OS) (p = 0.042), poor progression-free survival (PFS) (p = 0.007), and with resistance to taxanes (p = 0.012). Our data provide the aberrant expression of Zeb-1 in PC patients suggesting its potential diagnostic, prognostic, and theranostic role. Further functional studies are mandatory to strengthen these results and to uncover the molecular mechanism of this neoplasm. [ABSTRACT FROM AUTHOR]

Background: To date, the number of prostate cancer ranked first among newly diagnosed malignant tumors in men from multiple countries. Localized prostate cancer could be controlled by curative therapy. However, for patients with metastatic prostate cancer (mPC), the prognosis is poor. As among first-line treatments of systemic therapies for mPC, docetaxel and androgen receptor (AR)-targeted therapies have been widely used. However, mPC patients inevitably developed resistance to the current therapy. More importantly, there is a cross-resistance between docetaxel-based chemotherapy and AR-targeting therapy during the treatment process, which could impair the overall survival benefits without proper administration. Objective: Therefore, it is urgent to elucidate the mechanism of cross-resistance and explore the optimal sequential strategy. Methods: Here, in this review, we systematically reviewed and summarised the updated literature on clinical evidence and mechanistic research of treatment resistance in mPC. Results: Emerging evidence indicated that AR splice variants, AR overexpression or mutations, AR nuclear translocation, as well as AR signaling reactivation collectively contributed to the cross-resistance. With the current understanding of cross-resistance, multiple solutions are promising for improving the benefits, including refining the sequencing of available therapies for mPC, in combination with potential targeted inhibitors or immune checkpoint inhibitors. Further studies are needed to explore the combination of emerging strategies and eventually control the progression of prostate cancer. Conclusions: This review defined the mutual and unique resistant mechanism of these treatments, which might help to focus and accelerate therapeutic research that may ultimately improve clinical outcomes for patients with prostate cancer. Level of evidence: Not applicable [ABSTRACT FROM AUTHOR]

Introduction: The programmed death-1 (PD-1) immune checkpoint inhibitor pembrolizumab is currently approved in the US for the first-line (1L) treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), either alone or in combination with platinum and 5-fluorouracil (5-FU). However, the toxicity of 5-FU has motivated the study of alternate combinations that replace 5-FU with a taxane. The objective of the current study was to describe the baseline characteristics, treatment patterns and sequences, and real-world outcomes of individuals receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC in the US. Methods: This was a retrospective study of US adults ≥18 years of age receiving pembrolizumab + platinum + taxane as 1L treatment for R/M HNSCC, using electronic health record data from a nationwide deidentified database. Real-world overall survival (rwOS), time on treatment (rwToT), and time to next treatment (rwTTNT) outcomes were assessed using Kaplan-Meier analysis. Results: The study population comprised 83 individuals (80.7% male) with a median age of 64 years. The most common tumor site was the oropharynx (48.2%); 70.0% of these tumors were HPV-positive. A total of 71.1% of the study population had an Eastern Cooperative Oncology Group performance status of 0-1 at index date, 71.8% had a combined positive score for programmed death ligand-1 (PD-L1) expression of ≥1, and 30.8% had a score of ≥20. The median (95% CI) rwOS was 14.9 (8.8-23.3) months, rwToT was 5.3 (4.0-8.2) months, and rwTTNT was 8.7 (6.8-12.3) months. Among the 24 individuals who received a subsequent therapy, the most common second-line therapies were cetuximab-based (n = 9) or pembrolizumab-containing (n = 8) regimens. Conclusions: The rwOS and other real-world outcomes observed for this study population further support pembrolizumab + platinum + taxane combination therapy as a potential 1L treatment option for R/M HNSCC. [ABSTRACT FROM AUTHOR]

Introduction The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy. Methods This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data. Results A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%). Conclusion Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated. [ABSTRACT FROM AUTHOR]

Cancer cells evolve to be refractory to the intrinsic programmed cell death mechanisms, which ensure cellular tissue homeostasis in physiological conditions. Chemotherapy using cytotoxic drugs seeks to eliminate cancer cells but spare non-cancerous host cells by exploring a likely subtle difference between malignant and benign cells. Presumably, chemotherapy agents achieve efficacy by triggering programmed cell death machineries in cancer cells. Currently, many major solid tumors are treated with chemotherapy composed of a combination of platinum agents and taxanes. Platinum agents, largely cisplatin, carboplatin, and oxaliplatin, are DNA damaging agents that covalently form DNA addicts, triggering DNA repair response pathways. Taxanes, including paclitaxel, docetaxel, and cabazitaxel, are microtubule stabilizing drugs which are often very effective in purging cancer cells in clinical settings. Generally, it is thought that the stabilization of microtubules by taxanes leads to mitotic arrest, mitotic catastrophe, and the triggering of apoptotic programmed cell death. However, the precise mechanism(s) of how mitotic arrest and catastrophe activate the caspase pathway has not been established. Here, we briefly review literature on the involvement of potential cell death mechanisms in cancer therapy. These include the classical caspase-mediated apoptotic programmed cell death, necroptosis mediated by MLKL, and pore forming mechanisms in immune cells, etc. In particular, we discuss a newly recognized mechanism of cell death in taxane-treatment of cancer cells that involves micronucleation and the irreversible rupture of the nuclear membrane. Since cancer cells are commonly retarded in responding to programmed cell death signaling, stabilized microtubule bundle-induced micronucleation and nuclear membrane rupture, rather than triggering apoptosis, may be a key mechanism accounting for the success of taxanes as anti-cancer agents. [ABSTRACT FROM AUTHOR]

This article discusses a new method for synthesizing homoallylic diene halides, which are important compounds used in the preparation of the taxane A-ring system. Taxol, a compound with anticancer properties, has been synthesized using various methods, including a type II intramolecular Diels-Alder reaction. The authors of this article report a new synthesis method for homoallylic halides, which are important precursors for the taxane ring system. The synthesis of these compounds was achieved using readily available and inexpensive starting materials, and the reactions are potentially scalable for large-scale production. The article provides technical information about the synthesis and characterization of various chemical compounds, including data such as nuclear magnetic resonance (NMR) spectra, mass spectrometry (MS) results, and experimental procedures. The authors acknowledge Prof. Joaquín Tamariz for HRMS analysis, and supporting information for the article is available online. [Extracted from the article]

Introduction. This study aims to investigate the efficacy and tolerability of the vinorelbine-based combination chemotherapy with either cisplatin or capecitabine in metastatic triple-negative breast cancer (mTNBC) pretreated with anthracycline and taxane. Material and methods. This is an open-labeled randomized prospective single-institute study, that included all patients who received chemotherapy for mTNBC in the period between 1st of July 2016 and 30th of June 2017 and were pretreated with anthracycline and taxane. Patients were randomized to either vinorelbine 25 mg/m² i.v. on days 1 and 8 plus oral capecitabine 1000 mg/m² twice daily, on days 1-14 (NX); or vinorelbine 25 mg/m² i.v. on days 1 and 8 plus cisplatin 75 mg/m² (NP), every 21 days. The primary endpoint was time to progression (TTP), whereas the secondary endpoints were objective response rate (ORR), safety, and overall survival (OS). Results. Median TTP was 9.9 months with NP vs. 8 months with NX, (p = 0.22). ORR was 40% with NP vs. 36% with NX, (p = 0.77). Median OS was 13 months with NP vs. 13.2 months with NX (p = 0.599). Both regimens demonstrated similar rates of grade = 3 vomiting and neutropenia. A higher incidence of thrombocytopenia, tinnitus, and kidney function alteration were reported with NP. A higher incidence of anorexia, diarrhea, mucositis, and hand-foot syndrome were reported with NX. Conclusions. Vinorelbine-based combination chemotherapy regimens with either cisplatin or capecitabine are active in the treatment of mTNBC pretreated with anthracycline and taxane with manageable toxicity profiles. Both regimens have comparable TTP, ORR, OS, and safety profiles. [ABSTRACT FROM AUTHOR]

Background: Adenocarcinoma of the lung is the most common type of lung cancer. Platinum agents in combination with other chemotherapy are currently the cornerstone for chemotherapy of advanced cases with metastasis. Objective: To compare the response rate of pemetrexed doublets versus taxanes doublets in patients with metastatic lung adenocarcinoma. Patients and Methods: This a prospective study that included 60 patients with pulmonary adenocarcinoma. Those patients received a platinum based doublet chemotherapy with additional treatment protocol; combined with either pemetrexed or taxanes (paclitaxel or docetaxel) with 30 patients in each arm. Tumor size, response rate and side effects of chemotherapy were evaluated in both arms. Results: The median reduction in tumor size in pemetrexed and taxan arms were 4.72 cm2 and 6.53 cm2 respectively. Nausea, fatigue, constipation and anorexia were more common in pemetrexed arm, while leukopenia, arthralgia and peripheral neuropathy were more common in taxan arm. Conclusion: Serious side effects such as leukopenia, and peripheral neuropathy were more common in taxan than pemetrexed arm. Pemetrexed is preferable to use as a fist line treatment for patients with metastatic adenocarcinoma of the lung.

Background: Squamous-cell carcinoma (SCC) of the lung is a kind of non-small-cell lung carcinoma. Cytotoxic chemotherapy has been found to deliver benefits to patients in advanced disease settings. Objective: To compare response rate and side effects between first-line chemotherapies vinorelbine, gemcitabine, and taxanes in patients with metastatic SCC of the lung. Patients and Methods: This is a retrospective study including 45 patients with metastatic lung SCC. All patients had received platinum-based doublet chemotherapy for 4-6 cycles. Patients were allocated into three groups based on the additional treatment protocol, with fifteen patients per group. A reduction in tumor size was assessed from tumor measurements for patients who had at least two evaluable assessments with computed tomography. The side effects of each drug were evaluated. Results: The reduction in tumor size in the gemcitabine, taxan, and vinorelbine arms was -5.59±35.62 cm3, 1.3±39.98 cm3 and -10.55±14.62 cm3, respectively, with no significant differences. The response rates in the taxan, gemcitabine, and vinorelbine arms were 73.33%, 80%, and 86.67%, respectively, with no significant differences. The side effects, including nausea, alopecia, diarrhea, arthralgia, and peripheral neuropathy, were, in particular, more common in patients in the taxan arm than in other arms, with significant differences. Conclusion: The three therapeutic arms, vinorelbine, gemcitabine, and taxanes, had similar efficiency based on response rate, with a mild preponderance of vinorelbine.

The taxane family of microtubule poisons and chemotherapeutics have been studied for over 50 years and are among the most frequently used antineoplastic agents today. Still, limited research exists characterizing taxane-induced sex-specific mechanisms of action and toxicities in cancer and non-cancerous tissue. Such research is important to advance cancer treatment outcomes as well as to address clinically observed sex-differences in short- and long-term taxane-induced toxicities that have disproportionate effects on female and male cancer patients. To gain more insight into these underlying differences between the sexes, the following review draws from pre-clinical and clinical paclitaxel and taxane oncology literature, examines sex-discrepancies, and highlights uncharacterized sex-dependent mechanisms of action and clinical outcomes. To our knowledge, this is the first literature review to provide a current overview of the basic and clinical sex dimorphisms of taxane-induced effects. Most importantly, we hope to provide a starting point for improving and advancing sex-specific personalized chemotherapy and cancer treatment strategies as well as to present a novel approach to review sex as a biological variable in basic and clinical biology.

The characterization of microtubule-targeting drugs at the cellular level is an essential step in the development of drugs targeting the microtubule network. To that aim, we have previously developed a quantitative cell-based assay easy to perform in microplates that requires only a luminescence reader and no microscopic analysis. Here, we show that this assay can be easily adapted to different breast cancer cell lines. An ideal application of this test could be the comparative analysis of the response of human tumor samples to different microtubule targeting drugs, to optimize therapeutic treatment.

Taxanes are natural compounds for the treatment of lung cancer, but the molecular mechanism behind the effects is unclear. In the present study, through network pharmacology and molecular docking, the mechanism of the target and pathway of taxanes in the treatment of lung cancer was studied. The taxanes targets were determined by PubChem database, and an effective compounds-targets network was constructed. The GeneCards database was used to determine the disease targets of lung cancer, and the intersection of compound targets and disease targets was obtained. The Protein–Protein Interaction (PPI) network of the intersection targets was analyzed, and the PPI network was constructed by Cytoscape 3.6.0 software. The hub targets were screened according to the degree value, and the binding activity between taxanes and hub targets was verified by molecular docking. The results showed that eight taxane-active compounds and 444 corresponding targets were screened out, and 131 intersection targets were obtained after mapping with lung cancer disease targets. The hub targets obtained by PPI analysis were TP53, EGFR, and AKT1. Gene Ontology (GO) biological function enrichment analysis obtained 1795 biological process (BP) terms, 101 cellular component (CC) terms, and 164 molecular function (MF) terms. There were 179 signaling pathways obtained by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Twenty signaling pathways were screened out, mainly pathways in cancer, proteoglycans in cancer pathway, microRNAs in cancer pathway, and so on. Molecular docking shows that the binding energies of eight taxanes with TP53, EGFR, and AKT1 targets were less than −8.8 kcal/mol, taxanes acts on TP53, EGFR, and AKT1 targets through pathways in cancer, proteoglycans in cancer pathway and microRNAs in cancer pathway, and plays a role in treating lung cancer in biological functions such as protein binding, enzyme binding, and identical protein binding.