The role of ABCC10/MRP7 in anti-cancer drug resistance and beyond.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Obstetric and neonatal outcomes following taxane use during pregnancy: a systematic review.

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 < 7 at 5 min. Perinatal complications included acute respiratory distress syndrome (n = 14; 10.6%), hyperbilirubinemia (n = 5; 3.8%), and hypoglycemia (n = 2; 1.5%). In addition, 7 (5.3%) cases of congenital malformations were reported. At a median follow-up of 16 months, offspring health status was available for 86 (65.2%), of which 13 (15.1%) had a documented complication, including delayed speech development, recurrent otitis media, and acute myeloid leukemia. CONCLUSIONS: Taxanes appear to be safe following the first trimester of pregnancy, with obstetric and fetal outcomes being similar to those observed in the general obstetric population. Future studies should aim to determine the most effective taxane regimen and dosage for use during gestation, with a specific focus on treatment safety.

Co-expression of Twist and Snai1: predictor of poor prognosis and biomarker of treatment resistance in untreated prostate cancer.

BACKGROUND: Prostate cancer (PCa) remains one of the most complex tumors in men. The assessment of gene expression is expected to have a profound impact on cancer diagnosis, prognosis, and treatment decisions. The aim of this study was to determine the utility of the epithelial-mesenchymal transition (EMT) transcription factors Twist and Snai1 in the treatment of naïve prostate cancer. METHODS AND RESULTS: We analyzed formalin-fixed paraffin-embedded (FFPE) prostate tissues from 108 PCa patients and 20 control biopsies using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt methods for Twist and Snail gene expression. The expression of Twist and Snai1 mRNA was significantly overexpressed in primary tissues of PCa patients compared with controls using ROC curve. Statistical analysis showed that the mRNAs of these two genes expression Snai1 and Twist were positively correlated with tumor development and prognostic parameters as Gleason score (p < 0.001; r = 0.707) and (p < 0.001; r = 0.627) respectively. The results of Kaplan-Meier analysis showed that mRNA expression of Snai1 and Twist genes expression were significant predictors of poor overall survival (OS) (Log rank p < 0.001) and progression-free survival (PFS) of patients (Log rank p < 0.001). Furthermore, our results showed that the expression of Snai1 and Twist genes expression in primary tissues of PCa patients could predict resistance to androgen deprivation therapy (p < 0.001) and resistance to the acidic drugs abiraterone or enzalutamide (p < 0.001). However, these two transcription factors failed to predict taxanes resistance at the time of diagnosis (p > 0.05). CONCLUSION: These results suggest that Snai1 and Twist are overexpressed during the onset and progression of PCa malignancies and may be theranostic markers of resistance to ADT, abiraterone, or enzalutamide therapy.

Tyrosine kinase inhibitors (TKIs) for ovarian cancer treatment: from organic to inorganic chemotherapeutics towards selectivity-a perspective overview.

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.

Efficacy of cryotherapy in the prevention of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

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.

Mechanism of Taxanes in the Treatment of Lung Cancer Based on Network Pharmacology and Molecular Docking.

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.

The synergetic effect from the combination of different adsorption resins in batch and semi-continuous cultivations of S. Cerevisiae cell factories to produce acetylated Taxanes precursors of the anticancer drug Taxol.

In situ product recovery is an efficient way to intensify bioprocesses as it can perform adsorption of the desired natural products in the cultivation. However, it is common to use only one adsorbent (liquid or solid) to perform the product recovery. For this study, the use of an in situ product recovery method with three combined commercial resins (HP-20, XAD7HP, and HP-2MG) with different chemical properties was performed. A new yeast strain of Saccharomyces cerevisiae was engineered using CRISPR Cas9 (strain EJ2) to deliver heterologous expression of oxygenated acetylated taxanes that are precursors of the anticancer drug Taxol ® (paclitaxel). Microscale cultivations using a definitive screening design (DSD) were set to get the best resin combinations and concentrations to retrieve high taxane titers. Once the best resin treatment was selected by the DSD, semi-continuous cultivation in high throughput microscale was performed to increase the total taxanes yield up to 783 ± 33 mg/L. The best T5α-yl Acetate yield obtained was up to 95 ± 4 mg/L, the highest titer of this compound ever reported by a heterologous expression. It was also observed that by using a combination of the resins in the cultivation, 8 additional uncharacterized taxanes were found in the gas chromatograms compared to the dodecane overlay method. Lastly, the cell-waste reactive oxygen species concentrations from the yeast were 1.5-fold lower in the resin's treatment compared to the control with no adsorbent aid. The possible future implications of this method could be critical for bioprocess intensification, allowing the transition to a semi-continuous flow bioprocess. Further, this new methodology broadens the use of different organisms for natural product synthesis/discovery benefiting from clear bioprocess intensification advantages.

Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice.

There is currently great interest in developing oral taxanes due to their lower costs and greater patient friendliness. We here wanted to test whether oral ritonavir, a cytochrome P450 3A (CYP3A) inhibitor, could boost the pharmacokinetics and tissue distribution of orally administered cabazitaxel (10 mg/kg) in male wild-type, Cyp3a-/-, and Cyp3aXAV (transgenic overexpression of human CYP3A4 in liver and intestine) mice. Ritonavir was initially administered at a dose of 25 mg/kg, but lower dosages of 10 and 1 mg/kg were also studied to assess the remaining amount of boosting, aiming to minimize possible side effects. Compared to the respective vehicle groups, plasma exposure of cabazitaxel (AUC0-24h) was enhanced 2.9-, 10.9-, and 13.9-fold in wild-type mice and 1.4-, 10.1-, and 34.3-fold in Cyp3aXAV mice by treatment with 1, 10, and 25 mg/kg ritonavir, respectively. Upon treatment with 1, 10, and 25 mg/kg of ritonavir, the peak plasma concentration (Cmax) was increased by 1.4-, 2.3-, and 2.8-fold in wild-type mice, while it increased by 1.7-, 4.2-, and 8.0-fold in Cyp3aXAV mice, respectively. AUC0-24h and Cmax remained unchanged in Cyp3a-/-. Biotransformation of cabazitaxel to its active metabolites still took place when coadministered with ritonavir, but this process was delayed due to the Cyp3a/CYP3A4 inhibition. These data indicate that CYP3A is the primary limiting factor in the plasma exposure to cabazitaxel and that cabazitaxel oral bioavailability could be dramatically enhanced by coadministration of an effective CYP3A inhibitor such as ritonavir. These findings could be a starting point for the setup of a clinical study, which would be needed to verify the boosting of cabazitaxel by ritonavir in humans.

Management of chemotherapy hypersensitivity reactions and desensitization: An SGO clinical practice statement.

OBJECTIVE: The goal of this practice statement is to help members and their multidisciplinary teams recognize infusion reactions and hypersensitivity reactions in the clinical setting. It will provide recommendations to help guide response to reactions and desensitization when appropriate, to promote safe use of chemotherapeutic agents among all providers in the delivery process. METHODS: A multi-disciplinary team of healthcare professionals from the Society of Gynecologic Oncology Education Committee collaborated to review peer reviewed literature and guidelines to develop a practice statement on the management of chemotherapy hypersensitivity reactions and desensitization regimens. RESULTS: There is always potential for a patient to have a reaction to any medication, with both infusion reactions and hypersensitivity reactions potentially occurring in the treatment of gynecologic cancers. Premedication to prevent reactions should be given at least prior to infusion for regimens that include the most common agents associated with reactions. At the time when reaction is occurring it might be difficult to distinguish between an infusion reaction versus true hypersensitivity given the similarities in signs and symptoms, therefore it is important that orders to manage reactions be included in every chemotherapy order set so the infusion nurse can provide immediate interventions while waiting for the provider to arrive to assess the patient. Desensitization is a potential option to allow the patient to continue to receive the offending agent. While a variety of desensitization regimens have been presented in the literature, the goal is to minimize steps and variability to decrease opportunity for errors during chemotherapy preparation or administration. CONCLUSION: Incorporating a review of the literature and clinical experience from the SGO Education Committee, this paper provides an overview of current approaches for prevention and management of reactions to commonly used chemotherapy agents for gynecologic cancers.

Immunotherapy as a later-line option for HER2-altered advanced non-small-cell lung cancer: taxane might be a favorable partner.

Aim: To assess the effectiveness of different types of taxanes, including nab-paclitaxel, paclitaxel and docetaxel, and further compare the effectiveness of taxane-based chemotherapy, taxane-based chemotherapy plus angiogenesis inhibitors or taxane-based chemotherapy plus immune checkpoint inhibitors in HER2-altered non-small-cell lung cancer in the second- or third-line setting. Materials & methods: A total of 52 patients were included in the study. Progression-free survival was compared between subgroups. Results: A clinically meaningful improvement in progression-free survival was observed among patients in the nab-paclitaxel group compared with the docetaxel group. Taxane-based chemotherapy plus immune checkpoint inhibitors achieved longer progression-free survival than taxane-based chemotherapy. There was no difference between taxane-based chemotherapy plus immune checkpoint inhibitors and taxane-based chemotherapy plus angiogenesis inhibitors. Conclusion: Nab-paclitaxel appears to be a reasonable alternative to docetaxel. Chemotherapy plus immune checkpoint inhibitors might yield more survival benefits than chemotherapy alone.

Identification of a SNP cluster associated with taxane-induced peripheral neuropathy risk in patients being treated for breast cancer using GWAS data derived from a large cooperative group trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytics to describe taxane-associated CIPN risk. METHODS: We analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher's ratio (FR). We then ranked ordered those SNPs which discriminated CIPN-positive (CIPN +) from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross-validation (LOOCV). RESULTS: Using aggregated genotype data obtained from the previously reported ECOG-5103 clinical trial (in which two different arrays were used, HumanOmniExpress (727,227 SNPs) and HumanOmni1-Quad1 (1,131,857 SNPs)), we identified a 267 SNP cluster which was associated with a CIPN + phenotype with an accuracy of 96.1%. CONCLUSIONS: A cluster of SNPs was identified which prospectively discriminated patients most likely to develop symptomatic CIPN following taxane exposure as part of a breast cancer chemotherapy regimen. Validation using an independent patient cohort should be performed.

Relative dose intensity of taxane-based chemotherapy in breast cancer patients in a tertiary hospital.

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.

Rapid drug desensitization to taxanes: a descriptive study from Turkey.

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.

Taxanes hypersensitivity is not a risk factor for severe reactions to SARS-CoV-2 vaccines.

Summary: Background. Hypersensitivity reactions (HSR) to taxanes have been related to a complement activation by their excipients, polyoxyethylated castor oil and Polysorbate 80, structurally related to those of SARS-CoV-2 vaccines. The aim of this study was to verify the presence of a higher risk of HSR to SARS-CoV-2 vaccines in patients with history of HSR to taxanes. Methods. Patients with history of HSR to taxanes were evaluated before the vaccination in our center and underwent skin tests for PEG and Polysorbate 80 (PandP). Some patients completed the vaccination course in other centers without prior PandP skin tests because they had not manifested taxanes hypersensitivity before vaccination, or because those tests were not available. Results. 50 patients were evaluated. 100% of patients with history of hypersensitivity to taxanes completed the vaccine course with no cases of anaphylaxis. 33 underwent skin tests for PandP before the vaccination and no correlation was found between the positivity of PandP and taxanes skin tests (p = 0.538). 7 patients developed mild symptoms during skin tests and vaccination, similar but weaker than those suffered at the time of the taxane infusion, independently from the results of skin tests. Conclusions. In our cohort patients with history of reaction to taxanes were not at higher risk to develop anaphylaxis to SARS-CoV-2 vaccines. However, a common non-IgE mediated mechanism behind those HSRs cannot be completely excluded. This can only account for mild and harmless symptoms in case of SARS-CoV-2 vaccines. However, prudence is still recommended in these patients.

Epothilones as Natural Compounds for Novel Anticancer Drugs Development.

Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium Sorangium cellulosum. This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.

Parameter Optimization of Ultrasonic-Microwave Synergistic Extraction of Taxanes from Taxus cuspidata Needles.

Taxanes are the best-known compounds in Taxus cuspidata owing to their strong anticancer effects. However, the traditional taxanes extraction method is the solid-liquid extraction method, which is limited by a large energy consumption and low yield. Therefore, it is urgent to find an efficient method for taxanes extraction. The ultrasonic microwave synergistic extraction (UME) method integrates the cavitation effect of ultrasound and the intensifying heat transfer (ionic conduction and dipole rotation of molecules) effect of microwave to accelerate the release of intracellular compounds and is used in active ingredient extractions. This study aimed to evaluate the performance of UME in extracting taxanes from T. cuspidata needles (dichloromethane-ethanol as extractant). A single-factor experiment, Plackett-Burman design, and the response surface method showed that the optimal UME parameters for taxanes extraction were an ultrasonic power of 300 W, a microwave power of 215 W, and 130 sieve meshes. Under these conditions, the taxanes yield was 570.32 µg/g, which increased by 13.41% and 41.63% compared with the ultrasound (US) and microwave (MW) treatments, respectively. The reasons for the differences in the taxanes yield were revealed by comparing the physicochemical properties of T. cuspidata residues after the UME, US, and MW treatments. The cell structures were significantly damaged after the UME treatment, and numerous tiny holes were observed on the surface. The absorption peaks of cellulose, hemicellulose, and lignin increased significantly in intensity, and the lowest peak temperature (307.40 °C), with a melting enthalpy of -5.19 J/g, was found after the UME treatment compared with the US and MW treatments. These results demonstrate that UME is an effective method (570.32 µg/g) to extract taxanes from T. cuspidata needles by destroying cellular structures.

Impact of taxane-based chemotherapy among older women with breast cancer on cognition and quality of life: a longitudinal pooled analysis.

PURPOSE: Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and subjective measures of cognitive performance and well-being differ among older breast cancer survivors as a function of taxane-based chemotherapy treatment regimens. METHODS: Individual-level data were pooled and harmonized from two large prospective studies of older (greater than 60 years) breast cancer survivors. Assessments were conducted prior to systemic therapy and up to 36 months after. Cognitive performance was assessed with objective (working memory, processing speed, and executive functions) and subjective tests and physical, emotional, and functional well-being were also assessed. RESULTS: One hundred and sixty-seven (M age = 67.3 years) women with 116 receiving chemotherapy with taxanes and 51 without taxanes contributed data. Declines in subjective cognition for both groups were significant between pre-treatment and 12-month follow-up. Significant improvements were seen on a measure of objective cognition (working memory) from 12 to 36 months. Measures of well-being improved from prior to systemic therapy to 12 months. Longitudinal changes across all measures did not vary as a function of receipt of taxane-based treatment. CONCLUSION: Older women who received treatment with taxanes did not have greater declines in cognitive performance or well-being than women receiving other chemotherapy regimens. Despite older cancer survivors being at greater risk for negative outcomes, treatment with taxane-based chemotherapies does not appear to exacerbate these health consequences.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark.

PURPOSE: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98). CONCLUSION: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Biocatalysis of precursors to new-generation SB-T-taxanes effective against paclitaxel-resistant cancer cells.

A 10-O-deacetylbaccatin III 10-O-acetyltransferase biocatalyst from Taxus plants was expressed in bacteria whole-cells that were fed 10-O-deacetylbaccatin III and cyclopropane carboxylic acid. Product analysis by qualitative LC/ESI-MS suggested that the C10-acylated products baccatin III, 10-O-n-propionyl-10-O-deacetylbaccatin III, and 10-O-cyclopropanecarbonyl-10-O-deacetylbaccatin III were made in vivo. The results implied that the cells provided non-natural cyclopropanecarbonyl CoA, from a broad-specificity CoA ligase, and natural products, acetyl CoA and n-propionyl CoA, from reserves in the bacteria for use by acyltransferase to acylate 10-O-deacetylbaccatin III in vivo. The 10-acyl-10-O-deacetylbaccatin III are precursors used to synthesize new-generation paclitaxel analogs SB-T-1214 and SB-T-121303, which are effective against cancer cells resistant to paclitaxel and its drug derivatives. The kcat and KM of the acyltransferase for cyclopropanecarbonyl CoA (0.83 s-1, 0.15 M) and n-propionyl CoA (1.2 s-1, 0.15 M) guided scale-up efforts. The 10-acyl-10-O-deacetylbaccatin III analogs (∼45 mg each) were made in vitro by the acyltransferase when incubated with the commercial taxane 10-O-deacetylbaccatin III and synthesized cyclopropanecarbonyl or n-propionyl CoA. The structures of the 10-acyl products were verified by NMR analyses that confirmed C10 acylation of the taxane substrate. LC/ESI-MS/MS analysis also supported the identities of the biocatalyzed products. This effort provides a biocatalysis framework to produce new-generation taxane precursors.

Adverse Event Profile for Nanoparticle Albumin-Bound Paclitaxel Compared With Solvent-Based Taxanes in Solid-Organ Tumors: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an innovative form of taxane that has superior antitumor effects; however, the safety profile between nab-paclitaxel and traditional taxanes remains controversial. OBJECTIVE: To determine the burden of adverse events (AEs) in patients with multiple malignancies receiving nab-paclitaxel compared with that in patients receiving traditional taxanes. METHODS: Randomized clinical trials comparing nab-paclitaxel with traditional taxanes (solvent-based paclitaxel [sb-paclitaxel] or docetaxel) in the treatment of primary solid-organ malignancies were included if AEs were reported as an outcome. Statistical analyses were conducted to calculate the summary odds ratio (OR) of the relevant adverse outcomes related to nab-paclitaxel and traditional taxanes. Prespecified subgroup analyses based on intervention and doses, primary tumor sites, and different ethnic groups were also performed. RESULTS: Twelve clinical trials were included in the meta-analysis. Grade 3/4 anemia, thrombocytopenia, and neurotoxicity were more frequent with nab-paclitaxel than with traditional taxanes. Nab-paclitaxel at 100 or 125 mg/m2/w dosage was associated with fewer or similar grade 3/4 specific AEs. Allergy was less common with nab-paclitaxel. The median recovery times of neurotoxicity were 25, 64, and 37 days in patients receiving nab-paclitaxel, sb-paclitaxel, and docetaxel, respectively. Elevated incidences of specific AEs were more common in breast cancer and non-Asian patients than in other malignancies and ethnic groups, respectively. CONCLUSION AND RELEVANCE: Nab-paclitaxel increased the risk of hematologic and non-hematologic AEs in general, but anaphylaxis was less common, and the recovery duration of neurotoxicity was shorter. Weekly administration of nab-paclitaxel at a lower dosage provided better tolerance.