taxane and Neoplasms

Genetic polymorphisms can influence the chemotherapeutic response; however, previous studies have produced conflicting results, and have failed to identify the most relevant polymorphisms for predicting the response to treatment in patients with cancer. The present meta-analysis was conducted to determine the correlation between two polymorphisms (rs1045642 and rs1128503) in ATP-binding cassette transporter B subfamily member 1 (ABCB1), which is associated with multidrug resistance, and the survival of patients treated with taxane-containing chemotherapy.. Several databases, including PubMed and Embase, were used to retrieve articles evaluating the association between the ABCB1 rs1045642 and rs1128503 polymorphisms and survival, published prior to August 2019. The meta-analysis was conducted using R software to determine the pooled hazard ratio (HR) and 95% confidence intervals (95% CIs).. Fifteen studies involving 3320 patients were included in the meta-analysis. The effect of the rs1128503 polymorphism on progression-free survival remained significant in the heterozygote (HR 0.81; 95% CI: 0.67-0.98) and homozygote (HR 0.71; 95% CI: 0.58-0.88) models. The TT genotype rs1128503 was associated with better overall survival (HR 0.72; 95% CI: 0.53-0.97).. Carriers of the rs1128503 T allele of ABCB1 showed a survival benefit after taxane-containing chemotherapy.

Topics: ATP Binding Cassette Transporter, Subfamily B; Biomarkers, Tumor; Bridged-Ring Compounds; Humans; Neoplasms; Polymorphism, Single Nucleotide; Prognosis; Survival Rate; Taxoids

Network topology-based approaches prove to be highly efficient in addressing multifactorial phenomena such as acquired drug resistance in cancer. The aim of this study was to identify differentially expressed genes across multiple microarray datasets (meta-DEGs), to prioritize meta-DEGs to find the most promising genes linked to acquired taxane resistance (ATR), and to analyze the relevant biological networks using topology analysis. A total of 771 meta-DEGs were identified by performing a cross-platform meta-analysis of ATR-related microarray datasets. A gene prioritization method was used to simultaneously identify activated or deactivated genes on a co-expression map and protein-protein interaction (PPI) network. The top 10 prioritized genes in the gene co-expression and the top 1% highly ranked genes in the PPI network were identified. The selected meta-DEGs were used to construct biological networks, and topological analysis was performed using network centrality measures. Using integrative analyses, we identified ATR candidate genes, including several previously unidentified genes that were found to be associated with ATR. From the gene co-expression network, PRSS23 was the highest-ranking gene at local average connectivity measure and ADAM9 was ranked highest in other centralities. In protein interaction network, HSPA1A, ANXA1, and PA2G4 showed highest ranks in network centrality analyses. This study provides a comprehensive overview of the gene expression patterns associated with ATR. Furthermore, it presents a new approach to identification of unveiled candidate genes to ATR, using a gene prioritization method and network analysis.

Topics: Bridged-Ring Compounds; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Neoplasms; Protein Interaction Maps; Taxoids

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Cannabinoids; Chronic Pain; Clinical Trials as Topic; Humans; Neoplasms; Neuralgia; Organoplatinum Compounds; Taxoids; Treatment Outcome; Vinca Alkaloids

One in 2 Canadians is expected to acquire cancer in their lifetime. Many cancers, including breast, ovarian, and lung cancer, are treated using taxane chemotherapy with curative intent. A major adverse effect with the use of taxane chemotherapeutic agents is taxane-induced peripheral neuropathy (TIPN). Both positive (spontaneous pain, heightened sensitivity with light touch, tingling, itching, burning) and negative (loss of touch, loss of hot/cold sensations, and loss of pain) sensory symptoms can be experienced in the hands and feet and worsen with increasing dose and treatment duration. The pathophysiology of TIPN is still unknown but likely involves multiple mechanisms, including microtubule impairment, neuroimmune and inflammatory changes, ion channel remodeling, impaired mitochondrial function, and genetic predisposition. This review highlights current theories on the pathophysiology for TIPN, the cellular responses thought to maintain neuropathic pain, and the growing support for exercise in the treatment and prevention of peripheral neuropathy and neuropathic pain in both animal and human models.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Exercise Therapy; Humans; Neoplasms; Neuralgia; Peripheral Nervous System Diseases; Taxoids

Chemotherapy-induced alopecia as well as nail and cutaneous changes occur in up to 89% of patients receiving taxane-based chemotherapy and are associated with cosmetic concerns, psychosocial distress, and overall morbidity.. To review the efficacy and safety of interventions to prevent taxane-induced dermatologic adverse events.. PubMed and Scopus databases were systematically reviewed for studies published in the English language from January 1, 1980, to August 13, 2018. Specific search terms included but were not limited to taxane, docetaxel, paclitaxel, prevent, nail, skin, hair, alopecia, and onycholysis. Primary clinical studies that detailed preventive interventions for taxane-induced dermatologic adverse events and that classified results according to a taxane-specific chemotherapy regimen were reviewed and graded according to a 5-point scale, modified from the Oxford Centre for Evidence-based Medicine.. The 34 original reports that met the inclusion criteria consisted of 6 randomized clinical trials, 4 nonrandomized clinical trials, 18 cohort studies, 3 case-control studies, 1 cross-sectional study, and 2 case reports and involved a total of 5647 unique participants. A total of 22 studies addressed preventive interventions for alopecia associated with taxane use, whereas 12 studies focused on taxane-induced skin and nail changes. Specifically, 20 (95%) of 21 studies supported the use of either a cold cap or a scalp cooling system to reduce alopecia but reported substantial differences in efficacy depending on the chemotherapy regimen. Scalp cooling was generally considered safe by all pertinent studies despite a single report of scalp skin metastasis. Similarly, use of frozen gloves and frozen socks in the prevention of nail and cutaneous hand and foot toxic effects was considered safe in 7 (88%) of 8 studies, although discomfort was common and frostbite was noted in 1 patient. Overall, use of frozen gloves was endorsed by 4 (67%) of 6 studies to prevent nail toxic effects and by 3 (60%) of 5 studies to prevent cutaneous hand changes.. Scalp hypothermia with cold caps or scalp cooling systems has demonstrated efficacy as a monotherapy in preventing taxane-induced alopecia, and use of frozen gloves and socks has been associated with reduced nail and skin changes. Future studies should establish the routine usage protocols, standard outcome measures, and long-term efficacy and safety for these interventions.

Topics: Alopecia; Antineoplastic Agents; Bridged-Ring Compounds; Humans; Hypothermia, Induced; Neoplasms; Taxoids

ATP-binding cassette (ABC) transporters are transmembrane efflux transporters that mediate cellular extrusion of a broad range of substrates ranging from amino acids, lipids, and ions to xenobiotics including many anticancer drugs. ABCB1 (P-GP) and ABCG2 (BCRP) are the most extensively studied apical ABC drug efflux transporters. They are highly expressed in apical membranes of many pharmacokinetically relevant tissues such as epithelial cells of the small intestine and endothelial cells of the blood capillaries in brain and testis, and in the placental maternal-fetal barrier. In these tissues, they have a protective function as they efflux their substrates back to the intestinal lumen or blood and thus restrict the intestinal uptake and tissue disposition of many compounds. This presents a major challenge for the use of many (anticancer) drugs, as most currently used anticancer drugs are substrates of these transporters. Herein, we review the latest findings on the role of apical ABC transporters in the disposition of anticancer drugs. We discuss that many new, rationally designed anticancer drugs are substrates of these transporters and that their oral availability and/or brain disposition are affected by this interaction. We also summarize studies that investigate the improvement of oral availability and brain disposition of many cytotoxic (e.g., taxanes) and rationally designed (e.g., tyrosine kinase inhibitor) anticancer drugs, using chemical inhibitors of these transporters. These findings provide a better understanding of the importance of apical ABC transporters in chemotherapy and may therefore advance translation of promising preclinical insights and approaches to clinical studies.

Topics: Animals; Antineoplastic Agents; ATP-Binding Cassette Transporters; Biological Availability; Biological Transport; Blood-Brain Barrier; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Intestinal Absorption; Mice; Neoplasms; Taxoids

Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes.

Topics: Axons; Bridged-Ring Compounds; Docetaxel; Drug-Related Side Effects and Adverse Reactions; Humans; Nanoparticles; Neoplasms; Paclitaxel; Peripheral Nervous System Diseases; Randomized Controlled Trials as Topic; Taxoids

βIII-Tubulin (TUBB3) is predominantly expressed in neurons of the central and peripheral nervous systems, while in normal non-neoplastic tissues it is barely detectable. By contrast, this cytoskeletal protein is abundant in a wide range of tumors. βIII-Tubulin is linked to dynamic instability of microtubules (MTs), weakening the effects of agents interfering with MT polymerization. Based on this principle, early studies introduced the classical theory linking βIII-tubulin with a mechanism of counteracting taxane activity and accordingly, prompted its investigation as a predictive biomarker of taxane resistance.. We reviewed 59 translational studies, including cohorts from lung, ovarian, breast, gastric, colorectal and various miscellaneous cancers subject to different chemotherapy regimens.. βIII-Tubulin functions more as a prognostic factor than as a predictor of response to chemotherapy. We believe this view can be explained by βIII-tubulin's association with prosurvival pathways in the early steps of the metastatic process. Its prognostic response increases if combined with additional biomarkers that regulate its expression, since βIII-tubulin can be expressed in conditions, such as estrogen exposure, unrelated to survival mechanisms and without any predictive activity. Additional avenues for therapeutic intervention could emerge if drugs are designed to directly target βIII-tubulin and its mechanism of regulation.

Topics: Animals; Antineoplastic Agents; Biomarkers; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Taxoids; Tubulin; Tubulin Modulators

Natural products, especially microtubule-binding natural products, play important roles in the war against cancer. From the clinical use of vinblastine in 1961, paclitaxel in 1992, to ixabepilone in 2007, microtubule-binding natural products have continually contributed to the development of cancer therapy. The present review summarizes the development of representative microtubule-binding natural products including agents binding to the colchicine-binding site, the VINCA alkaloid-binding site, the taxane-binding site and other binding sites. Future directions for the development of new anticancer microtubule-binding natural products are discussed. Finding new formulations, new targets and new sources of microtubule-binding natural products may enable more members of this kind of agent to be introduced into the clinic for cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; Binding Sites; Bridged-Ring Compounds; Clinical Trials as Topic; Colchicine; Epothilones; Humans; Microtubules; Neoplasms; Taxoids; Tubulin Modulators; Vinca Alkaloids

Microtubule-targeting agents, such as taxanes and epothilones, block mitosis and cell proliferation by targeting the dynamics of the cytoskeleton. The taxanes are widely used for treatment of various malignancies, but primary and acquired resistance to chemotherapy remains a significant clinical concern. Class I, II, III, IV, and V beta-tubulin isotypes are expressed in human tumors. Overexpression of the betaIII-tubulin isotype is one mechanism that can render tumor cells resistant to taxanes. The relative expression of betaIII-tubulin correlates with clinical outcomes in several tumor types, including breast cancer, non-small cell lung cancer, and ovarian cancer. A novel analogue of epothilone B, ixabepilone, has recently been approved in combination with capecitabine for the treatment of patients with anthracycline- and taxane-resistant locally advanced or metastatic breast cancer and as monotherapy in patients whose tumors are resistant or refractory to an anthracycline, a taxane, and capecitabine. The significant antitumor activity of ixabepilone in taxane-resistant tumors may be related to its preferential suppression of the dynamic instability of alpha/betaIII-microtubules in cells expressing high levels of betaIII-tubulin.

Topics: Animals; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Epothilones; Humans; Neoplasms; Taxoids; Treatment Outcome; Tubulin

Over the past two decades, the taxanes have played a significant role in the treatment of various malignancies. However, the poor solubility of these compounds necessitates the inclusion of surfactant vehicles in their commercial formulations. Cremophor EL and polysorbate 80 have long comprised the standard solvent system for paclitaxel and docetaxel, respectively. A number of pharmacologic and biologic effects related to both of these drug formulations have been described, including clinically relevant acute hypersensitivity reactions and peripheral neuropathy. In addition, these solvents affect the disposition of intravenously administered solubilized drugs and leach plasticizers from polyvinylchloride infusion sets. A number of strategies to develop formulations of surfactant-free taxanes have been developed. They include albumin nanoparticles, polyglutamates, taxane analogs and prodrugs, emulsions, and lipsomes. An overview of these novel formulations of taxanes, their mechanisms of action, pharmacokinetics, dose and administration, adverse effects, and clinical efficacy will be discussed.

Topics: Bridged-Ring Compounds; Chemistry, Pharmaceutical; Humans; Liposomes; Neoplasms; Taxoids

Taxanes represent the most important class of antitumor agents introduced in cancer therapy in the last decade. The first member of the family was paclitaxel, firstly isolated from Taxus Brevifolia and found active as antitumor agent at the end of 60's. In the mid of 90's, a semi-synthetic taxane derived from 10-deacetylbaccatin III was introduced and thereafter named as docetaxel. Taxanes act by inhibiting microtubule dynamics, thereby inducing the arrest in M phase and the consequent activation of the apoptotic program. Since target of taxanes is not directly the genome, they are effective alone or in combination with DNA-damaging drugs in tumors not responding to conventional chemotherapeutics, such as advanced breast and non small cell lung cancer. In this review we will cover the aspects of clinical applications of the currently used taxanes as well as the clinical problems related to their use. Taking into consideration such problems, new taxanes have been developed in order to extend the spectrum of taxane-sensitive tumors and several of them are currently undergoing clinical trials. Among these agents, a newly developed taxane (BAY 59-8862) appears particularly interesting for the fact that it shows excellent oral bioavailability and activity in tumors with inherent resistance to paclitaxel.

Topics: Animals; Antineoplastic Agents; Bridged-Ring Compounds; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Neoplasms; Taxoids

Ongoing research in cancer therapy has led to the development of antineoplastic agents which target specific components of the cell cycle. In Part II of this series, we discuss agents which target the mitotic mechanism by inhibiting microtubules. Although many of these agents are being shown to have multiple effects, the Vinca alkaloids and the taxanes are known as antimitotic drugs. They are among the most important anticancer agents currently available, and because of their unique mechanisms, can be combined with a wide variety of other antineoplastic agents in a spectrum of diseases. In addition, in part II, we are discussing agents that target DNA and prevent replication and thus cell growth by inhibiting the enzymes which protect DNA during replication, the topoisomerases. These drugs, too, have unique mechanisms of action and have become major components of combination regimens. The topoisomerase I inhibitors are new drugs derived from an older parent drug, and their full possibilities are still being explored.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Camptothecin; Drug Therapy; Humans; Neoplasms; Podophyllotoxin; Taxoids; Topoisomerase I Inhibitors; Vinca Alkaloids

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.

Topics: Animals; Antineoplastic Agents; Biological Availability; Bridged-Ring Compounds; Capecitabine; Cyclophosphamide; Deoxycytidine; Disease Models, Animal; Drug Administration Schedule; Drug Design; Fluorouracil; Humans; Liver; Mice; Neoplasms; Taxoids; Thymidine Phosphorylase; Up-Regulation

Among new taxoids, taxuspines A-H and J-T, and known taxoids containing taxol and taxol-type compounds with an N-acylphenylisoserine group at C-13 and an oxetane ring at C-4 and C-5 isolated from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc., two non-taxol-type compounds remarkably reduced CaCl2-induced depolymerization of microtubules. Furthermore, seven non-taxol-type compounds increased cellular accumulation of vincristine in multidrug-resistant(MDR) tumor cells as potent as verapamil, while taxol and taxol-type compounds did not show such an activity. In addition, the non-taxol-type compounds enhancing vincristine accumulation inhibited competitively binding of azidopine to P-glycoprotein. These results suggest that some non-taxol-type taxoids may be useful for overcoming MDR in tumor cells.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bridged-Ring Compounds; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Structure-Activity Relationship; Taxoids; Tumor Cells, Cultured

The taxanes are a new group of anticancer agents with a novel mechanism of action. They promote microtubule assembly and stabilize the microtubules. Paclitaxel (Taxol), the first agent in this group in clinical trials was isolated from the Pacific yew, Taxus brevifolia in 1971. Both in preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review will provide an overview of the clinical experience with the group of anti-microtubular agents, the taxanes in pediatric oncology.

Topics: Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Child; Clinical Trials, Phase I as Topic; Humans; Microtubules; Neoplasms; Taxoids

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of chemotherapy. Several trials have evaluated the protective effect of vitamin E in preventing CIPN with controversial results. This study aims to outline the role of vitamin E in preventing CIPN.. A prospective phase II, open-label randomized controlled study was conducted in patients receiving taxane-based chemotherapy in Ain Shams University Hospitals, using vitamin E at a dose of 400 mg twice daily. The primary endpoint was the incidence of grade ≥ 2 sensory neuropathy according to CTCAE v 5.0 in each treatment arm. Secondary endpoints include time to onset and the duration of grade ≥ 2 sensory neuropathy.. A total of 140 patients were randomized between the control and vitamin E arms. There was no difference in the incidence of grade ≥ 2 sensory neuropathy between the two arms (25.7% in each arm; P = 1.0), as well as the time to onset of neuropathy (P = 0.24). However, there was a statistically significant difference between the 2 arms as regards the duration of neuropathy. The median duration was 12.5 vs. 5 weeks in the control and vitamin E arms respectively (P = 0.01).. Our study did not demonstrate a protective role of vitamin E in decreasing the incidence of CIPN in patients receiving taxane-based chemotherapy. However, the recovery from CIPN was much better as compared to the control arm, which may indicate a role for vitamin E in decreasing the duration and severity of CIPN.

Topics: Antineoplastic Agents; Antioxidants; Bridged-Ring Compounds; Case-Control Studies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Peripheral Nervous System Diseases; Prognosis; Prospective Studies; Taxoids; Vitamin E

Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms.. Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness.. Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076).. Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients.. Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov .

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Exercise Therapy; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Organoplatinum Compounds; Peripheral Nervous System Diseases; Taxoids; Vinca Alkaloids

G3139 is a BCL-2 antisense oligonucleotide whose antitumor effects in preclinical models are enhanced when combined with taxane-based chemotherapy. This trial determined the safety and biologic activity of G3139 given with paclitaxel and docetaxel for the treatment of progressive solid tumors. Three cohorts of patients received weekly paclitaxel 100 mg/m2 on days 1, 8, and 15 concurrently with a 21-day continuous infusion of G3139 at 4.1, 5.3, and 6.9 mg/kg/d, depending on the cohort. Two subsequent cohorts received docetaxel (75 mg/m2) on day 5 of a 5-day infusion of G3139 at 5 or 7 mg/kg/d. Bcl-2 protein levels in peripheral blood mononuclear cells (PBMCs) were assayed on an exploratory basis. Fifteen patients were treated. Eight received a total of 14 cycles of G3139 and paclitaxel; seven received a total of 22 cycles of G3139 and docetaxel. Eight patients required dose modifications for either grade 4 neutropenia (6 patients) or grade 1-2 reversible transaminitis (2 patients). No radiographic responses were seen, although two of the six taxane-naive prostate cancer patients exhibited a prostate-specific antigen decline greater than 50%. Bcl-2 protein levels in PBMCs declined with treatment as assessed by immunohistochemistry. The authors conclude that G3139, whether given as a 5- or 21-day infusion, is well tolerated with taxane chemotherapy and is biologically active by immunohistochemistry at doses up to and including 7 mg/kg/d, using weekly paclitaxel (100 mg/m2) or docetaxel every 3 weeks (75 mg/m2). These data support the dose selection of ongoing phase 2 studies of G3139 at 7 mg/kg/d and docetaxel 75 mg/m2.

Topics: Aged; Antineoplastic Agents; Bridged-Ring Compounds; Drug Administration Schedule; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Taxoids; Thionucleotides

Using GWAS data derived from a large collaborative trial (ECOG-5103), we identified a cluster of 267 SNPs which predicted CIPN in treatment-naive patients as reported in Part 1 of this study. To assess the functional and pathological implications of this set, we identified collective gene signatures were and evaluated the informational value of those signatures in defining CIPN's pathogenesis.. In Part 1, we analyzed GWAS data derived from ECOG-5103, first identifying those SNPs that were most strongly associated with CIPN using Fisher's ratio. After identifying those SNPs which differentiated CIPN-positive from CIPN-negative phenotypes, we ranked them in order of their discriminatory power to produce a cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross validation (LOOCV). An uncertainty analysis was included. Using the best predictive SNP cluster, we performed gene attribution for each SNP using NCBI Phenotype Genotype Integrator and then assessed functionality by applying GeneAnalytics, Gene Set Enrichment Analysis, and PCViz.. Using aggregate data derived from the GWAS, we identified a 267 SNP cluster which was associated with a CIPN+ phenotype with an accuracy of 96.1%. We could attribute 173 genes to the 267 SNP cluster. Six long intergenic non-protein coding genes were excluded. Ultimately, the functional analysis was based on 138 genes. Of the 17 pathways identified by Gene Analytics (GA) software, the irinotecan pharmacokinetic pathway had the highest score. Highly matching gene ontology attributions included flavone metabolic process, flavonoid glucuronidation, xenobiotic glucuronidation, nervous system development, UDP glycosyltransferase activity, retinoic acid binding, protein kinase C binding, and glucoronosyl transferase activity. Gene Set Enrichment Analysis (GSEA) GO terms identified neuron-associated genes as most significant (p = 5.45e-10). Consistent with the GA's output, flavone, and flavonoid associated terms, glucuronidation were noted as were GO terms associated with neurogenesis.. The application of functional analyses to phenotype-associated SNP clusters provides an independent validation step in assessing the clinical meaningfulness of GWAS-derived data. Functional analyses following gene attribution of a CIPN-predictive SNP cluster identified pathways, gene ontology terms, and a network which were consistent with a neuropathic phenotype.

Topics: Genome-Wide Association Study; Humans; Neoplasms; Peripheral Nervous System Diseases; Polymorphism, Single Nucleotide; Taxoids

A limited number of studies are devoted to regulating

Topics: Adaptor Proteins, Signal Transducing; ATP Binding Cassette Transporter, Subfamily B; Cyclic AMP; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; LIM Domain Proteins; MCF-7 Cells; Neoplasms; Response Elements; Taxoids; Transcription Factors

A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.

Topics: Animals; Cytokines; Docetaxel; Granulocyte Colony-Stimulating Factor; Interleukin-6; Mice; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Taxoids

The mechanistic underpinnings of breast cancer recurrence following periods of dormancy are largely undetermined. A new study in PLOS Biology reveals that docetaxel-induced injury of tumour stromal cells stimulates the release of cytokines that support dormancy escape of breast cancer cells.

Topics: Bridged-Ring Compounds; Cytokines; Docetaxel; Neoplasms; Taxoids

Topics: Animals; Bridged-Ring Compounds; Disease Models, Animal; Female; Humans; Mice; Neoplasms; Programmed Cell Death 1 Receptor; Receptor, EphA2; Taxoids

Hypersensitivity reactions to antineoplastic agents may lead to discontinuation of first-line treatments. Rapid drug desensitization (RDD) allows for a safe reintroduction in patients who are allergic to them.. To evaluate the safety and efficacy of the Brigham and Women's Hospital's 12-step RDD in a Portuguese patient population with cancer and to identify markers associated with breakthrough reactions (BTRs) to platins.. We conducted a retrospective review of desensitizations undertaken at the Immunoallergology Day-Care Unit of the Santa Maria Hospital in Lisbon, Portugal, from July 2008 to July 2019. Adult patients with cancer and with immediate hypersensitivity reactions were included. Skin testing was performed to platins, trastuzumab, and cetuximab. The 12-step protocol was used for most patients, and a shorter protocol was used in 9 patients who were taxane-reactive to resume regular infusions.. A total of 1471 RDDs were performed in 272 patients to 136 platins, 124 taxanes, 13 monoclonal antibodies, and 10 other drugs. Skin test results were positive in 127 of patients who were platin-reactive (95.3%) and negative in patients who were cetuximab- and trastuzumab-reactive. There were 141 BTRs during RDD (9.6% of infusions), 79.4% induced by platins with the majority having mild reactions (68.8%). There were 8 patients who were paclitaxel-reactive, and who completed a shorter protocol and resumed regular infusions successfully. Multiple platin infusions (cutoff: ≥10) and total immunoglobulin E greater than or equal to 100 U/mL were identified as independent risk factors for BTRs in patients who were platin-reactive.. This large single-center study confirmed the safety and efficacy of the 12-step RDD protocol in a diverse cancer population, providing evidence of its universal applications. Total immunoglobulin E is a potentially useful biomarker to identify high-risk patients who are platin-reactive.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Bridged-Ring Compounds; Cetuximab; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Immunoglobulin E; Male; Middle Aged; Neoplasms; Outpatients; Paclitaxel; Portugal; Retrospective Studies; Risk Factors; Skin Tests; Taxoids; Trastuzumab; Young Adult

The absolute risk reduction by prophylaxis in chemotherapy-induced febrile neutropenia (FN) is largest in patients at highest underlying risk. Therefore, reliable predictive models are needed. Here, we develop and validate such a model for risk of FN during chemotherapy cycles 2-6. A prediction score for risk of FN during the first cycle has recently been published. Patients with solid cancers initiating first-line chemotherapy in 2010-2016 were included. Cycle-specific risk factors were assessed by Poisson regression using generalized estimating equations and random split sampling. The derivation cohort included 4,590 patients treated with 15,419 cycles, wherein 326 (2.1%) FN events occurred. Predictors of FN in multivariable analyses were: higher predicted risk of FN in the first cycle, platinum- or taxane-containing therapies, concurrent radiotherapy, treatment in cycle 2 compared to later cycles, previous FN or neutropenia and not receiving granulocyte colony-stimulating factors. Each predictor added between -2 and 8 points to each patient's score (median score 4; interquartile range, 1-6). The incidence rate ratios for developing FN in the intermediate (score 1-4), high (score 5-6) and very high risk groups (score ≥7) were 7.8 (95% CI, 2.4-24.9), 18.6 (95% CI, 5.9-58.8) and 51.7 (95% CI, 16.5-162.3) compared to the low risk group (score ≤0), respectively. The score had good discriminatory ability with a Harrell's C-statistic of 0.78 (95% CI, 0.76-0.80) in the derivation and 0.75 (95% CI, 0.72-0.78) in the validation cohort (patient n = 2,295, cycle n = 7,670). The Cycle-Specific Risk of FEbrile Neutropenia after ChEmotherapy score is the first published method to estimate cycle-specific risk of FN.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Chemotherapy-Induced Febrile Neutropenia; Denmark; Drug Administration Schedule; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Male; Middle Aged; Models, Biological; Neoplasms; Platinum Compounds; Poisson Distribution; Risk Assessment; Risk Factors; Taxoids

Treatment-induced peripheral neuropathy (TIPN) is a difficult problem experienced by patients with cancer that can interfere with their ability to receive optimal therapy. The Treatment-Induced Peripheral Neuropathy Scale (TNAS) is a patient-reported outcome (PRO) measure developed to assess TIPN symptom burden. However, PRO validation is an ongoing process. The aim of this qualitative study was to define the conceptual model, establish content domain validity, and refine items for the TNAS based on patient input.. Patients who received bortezomib, oxaliplatin, or platinum-taxane combination therapy reported their experience of TIPN in single qualitative audiotaped interviews. Themes of the TIPN experience were identified by descriptive analysis of the transcribed interviews.. Three groups of 10 patients each who had received bortezomib, oxaliplatin, or platinum-taxane combination therapy, for a total of 30 patients, reported their experiences. Two themes reported by patients were TIPN sensations and functional interference. Five sensations (numbness, tingling, pain, heat or burning, and coldness) and five functional impacts (using hands, walking, maintaining balance or falling, wearing shoes, and sleeping) were reported by at least 20% of patients and were selected for inclusion in the TNAS v3.0 for additional psychometric testing.. The assessment of TIPN must be convenient, reliable, and practical for patients, who are the most reliable source of information about symptoms. The TNAS, developed with direct patient input, provides an easily administered and conceptually valid method of patient report of TIPN burden for use in research and practice.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bortezomib; Bridged-Ring Compounds; Female; Humans; Male; Middle Aged; Neoplasms; Oxaliplatin; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Psychometrics; Taxoids

While older adults with cancer are more likely to develop chemotherapy-induced peripheral neuropathy (CIPN), the study aimed to determine if patient-reported and objective measures of CIPN differ by age among cancer survivors.. Cancer survivors with persistent CIPN after completion of platinum and/or taxane chemotherapy completed CIPN questionnaires (severity, interference with activities, sensory, and motor symptoms) and objective testing (light touch, vibration, pain, cold sensation). CIPN measures were compared by age group (< 65 n = 260 versus ≥ 65 n = 165) using parametric and nonparametric tests.. Among 425 cancer survivors with CIPN, mean age was 60.9 (SD 10.5). CIPN location did not differ by age (overall 68% hands and feet, 27% only feet, 5% only hands). For patient-reported measures, older survivors reported less severe pain in the hands and feet than younger survivors. In addition, older survivors reported lower interference with general activity, routine activities, normal work, enjoyment of life, sleep, mood, relations with other people, and sexual activity. No age differences in sensory and motor symptom scores were found. In contrast, for objective measures, older survivors had worse light touch and cold sensations in their feet and worse vibration detection in their hands and feet.. Despite having worse light touch, cold, and vibration sensations, older cancer survivors with CIPN reported less severe pain and interference with activities. This discordance highlights the importance of including both patient-reported and objective measures to assess CIPN in cancer survivors to better evaluate this clinical condition.

Topics: Aged; Antineoplastic Agents; Bridged-Ring Compounds; Cancer Survivors; Female; Humans; Induction Chemotherapy; Male; Middle Aged; Neoplasms; Pain; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Platinum; Self Report; Surveys and Questionnaires; Taxoids

To evaluate the frequency of nasal symptoms termed nasal vestibulitis, including nasal dryness, crusting, bleeding, and pain, among patients receiving systemic, antineoplastic therapy.. Patients undergoing systemic antineoplastic therapy were interviewed regarding the presence of nasal symptoms. In an explorative approach, Fisher's exact tests were used to identify groups in which frequencies of nasal symptoms were higher than the comparator arm. To account for potential confounding factors, including demographic variables and concurrent therapies, logistic regression analyses were performed, and estimated proportions with their standard errors (SEs) and odds ratios (ORs) were reported.. Forty-one percent of the 100 surveyed patients had nasal symptoms, including dryness, pain, bleeding, and scabbing. Higher frequencies were reported among those who had received taxanes (71%) and VEGF-related therapies (78%). For the patients who had received taxanes, after controlling for other factors, the odds of experiencing nasal symptoms were 4.86 times higher than those for patients who did not receive taxanes (90% CI 2.01, 11.76). For patients who received VEGF-related therapies, after controlling for other factors and exposure to taxanes, the odds of experiencing nasal symptoms were 7.38 (90% CI 1.68, 32.51) times higher than those for patients who did not. Sixty-one percent of patients with symptoms said they reported them to their provider, but only 41% of chart notes contained documentation of such; 49% of patients reported treating their symptoms.. Nasal vestibulitis is common among patients receiving taxane- and VEGF-related therapies; these symptoms are infrequently recorded or treated by healthcare providers.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged-Ring Compounds; Diagnostic Errors; Female; Humans; Male; Middle Aged; Neoplasms; Nose Diseases; Quality of Life; Taxoids; Vascular Endothelial Growth Factor A

To structurally modify our existing cholic acid (CA)-based telodendrimer (TD; PEG. Generation of hybrid TDs was achieved by replacing four of the eight CAs with biocompatible organic moieties using solution-phase peptide synthesis. Drug loading was done using the standard evaporation method.. Hybrid TDs can generate micelles with narrow size distributions, low critical micelle concentration values (1-6 μM), better hematocompatibility and lack of in vitro cytotoxicity.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Cell Line, Tumor; Cholic Acid; Docetaxel; Drug Carriers; Humans; Micelles; Nanoparticles; Neoplasms; Paclitaxel; Taxoids

Neuropathic pain can be present in patients developing chemotherapy-induced peripheral neuropathy (CIPN). Nerve growth factor (NGF) is trophic to small sensory fibers and regulates nociception.. We investigated the changes in serum NGF and intraepidermal nerve fiber density in skin biopsies of cancer patients receiving neurotoxic chemotherapy in a single-center prospective observational study.. Patients were evaluated before and after chemotherapy administration. CIPN was graded with Total Neuropathy Score. Neuropathic pain was present in 13 of 60 patients (21%), who reported shooting or burning pain in the hands (n = 9) and the feet (n = 12). Patients displaying painful CIPN presented higher NGF after treatment compared with patients with painless or absent CIPN (8.7 ± 11.9 vs. 2.5 ± 1.4 pg/mL, P = 0.016). The change of NGF significantly correlated with neuropathic pain. Patients with painful CIPN did not show significant loss of IEFND compared with patients with painless or absent CIPN (6.16 ± 3.86 vs. 8.37 ± 4.82, P = 0.12). No correlation between IEFND and NGF was observed.. Serum NGF increases in cancer patients receiving taxane or platinum with painful CIPN, suggesting that it might be a potential biomarker of the presence and severity of neuropathic pain in this population. Long-term comprehensive studies to better define the course of NGF in relation with neurological outcomes would be helpful in the further design of therapies for CIPN-related neuropathic pain.

Topics: Antineoplastic Agents; Bridged-Ring Compounds; Female; Humans; Leg; Male; Middle Aged; Neoplasms; Nerve Growth Factor; Neural Conduction; Neuralgia; Pain Measurement; Platinum Compounds; Prospective Studies; Skin; Surveys and Questionnaires; Taxoids

The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence and severity of peripheral sensory neuropathy (PSN) in patients using taxane therapy.. A retrospective single-center analysis was conducted: Patients with PSN at baseline were excluded. The incidence of PSN was evaluated retrospectively in patient subgroups who received taxane arm and taxane-plus-platinum-agents combination arm with or without known DM at baseline.. Three hundred seventy-four patients were enrolled in this study, 81 (21.6%) of patients had DM at baseline. The incidence of grade 1 PSN (non-DM/DM) in patients receiving taxane-based chemotherapy was 33.4/25.9% and more than grade 2 PSN (non-DM/DM) was 15/34.6%. The rate of neuropathy of non-diabetic patients was 48.8%, while the rate of diabetic patients was 52.8 and 75% in DM duration below 5 years and above 5 years group, respectively.. This retrospective analysis indicates that taxane-based therapy in DM patients whose disease duration is above 5 years appears to affect the incidence and severity of PSN without known baseline neuropathy. The probability of PSN with taxane-based therapy was similar in DM duration below 5 years and non-DM patients.

Topics: Aged; Bridged-Ring Compounds; Diabetes Complications; Female; Humans; Incidence; Male; Neoplasms; Peripheral Nervous System Diseases; Retrospective Studies; Taxoids

Oxaliplatin and taxane-induced neurosensory toxicity is dose-limiting and mostly presents with acute symptoms that affect the activities of daily living and overall quality of life. The objective of the present study is to assess the relief of acute neuropathy with venlafaxine treatment during the chemotherapy period.. In this retrospective case-control study, from January 2010 to February 2015, patients who experienced treatment with oxaliplatin and taxane-induced acute neurotoxicity were evaluated according to the NCI-CTCAE v. 4.03 grading scale. Neurotoxicity was evaluated using a numeric rating scale (NRS) for pain intensity and experienced relief under the treatment of venlafaxine and using a neuropathic pain symptom inventory scale (NPSI) for the style of complaints. Patients who were diagnosed as mildly depressed according to the HOST anxiety and depression scale and who had grade 1 to 3 sensory neurotoxicity based on the NCI-CTCAE v. 4.03 grading scale, and who also reported ≥ 4/10 on a NRS were eligible. The primary end point was the rate of more than 75 % symptomatic relief under venlafaxine treatment.. Two hundred six patients were included (82 % female, median age: 52.7 years). Most patients had breast, gynecologic, and colon cancer (93.4 %). Ninety-one patients who received venlafaxine and 115 patients as the control group were assessed for neurotoxicity every 3 weeks. Based on the NRS, a rate of more than 75 % symptomatic relief was 53.5, 58.3, and 45.2 % in venlafaxine arm versus 0, 0, and 0 % in the control arm in the first, second, and third visits, respectively. Side-effects of venlafaxine (n = 7) were grade 1-2 nausea/vomiting (3.2 %) and asthenia/somnolence (3.2 %) without grade 3-4 events.. Venlafaxine has a significant clinical activity against taxane-oxaliplatin-induced acute neurosensory toxicity.

Topics: Activities of Daily Living; Adult; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Case-Control Studies; Female; Humans; Middle Aged; Neoplasms; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Retrospective Studies; Selective Serotonin Reuptake Inhibitors; Taxoids; Treatment Outcome; Venlafaxine Hydrochloride

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.

Topics: Animals; Antigens, CD; Antineoplastic Agents; Bridged-Ring Compounds; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Membrane Microdomains; Mice, Inbred BALB C; Models, Biological; Neoplasms; Neoplastic Stem Cells; Phenotype; Protein Kinase Inhibitors; Signal Transduction; Taxoids; Time Factors

Despite widespread clinical use, delivery of taxane chemotherapeutics remains a challenge due to poor solubility and lack of selectively. Polymeric nanomicelle strategies have been pursued to overcome these issues; however current formulations are often limited by low drug loading and poor serum stability. To achieve a drug delivery system that addresses these issues, poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-g-poly(ethylene glycol) was covalently modified with the taxol binding peptide – a peptide from the β-tubulin-taxane binding site. This modification resulted in drug loadings five times higher than unmodified polymers, which is significantly higher than typical hydrophobic modifications, including with benzyl and docetaxel functionalization. Unlike many formulations with high drug loading, these nanomicelles were stable in serum for up to 24 h and maintained docetaxel cytotoxicity. By incorporating the taxane binding peptide into the polymer chemistry, a new twist was applied to an old problem, which is broadly applicable to other polymeric micelle systems and drug-peptide combinations in general.

Topics: Amino Acid Sequence; Antineoplastic Agents; Binding Sites; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Carriers; Drug Delivery Systems; Humans; Micelles; Molecular Sequence Data; Neoplasms; Paclitaxel; Peptides; Polyethylene Glycols; Taxoids

The taxanes are a class of chemotherapeutic agents that are widely used in the treatment of various solid tumors. Although taxanes are highly effective in cancer treatment, their use is associated with serious complications attributable to large interindividual variability in pharmacokinetics and a narrow therapeutic window. Unpredictable toxicity occurrence necessitates close patient monitoring while on therapy and adverse effects frequently require decreasing, delaying or even discontinuing taxane treatment. Currently, taxane dosing is based primarily on body surface area, ignoring other factors that are known to dictate variability in pharmacokinetics or outcome. This article discusses three potential strategies for individualizing taxane treatment based on patient information that can be collected before or during care. The clinical implementation of pharmacogenetics, enzyme probes or therapeutic drug monitoring could enable clinicians to personalize taxane treatment to enhance efficacy and/or limit toxicity.

Topics: Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Docetaxel; Drug Monitoring; Female; Humans; Neoplasms; Paclitaxel; Pharmacogenetics; Precision Medicine; Taxoids

Tumor resistance, especially that mediated by P-glycoprotein (P-gp) and β-III tubulin, is a major obstacle to the efficacy of most microtubule-targeting anticancer drugs in clinics. A novel semisynthetic taxane, 2-debenzoyl-2-(3-azidobenzyl)-10-propionyldocetaxel (Yg-3-46a) was shown to be highly cytotoxic to breast cancer cell lines MCF-7 and MCF/ADR which overexpressed P-gp via long term culture with doxorubicin, and cervical cancer cell lines Hela and Hela/βIII which overexpressed βIII-tubulin via stable transfection with TUBB3 gene. siRNA transfection experiments also confirmed that Yg-3-46a can circumvent P-gp and β-III tubulin mediated drug resistance. In addition, its cytotoxicity was lower than that of paclitaxel in the human mammary cell line HBL-100 and the human telomerase-immortalized retinal pigment epithelium cell line (hTERT-RPE1), suggesting a better safety margin for this compound in vivo. It exhibited more potent microtubule polymerization ability than paclitaxel in vitro, and also induced G2/M phase arrest in MCF-7/ADR cells. Moreover, it was found to induce apoptosis in MCF-7/ADR cells through the caspase-dependent death-receptor pathway by enhancing levels of Fas and FasL, and activating caspase-8 and 3. Yg-3-46a was found to be a poorer substrate of P-gp compared to paclitaxel, in both binding and ATPase experiments, which is likely responsible for its ability to circumvent P-gp mediated multidrug resistance (MDR). All of these results indicate that Yg-3-46a is a novel microtubule-stabilizing agent that has the potential to evade drug resistance mediated by P-gp and β-III tubulin overexpression.

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Bridged-Ring Compounds; Caspase 8; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Fas Ligand Protein; fas Receptor; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; MCF-7 Cells; Microscopy, Fluorescence; Molecular Structure; Neoplasms; Paclitaxel; Polymerization; RNA Interference; Taxoids; Tubulin

Resistance to anticancer drugs is a major obstacle to successful chemotherapy. Thus, the exploration of new drugs and strategies in combating resistance is of great importance. In this study, we investigated the anti-tumor drug resistance (anti-resistance for short) activity of Lx2-32c, a novel taxane, and its possible mechanisms. Lx2-32c was cytotoxic to various drug-resistant tumor cell lines, and significantly suppressed the growth of tumor xenografts in paclitaxel-resistant MX-1 nude mice. It promoted microtubule polymerization and G(2)/M phase arrest in MX-1/T cells. Moreover, it induced typical apoptotic characteristics indicated by morphological changes and DNA fragmentation. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c and apoptosis-inducing factor (AIF) release, elevation of the Bax/Bcl-2 ratio, activation of caspase-9,-3 but not caspase-8 and Fas/FasL, and degradation of poly(ADP-ribose) polymerase (PARP). In conclusion, Lx2-32c is an effective microtubule-stabilizing agent in overcoming paclitaxel resistance by inducing apoptosis via the intrinsic apoptotic pathway. It also displayed robust anti-paclitaxel-resistance activity in vivo. Therefore, these findings provide new insight into the strategy to overcome resistance by manipulating dysregulated apoptosis pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Bridged-Ring Compounds; Caspase 3; Caspase 9; Cell Cycle Checkpoints; Cell Line, Tumor; Cytochromes c; DNA Fragmentation; Drug Resistance, Neoplasm; Fas Ligand Protein; fas Receptor; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; Microtubules; Mitochondria; Neoplasms; Paclitaxel; Poly(ADP-ribose) Polymerases; Polymerization; Proto-Oncogene Proteins c-bcl-2; Taxoids; Xenograft Model Antitumor Assays

Cancer chemotherapeutic treatment is a complex scientific task. The ChemoFx Drug Response Marker (DRM) assists physicians in identifying treatment protocols likely to be effective for specific patients.. The ChemoFx DRM was used to study drug response in vitro. Established human cancer cell lines and primary cultures of patient tumor specimens were challenged with chemotherapeutic agents to observe response of multiple tumor samples and determine whether drugs with similar mechanisms of action elicit similar response.. These studies demonstrated heterogeneous response among patient tumor samples and clustering of drug response with similar mechanisms of action. Also highlighted was the reproducibility of ChemoFx DRM and its utility in characterizing tumor response to chemotherapy.. Heterogeneous drug responses observed in vitro were similar to those observed clinically. Response characteristics were similar for drugs with similar mechanisms of action, suggesting response heterogeneity is determined at a cellular and molecular level.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Neoplasms; Ovarian Neoplasms; Platinum Compounds; Reproducibility of Results; Taxoids

In the era of personal genomics, predicting the individual response to drug-treatment is a challenge of biomedical research. The aim of this study was to validate whether interaction information between genetic and transcriptional signatures are promising features to predict a drug response. Because drug resistance/susceptibilities result from the complex associations of genetic and transcriptional activities, we predicted the inter-relationships between genetic and transcriptional signatures. With this concept, captured genetic polymorphisms and transcriptional profiles were prepared in cancer samples. By splitting ninety-nine samples into a trial set (n = 30) and a test set (n = 69), the outperformance of relationship-focused model (0.84 of area under the curve in trial set, P = 2.90 x 10⁻⁴) was presented in the trial set and validated in the test set, respectively. The prediction results of modeling show that considering the relationships between genetic and transcriptional features is an effective approach to determine outcome predictions of drug-treatment.

Topics: Antineoplastic Agents; Area Under Curve; Bridged-Ring Compounds; Gene Expression Profiling; Humans; Neoplasms; Platinum Compounds; Polymorphism, Genetic; ROC Curve; Taxoids; Treatment Outcome

Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival" genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.

Topics: Bridged-Ring Compounds; Cell Survival; Chromosomal Instability; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Microtubules; Neoplasms; Paclitaxel; Polymerase Chain Reaction; Prognosis; Taxoids

Topics: Antineoplastic Agents; Biomedical Research; Bridged-Ring Compounds; Clinical Trials as Topic; Doxorubicin; Humans; Molecular Structure; Neoplasms; Prodrugs; Taxoids; Treatment Outcome

Topics: 17-Hydroxysteroid Dehydrogenases; Animals; Antineoplastic Agents; Bridged-Ring Compounds; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Humans; Microspheres; Neoplasms; Oncogene Protein v-akt; Protein Tyrosine Phosphatases; Retroviridae Proteins, Oncogenic; Taxoids; Vitamin D

Lonafarnib (SCH66336) is a farnesyl transferase inhibitor (FTI) that inhibits the post-translational lipid modification of H-Ras and other farnesylated proteins. K- and N-Ras are also substrates of farnesyl transferase; however, upon treatment with FTIs, they are alternatively prenylated by geranylgeranyl transferase-1. Despite the failure to abrogate prenylation of K- and N-Ras, growth of many tumors in preclinical models is inhibited by FTIs. This suggests that the anti-proliferative action of FTIs is dependent on blocking the farnesylation of other proteins. Rheb (Ras homologue enriched in brain) is a farnesylated small GTPase that positively regulates mTOR (mammalian target of rapamycin) signaling. We found that Rheb and Rheb2 mRNA were elevated in various tumor cell lines relative to normal cells. Peptides derived from the carboxyl termini of human Rheb and Rheb2 are in vitro substrates for farnesyl transferase but not geranylgeranyl transferase-1. Rheb prenylation in cell culture was completely inhibited by SCH66336, indicating a lack of alternative prenylation. SCH66336 treatment also inhibited the phosphorylation of S6 ribosomal protein, a downstream target of Rheb and mTOR signaling. SCH66336 did not inhibit S6 phosphorylation in cells expressing Rheb-CSVL, a mutant construct of Rheb designed to be geranylgeranylated. Importantly, expression of Rheb-CSVL also abrogated SCH66336 enhancement of tamoxifen- and docetaxel-induced apoptosis in MCF-7 breast cancer cells and ES-2 ovarian cancer cells, respectively. Further, inhibition of Rheb signaling by rapamycin treatment, small interfering RNA, or dominant negative Rheb enhanced tamoxifen- and docetaxel-induced apoptosis, similar to FTI treatment. These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the anti-tumor response to other chemotherapeutics.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Bridged-Ring Compounds; Caspases; Cell Line, Tumor; Farnesyltranstransferase; Humans; Monomeric GTP-Binding Proteins; Neoplasms; Neuropeptides; Phosphorylation; Piperidines; Protein Kinases; Protein Prenylation; Pyridines; Ras Homolog Enriched in Brain Protein; Recombinant Fusion Proteins; RNA, Messenger; Signal Transduction; Tamoxifen; Taxoids; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Docosahexaenoic Acids; Humans; Neoplasms; Paclitaxel; Polyglutamic Acid; Prodrugs; Taxoids

A series of taxane prodrugs with 2-bromoacyl chains attached at the 2'-position of the paclitaxel side chain, varying from six, eight, 12, 14 to 16 carbons in length, were synthesized, characterized and evaluated against human breast MCF-7 cancer cell line for their growth inhibitory (GI50) activities. The GI50 is the drug concentration required to inhibit cell growth by 50%. For comparison, hydrophobic taxanes varying in acyl chain lengths from six to 16 carbons were also synthesized and compared for their G050s with taxanes having equivalent bromoacyl chain lengths. The bromoacyl taxanes bearing six, eight and 12 carbon acyl chain lengths had GI50 values very similar to parent paclitaxel. The GI50 was 3 nM for three taxanes versus 1 nM for paclitaxel on the MCF-7 cell line. Increasing the acyl chain length to 14 or 16 carbons resulted in a significant decrease in cytotoxicity and an increase in the GI50 to 20 or 70 nM, respectively. In general, the GI50 values were directly related to the bromoacyl chain lengths in cultured tumor cells. Unlike bromoacyl taxanes, the taxanes lacking bromine in their acyl chain composition were 50- to 250-fold less active, suggesting that the heteroatom facilitated the hydrolysis of acyl chains to yield free paclitaxel. These differences in growth inhibitory activities may indirectly reflect differences in the susceptibility of the acyl chain to bromine-induced hydrolysis after association of the derivative with cell membranes. Liposome formulations of 2-bromoacyl taxanes bearing six, eight, 12 and 16 carbons were prepared and tested in SCID mice against a xenografted human ovcar-3 ovarian tumor. In vivo results showed that bromoacyl taxanes with a longer chain were therapeutically more efficacious than those with a short chain, presumably due to slow hydrolysis of the prodrug followed by sustained delivery of paclitaxel to the tumor.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged-Ring Compounds; Cell Cycle; DNA, Neoplasm; Drug Screening Assays, Antitumor; Female; Flow Cytometry; Humans; Mice; Mice, Nude; Molecular Structure; Neoplasms; Paclitaxel; Taxoids; Tubulin; Tumor Cells, Cultured

Topics: Bridged Bicyclo Compounds; Bridged-Ring Compounds; Humans; Neoplasm Staging; Neoplasms; Paclitaxel; Survival Rate; Taxoids