Taxane Anticancer Agents Research Articles

Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.

The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1months and overall survival was 14months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7months. Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

CYP2C8 rs11572080 and CYP3A4 rs2740574 risk genotypes in paclitaxel-treated premenopausal breast cancer patients

Breast cancer (BC) is the most prevalent malignancy in women globally. At time of diagnosis, premenopausal BC is considered more aggressive and harder to treat than postmenopausal cases. Cytochrome P450 (CYP) enzymes are responsible for phase I of estrogen metabolism and thus, they are prominently involved in the pathogenesis of BC. Moreover, CYP subfamily 2C and 3A play a pivotal role in the metabolism of taxane anticancer agents. To understand genetic risk factors that may have a role in pre-menopausal BC we studied the genotypic variants of CYP2C8, rs11572080 and CYP3A4, rs2740574 in female BC patients on taxane-based therapy and their association with menopausal status. Our study comprised 105 female patients with histologically proven BC on paclitaxel-therapy. They were stratified into pre-menopausal (n = 52, 49.5%) and post-menopausal (n = 53, 50.5%) groups. Genotyping was done using TaqMan assays and employed on Quantstudio 12 K flex real-time platform. Significant increased frequencies of rs11572080 heterozygous CT genotype and variant T allele were established in pre-menopausal group compared to post-menopausal group (p = 0.023, 0.01, respectively). Moreover, logistic regression analysis revealed a significant association between rs11572080 CT genotype and premenopausal BC. However, regarding rs2740574, no significant differences in genotypes and allele frequencies between both groups were detected. We reported a significant association between CYP2C8 genotypic variants and premenopausal BC risk in Egyptian females. Further studies on larger sample sizes are still needed to evaluate its importance in early prediction of BC in young women and its effect on treatment outcome.

Simultaneous Pseudoprogression and an Immune-related Adverse Event of Pulmonary Pleomorphic Carcinoma after Combined Therapy with Cytotoxic Anticancer Agents and Immune Checkpoint Inhibitor.

Pulmonary pleomorphic carcinoma is rare among lung tumors. Pulmonary pleomorphic carcinoma is resistant to chemotherapy. However, treatment with taxane anticancer agents and immune checkpoint inhibitors has been reported to be effective. When using immune checkpoint inhibitors, pseudoprogression and true progression are difficult to distinguish, and immune-related adverse events (irAEs) are common. We herein report a patient with simultaneous pseudoprogression and irAEs after combined therapy with cytotoxic agents and an immune checkpoint inhibitor for pulmonary pleomorphic carcinoma. Immune checkpoint inhibitors are effective against pulmonary pleomorphic carcinoma, but patients should be monitored for pseudoprogression and irAEs.

Human mesenchymal stem cells lose their functional properties after paclitaxel treatment

Mesenchymal stem cells (MSCs) are an integral part of the bone marrow niche and aid in the protection, regeneration and proliferation of hematopoietic stem cells after exposure to myelotoxic taxane anti-cancer agents, but the influence of taxane compounds on MSCs themselves remains incompletely understood. Here, we show that bone marrow-derived MSCs are highly sensitive even to low concentrations of the prototypical taxane compound paclitaxel. While MSCs remained metabolically viable, they were strongly impaired regarding both their proliferation and their functional capabilities after exposure to paclitaxel. Paclitaxel treatment resulted in reduced cell migration, delays in cellular adhesion and significant dose-dependent inhibition of the stem cells’ characteristic multi-lineage differentiation potential. Cellular morphology and expression of the defining surface markers remained largely unaltered. Paclitaxel only marginally increased apoptosis in MSCs, but strongly induced premature senescence in these stem cells, thereby explaining the preservation of the metabolic activity of functionally inactivated MSCs. The reported sensitivity of MSC function to paclitaxel treatment may help to explain the severe bone marrow toxicities commonly caused by taxane-based anti-cancer treatments.

Effects of Cryotherapy on Objective and Subjective Symptoms of Paclitaxel-Induced Neuropathy: Prospective Self-Controlled Trial.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting and disabling side effect of taxane anticancer agents. We prospectively evaluated the efficacy of cryotherapy for CIPN prevention.MethodsBreast cancer patients treated weekly with paclitaxel (80 mg/m2 for one hour) wore frozen gloves and socks on the dominant side for 90 minutes, including the entire duration of drug infusion. Symptoms on the treated sides were compared with those on the untreated (nondominant) sides. The primary end point was CIPN incidence assessed by changes in tactile sensitivity from pretreatment baseline in a monofilament test at a cumulative dose of 960 mg/m2. We also assessed thermosensory deficits, subjective symptoms (Patient Neuropathy Questionnaire [PNQ]), manipulative dexterity, and the time to events and hazard ratio by PNQ. All statistical tests were two-sided.ResultsAmong the 40 patients, four did not reach the cumulative dose (due to the occurrence of pneumonia, severe fatigue, severe liver dysfunction, and macular edema), leaving 36 patients for analysis. None dropped out due to cold intolerance. The incidence of objective and subjective CIPN signs was clinically and statistically significantly lower on the intervention side than on the control (hand: tactile sensitivity = 27.8% vs 80.6%, odds ratio [OR] = 20.00, 95% confidence interval [CI] = 3.20 to 828.96, P < .001; foot: tacile sensitivity = 25.0% vs 63.9%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; hand: warm sense = 8.8% vs 32.4%, OR = 9.00, 95% CI = 1.25 to 394.48, P = .02; foot: warm sense: 33.4% vs 57.6%, OR = 5.00, 95% CI = 1.07 to 46.93, P = .04; hand: PNQ = 2.8% vs 41.7%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; foot: PNQ = 2.8% vs 36.1%, OR = infinite, 95% CI = 2.78 to infinite, P < .001; hand: hazard ratio [HR] = 0.13, 95% CI = 0.05 to 0.34; foot: HR = 0.13, 95% CI = 0.04 to 0.38, dexterity mean delay = −2.5 seconds, SD = 12.0 seconds, vs + 8.6 seconds, SD = 25.8 seconds, P = .005).ConclusionsCryotherapy is useful for preventing both the objective and subjective symptoms of CIPN and resultant dysfunction.

Abstract 2238: Novel sylibin analogues target ovarian cancer EMT-Wnt/β-catenin resistance pathways

Abstract Ovarian cancer (OC) is one of most lethal malignancies in woman reproductive tract. The OC diagnosed in advanced stage (III-IV) patients is highly aggressive and relapses back in over 80% patient after initial response to chemotherapy. Currently used chemotherapies are limited due to significant adverse/toxic effects, a narrow therapeutic index, and development of multidrug resistance mediated by the epithelial-to-mesenchymal transition (EMT) and cancer cell membrane efflux transporters. It is presumed that an ideal anti-OC drug that has diverse mechanisms, would inhibit several key cell-survival signaling and resistance pathways when combined with conventional chemotherapy (paclitaxel and cisplatin). Silybin, a polyphenolic flavonoid, has previously shown to inhibit metastasis by inhibition of EMT pathways and bypass other drug resistance factors i.e. efflux transporters in ovarian cancer both in vitro and in vivo. However, clinical use of silybin is limited due to their poor absorption and low bioavailability and poor potency. To overcome this, we designed and synthesized 11 silybin derivatives using molecular modeling, computer aided drug design, structure activity relationship, natural product lead optimization and ring disjunction approaches. In our preliminary findings, we found the lead molecule (15k) to have a cytotoxicity (IC50&amp;lt1µM) with potency more than 200-fold compared to silybin (IC50~150µM). The 15k was found to be around 10-fold selective in OC cells (OV2008, A2780) compared to normal ovarian cells. Additionally, compared to other cancer cells belonging to prostate, breast, lung, 15k was (3-6)-fold selective in OC cells (OV2008, A2780). The 15k produced synergistic activity and potentiated the cytotoxic effects of platinum (cisplatin), anthracyclines (doxorubicin) and taxane (paclitaxel) anticancer agents. While 15k also reversed the drug resistance mediated by ABC-efflux transporters to paclitaxel and doxorubicin. Mechanistically, the cytotoxic effect of lead compound 15k, as determined by using molecular biology assays, was found to be due to inhibition of apoptosis, tubulin inhibition, and inhibition of stemness pathways (Wnt-β-catenin-EMT). The 15k had significant anti-metastatic effects as shown by their inhibition of migration and invasion potential on OC cells. In silico findings suggest that pharmacokinetic [PK] profiles of these compounds are favorable compared to silybin. Further in vivo PK/pharmacodynamic studies are underway to establish the clinical use of lead molecule in advanced metastasized, drug resistant OC patients. Citation Format: Haneen A. Amawi, Noor Hussein, Aubry Fetcenkoa, Rawan Alnafisah, Karthikeyan Chandrabose, Elangovan Manivannan, Piyush Trivedi, Amit K. Tiwari. Novel sylibin analogues target ovarian cancer EMT-Wnt/β-catenin resistance pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2238. doi:10.1158/1538-7445.AM2017-2238

Modern Methods of Controlling Wound Healing after Fistulizing Glaucoma Surgery. Risk Factors and Antimetabolites

The article describes modern approaches to controlling wound healing after fistulizing glaucoma surgery. It provides a classification of refractory glaucoma degrees and summarizes risk factors for excessive scarring. Author describes various applications of widely administered in clinical practice antimetabolites (5 fluorouracil, mitomycin C) in patients with different degrees of excessive wound healing risk. The review also recounts international experience of steroidal and nonsteroidal anti-inflammatory drug use and their efficacy research study results. Much attention is given to new strategies of wound healing regulation after fistulizing glaucoma surgery, aimed at enhancing its results. The article describes characteristics and modes of action of medicinal agents effecting the cytoskeleton, such as Rho-kinase inhibitors and taxane anticancer agents. A detailed account of modes of effecting wound healing through regulating the process growth factors, proteinases and cytokines is also given. Possible strategies include antifibrotic cytokine interferon-α application and inhibiting the following agents: transforming growth factor β; connective tissue growth factor (CTGF), that controls extracellular matrix components production and cicatrical tissue formation; vascular endothelial growth factor (VEGF), that indirectly influences fibrotic activity through its angiogenic effect and also has a supposed direct effect on fibroblast activity; proinflammatory placental growth factor (PIGF), that increases bleb area size and its survival time, and decreases postoperative angiogenesis, inflammation and fibrosis intensity. The last part of the article gives a brief report on less widespread and researched methods of wound healing regulation, such as suppressing the activity of matrix metalloproteinases and amniotic membrane application.

Recent Advances in Synthesis of α‐Hydroxy‐β‐amino Acids and Their Use in SAR Studies of Taxane Anticancer Agents

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Discovery and Development of New Generation Taxane Anticancer Agents

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF.

Recent Advances in the New Generation Taxane Anticancer Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Recent Advances in the New Generation Taxane Anticancer Agents

Recent advances in the design and preclinical evaluations of promising new generation taxane anticancer agents are reviewed in this article. Paclitaxel and docetaxel are two of the most important anticancer drugs today. However, recent reports have shown that treatment with these drugs often encounters undesirable side effects as well as drug resistance. Therefore, it is important to develop new taxane anticancer agents with fewer side effects, superior pharmacological properties, and improved activity against drug-resistant human cancers. Structure-activity relationship (SAR) studies led to the discovery of a series of highly active second-generation taxanes. One of them, "Ortataxel" (SB-T-101131, IDN5109, BAY59-8862), exhibits excellent activity against a variety of drug-sensitive and drug-resistant cancer cell lines, as well as human tumor xenografts in mice. It is orally active and is currently in phase II clinical trials. Photoaffinity labeling of microtubules and P-glycoprotein using photoreactive radiolabeled taxoids has disclosed the drug-binding domain of tubulin as well as Pgp. Together with information on microtubule-bound fluorine-labeled taxoids obtained by solid-state NMR studies, the bioactive conformation of paclitaxel and taxoids appears to emerge. Novel taxane-monoclonal antibody (mAb) immunoconjugates, have shown highly promising results for the tumor-specific delivery and release of an extremely cytotoxic, second-generation taxane. Also, another novel series of second generation taxanes conjugated with n-3 polyunsaturated fatty acids, e.g. decosahexaenoic acid (DHA), has exhibited impressive antitumor activity with minimum general toxicity against the highly drug-resistant DLD-1 human colon cancer xenografts in SCID mice.

Use of fluorine in the medicinal chemistry and chemical biology of bioactive compounds--a case study on fluorinated taxane anticancer agents.

Flurinated prodrugs. This minireview describes the exploitation of the unique nature of fluorine in the medicinal chemistry and chemical biology of taxane anticancer agents as a showcase in this field of research.

Treatment and care of neurotoxicity from taxane anticancer agents.

Taxane anticancer agents play a central role in drug therapy for breast cancer today; however, they have a dose-limiting neurotoxicity that is difficult to prevent and treat. To protect against this neurotoxicity it is important to avoid large doses greater than 200 mg/m2, and to adopt 24-hour administration regimens. Care is also needed with regard to the cumulative dose. Glutamine and amitriptyline are two of the very few drugs that have been found to be clinically effective against drug-induced peripheral neuropathy. Drugs are discontinued if neuropathy appears. If administration is to be later restarted, it is recommended that combined use of glutamine or amitriptyline be considered and that patients be given guidance for daily life.

Pharmacological effects of formulation vehicles : implications for cancer chemotherapy.

The non-ionic surfactants Cremophor EL (CrEL; polyoxyethyleneglycerol triricinoleate 35) and polysorbate 80 (Tween) 80; polyoxyethylene-sorbitan-20-monooleate) are widely used as drug formulation vehicles, including for the taxane anticancer agents paclitaxel and docetaxel. A wealth of recent experimental data has indicated that both solubilisers are biologically and pharmacologically active compounds, and their use as drug formulation vehicles has been implicated in clinically important adverse effects, including acute hypersensitivity reactions and peripheral neuropathy.CrEL and Tween 80 have also been demonstrated to influence the disposition of solubilised drugs that are administered intravenously. The overall resulting effect is a highly increased systemic drug exposure and a simultaneously decreased clearance, leading to alteration in the pharmacodynamic characteristics of the solubilised drug. Kinetic experiments revealed that this effect is primarily caused by reduced cellular uptake of the drug from large spherical micellar-like structures with a highly hydrophobic interior, which act as the principal carrier of circulating drug. Within the central blood compartment, this results in a profound alteration of drug accumulation in erythrocytes, thereby reducing the free drug fraction available for cellular partitioning and influencing drug distribution as well as elimination routes. The existence of CrEL and Tween 80 in blood as large polar micelles has also raised additional complexities in the case of combination chemotherapy regimens with taxanes, such that the disposition of several coadministered drugs, including anthracyclines and epipodophyllotoxins, is significantly altered. In contrast to the enhancing effects of Tween 80, addition of CrEL to the formulation of oral drug preparations seems to result in significantly diminished drug uptake and reduced circulating concentrations. The drawbacks presented by the presence of CrEL or Tween 80 in drug formulations have instigated extensive research to develop alternative delivery forms. Currently, several strategies are in progress to develop Tween 80- and CrEL-free formulations of docetaxel and paclitaxel, which are based on pharmaceutical (e.g. albumin nanoparticles, emulsions and liposomes), chemical (e.g. polyglutamates, analogues and prodrugs), or biological (e.g. oral drug administration) strategies. These continued investigations should eventually lead to more rational and selective chemotherapeutic treatment.

Chemistry and chemical biology of taxane anticancer agents.

Taxol (paclitaxel) and Taxotere (docetaxel) are currently considered to be among the most important anticancer drugs in cancer chemotherapy. The anticancer activity of these drugs is ascribed to their unique mechanism of action, i.e., causing mitotic arrest in cancer cells, leading to apoptosis through inhibition of the depolymerization of microtubules. Although both paclitaxel and docetaxel possess potent antitumor activity, treatment with these drugs often results in a number of undesirable side effects, as well as multidrug resistance (MDR). Therefore, it has become essential to develop new anticancer agents with superior pharmacological properties, improved activity against various classes of tumors, and fewer side effects. This paper describes an account of our research on the chemistry of paclitaxel and taxoid anticancer agents at the biomedical interface, including: 1. The structure-activity relationship (SAR) study of taxoids leading to the development of the "second-generation" taxoids, which possess exceptional activity against drug-resistant cancer cells expressing the MDR phenotype. 2. Development of fluorinated taxoids to study the bioactive conformation of paclitaxel and photoaffinity labeling taxoids for mapping of the drug-binding domain on both microtubules and P-glycoprotein. 3. The synthesis of novel macrocyclic taxoids for the investigation into the common pharmacophore for microtubule stabilizing anticancer agents.

Taxol Analysis by High Performance Liquid Chromatography: A Review

High performance liquid chromatographic analysis of taxol and related taxane anticancer agents is reviewed with respect to separation mode and conditions, detection modes, extraction procedures and techniques. The application of the analysis to plant material, cell cultures and other biological material is discussed.

Book Review, Taxane Anticancer Agents: Basic Science and Current Status

Book Review, Taxane Anticancer Agents: Basic Science and Current Status

Taxane anticancer agents. Basic science and current status

Taxane anticancer agents. Basic science and current status