Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

Berruti, Alfredo; Bitossi, Raffaella; Gorzegno, G.; Bottini, Alberto; Generali, Daniele; Milani, Manuela; Katsaros, Dionyssios; Longrais, Irene A. Rigault de la; Bellino, R; Donadio, Michela; Ardine, Mara; Bertetto, Oscar; Danese, Saverio; Sarobba, Maria Giuseppa; Farris, A.; Lorusso, Vito; Dogliotti, Luigi

doi:10.1038/sj.bjc.6602335

Cited by 12 publications

(10 citation statements)

References 29 publications

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“…Anti-cancer strategies based on the concomitant administration of taxanes and depolymerizing agents such as vinorelbine have been reported [ 34 , 35 , 36 ]. However, these approaches used high doses of each of these drugs.…”

Section: Discussionmentioning

confidence: 99%

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Peronne

Denarier

Rai

et al. 2020

Cancers

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Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Peronne

Denarier

Rai

et al. 2020

Cancers

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“…Anti-cancer strategies based on the concomitant administration of taxanes and depolymerizing agents such as vinorelbine have been reported [32–34]. However, these approaches used high doses of each of these drugs.…”

Section: Discussionmentioning

confidence: 99%

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Peronne

Denarier

Rai

et al. 2020

Preprint

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Phone number +33(0)4 24 76 54 95 71 laurence.lafanechere@univ-grenoble-alpes.fr 25 2 Running title: A new paclitaxel sensitizer that targets tubulin 26 Scientific Research (NWO) CW ECHO grant (711.015.005) to AA. 32 33 The authors declare no potential conflicts of interest 34 35 Word count: 36 Abstract: 158 words 37 Main manuscript, including acknowledgments: 4667 words 38 Figure legends: 1115 words 39 Number of references: 34 40 Abstract 43Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy 44 inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched 45 for drugs which could potentiate its therapeutic effect. We have screened a chemical library 46 3 and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells 47 grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the 48 colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-49 induced modulation of microtubule dynamics increases the accumulation of fluorescent 50 paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy 51 between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell 52 viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring 53 paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, 54 paving the way for new therapeutic strategies combining low doses of microtubule targeting 55 agents with opposite mechanisms of action. 56 Introduction 57 Microtubules (MTs), dynamic polymeric filaments composed of -tubulin and -tubulin 58 heterodimers, are key components of the cytoskeleton of eukaryotic cells. Their crucial roles 59 in cell division and physiology mainly rely on their ability to rapidly polymerize or 60 depolymerize. Targeted perturbation of this finely tuned process constitutes a major 61 therapeutic strategy. Drugs interfering with MTs are major constituents of chemotherapies for 62 the treatment of carcinomas. A number of compounds bind to the tubulin-MT system. They 63 can be roughly classified into MT-stabilizers such as taxanes or epothilones, and MT-64 destabilizers such as vinca alkaloids, combretastatin and colchicine [1]. It has been 65 demonstrated that binding of vinca alkaloids or colchicine prevents the curved-to-straight 66 conformational change of tubulin at the tip of the growing MT, necessary for proper 67 incorporation of new tubulin dimers into the MT lattice (see reviews [1,2]). 68 Paclitaxel (PTX) binds to the taxane-site of -tubulin and stabilizes the MT lattice by 69 strengthening lateral and/or longitudinal tubulin contacts within the MT [1]. At stoichiometric 70 concentrations, it promotes MT assembly. At low and clinically relevant concentrations, PTX 71

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“…The scheme was extremely active in this setting [36]. On the basis of these encouraging results, we tested this combination in association with weekly epirubicin as first-line approach in a phase II study including patients with anthracycline-naïve metastatic patients [37] and in association to weekly paclitaxel as first-line approach in a further phase II study enrolling metastatic breast cancer patients pretreated with anthracyclines [38]. These two schemes were active, but the response rates and response durations did not seem to be superior than those currently obtained with anthracycline and taxane regimens administered on a conventional MTD.…”

Section: Future Perspectives Of Metronomic Chemotherapy In Acc Patientsmentioning

confidence: 96%

Metronomic Therapy Concepts in the Management of Adrenocortical Carcinoma

et al. 2011

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Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.

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Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

Cited by 12 publications

References 29 publications

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Metronomic Therapy Concepts in the Management of Adrenocortical Carcinoma

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