S-phase specificity of cell killing by docetaxel (Taxotere) in synchronised HeLa cells

Hennequin, Christophe; Giocanti, Nicole; Favaudon, V.

doi:10.1038/bjc.1995.232

Cited by 94 publications

(52 citation statements)

References 34 publications

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“…Docetaxel exhibits greater affinity to β-tubulin, targeting centrosome organization and acting on cells in three phases of the cell cycle (S/G 2 /M), whereas paclitaxel causes cell damage by affecting the mitotic spindle in the G 2 and M phases of the cell cycle [2]. Docetaxel was proven to be almost totally lethal against S-phase cells, while the maximum resistance to paclitaxel is early in the S phase [3]. The bcl-2 gene encodes the oncoprotein that prevents apoptosis, and this gene is overexpressed in several solid tumors, including breast, lung, prostate, and nasopharyngeal cancers.…”

Section: Molecular Pharmacologymentioning

confidence: 99%

Preclinical Pharmacology of the Taxanes: Implications of the Differences

2004

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Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to β β-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. Docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition, docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux. Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio-and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons. The Oncologist 2004;9(suppl 2):3-8 The Oncologist 2004;9(suppl 2):3-8 www.TheOncologist.com

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Section: Molecular Pharmacologymentioning

confidence: 99%

Preclinical Pharmacology of the Taxanes: Implications of the Differences

2004

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“…Docetaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilising microtubules and inducing cell-cycle arrest and apoptosis (Hennequin et al, 1995;Pienta, 2001). Estramustine phosphate is a nornitrogen mustard -estradiol conjugate that was developed as an alkylating agent specific for oestrogen receptorpositive cells (Smith, 1999).…”

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confidence: 99%

Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles

et al. 2006

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Caspase-cleaved proteins are released from disintegrated apoptotic cells and can be detected in the circulation. We here addressed whether caspase-cleaved cytokeratin 18 (CK18-Asp396) can be used as a serum biomarker for assessment of the clinical efficiency of chemotherapy in hormone-refractory prostate cancer (HRPC). A total of 82 patients with HRPC were evaluated during 751 treatment cycles, either with estramustine (EMP)/vinorelbine or with EMP/docetaxel. The levels of CK18-Asp396 and of total CK18 were measured in patient serum before and during therapy by ELISA. Docetaxel induced significant increases in serum CK18-Asp396 (Po0.0001) and total CK18 (Po0.0002), suggesting induction of apoptosis. Similarly, vinorelbine induced increases in both CK18-Asp396 and CK18 (Po0.001 and 0.011). In contrast, EMP induced increases in total serum CK18 (Po0.0001), but not in CK18-Asp396 (P ¼ 0.13). The amplitudes of docetaxel-induced increases were associated with baseline prostate-specific antigen (PSA) and CK18 serum levels in these patients, consistent with tumoral origin of caspase-cleaved fragments. Docetaxel induced significant increases in CK18-Asp396 during second-, third-and fourth-line therapy and induced increased levels of CK18-Asp396 during treatment cycles 1 -8. In contrast, vinorelbine induced significant increases only during cycles 1 -3. In a subgroup of 32 patients that received EMP/vinorelbine in second line followed by EMP/docetaxel in third line, docetaxel induced stronger increases than vinorelbine (P ¼ 0.008). These results show that the CK18-Asp396 serum marker can be used to assess tumour apoptosis in vivo and suggest that the clinical efficiency of docetaxel in HRPC is due to induction of apoptosis during multiple treatment cycles.

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“…Pemetrexed, as a multitargeted antifolate, causes an arrest in the S phase of the cell cycle. 38 Docetaxel is lethal towards cells in S phase by affecting centrosome organization 39 whereas bortezomib causes a G 2 /M-phase arrest. 40 Consequently, when bortezomib and a chemotherapeutic drug are administered simultaneously, the bortezomib-mediated G 2 /M arrest prevents cells from entering the part of the cell cycle in which the chemotherapeutical agents develop their definitive lethal activity as observed by Nawrocki et al…”

Section: Discussionmentioning

confidence: 99%

The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells

et al. 2007

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In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adenoassociated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vectormediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.

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S-phase specificity of cell killing by docetaxel (Taxotere) in synchronised HeLa cells

Cited by 94 publications

References 34 publications

Preclinical Pharmacology of the Taxanes: Implications of the Differences

Preclinical Pharmacology of the Taxanes: Implications of the Differences

Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles

The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells

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