Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer, breast cancer, ovarian cancer, soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI)

Schöffski, Patrick; Blay, Jean‐Yves; Grève, Jacques De; Brain, Étienne; Machiels, Jean‐Pascal; Soria, Jean‐Charles; Sleijfer, Stefan; Wolter, Pascal; Fontaine, Christel; Munzert, Gerd; Fritsch, Holger; Hanft, Gertraud; Aerts, Claire; Rapion, Jérôme; Allgeier, Anouk; Bogaerts, Jan; Lacombe, Denis

doi:10.1016/j.ejca.2010.03.039

Cited by 97 publications

(78 citation statements)

References 17 publications

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“…BI2536 induces G2/M arrest and the formation of abnormal mitotic figures, such as monopolar spindles. Although there are already clinical phase I and II trials conducted in which BI2536 is administered in different tumor entities there remains a need for further in vitro studies focusing on the pharmacological profile of BI2536 (16). In the present study, we systematically evaluated the effect of BI2536 in nine different squamous cell carcinoma cell lines for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…Although outcomes can differ between tumors of the same stage, the prognosis of patients suffering from head and neck cancer is mainly dependent on the tumor stage, particularly the lymph node status. Besides tobacco and alcohol abuse, an oropharyngeal infection with high-risk human papillomavirus, such as HPV 16 and HPV 18, may lead to the development of a squamous cell carcinoma, particularly of organs of the oral cavity such as the tonsils, tongue and palate (2). Based on the fact that primarily younger patients suffer from HPV-induced cancer of the head and neck, it seems as if high-risk HPV presents an additional risk factor.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the Polo-like-kinase-1-inhibitor BI2536 in squamous cell carcinoma cell lines of the head and neck

et al. 2012

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Abstract. Inhibition of the Polo-like-kinase-1 (PLK1) has been shown to be effective in a number of solid tumor models. In this in vitro study, we examined the antitumor effect of BI2536, a small molecule inhibitor of PLK1, in squamous cell carcinoma of the head and neck (SCCHN) cell lines. Dose escalation studies were performed with nine SCCHN cell lines using BI2536. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and a Human Apoptosis Array Kit. BI2536 demonstrated a significant antiproliferative and apoptotic activity in all nine SCCHN cell lines investigated (p<0.009). Our results indicate that inhibition of PLK1 by BI2536 leads to an antiproliferative and apoptotic effect in SCCHN cell lines. In vivo and in the clinical setting, the application of BI2536 may support the antitumoral activity of conventional drugs that are in current use and could decrease the systemic toxicity of these drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of the Polo-like-kinase-1-inhibitor BI2536 in squamous cell carcinoma cell lines of the head and neck

et al. 2012

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“…45 Yet, the clinical outcomes of these drugs are very disappointing due to severe side effects and poor anticancer activity when compared with the taxane Paclitaxel (PTX). [18][19][20][21][22][23] Besides the efforts toward novel drugs development, several groups focused on understanding how we can predict the response to PTX and thus circumvent the resistance mechanisms. Studies in cell lines demonstrated that the cell fate after exposure to PTX is extremely variable.…”

Section: Discussionmentioning

confidence: 99%

“…Such drugs have shown scarce efficacy in clinical application in spite of outstanding results in preclinical studies. [18][19][20][21][22][23] Thus, despite of the toxicity and high resistance rates, taxanes are a mainstay in the clinical landscape. 24 In order to overcome resistance mechanisms and more efficiently kill tumor cells, it was recently proposed to target mitotic exit.…”

Section: Introductionmentioning

confidence: 99%

Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy

et al. 2013

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Microtubule-poisoning drugs, such as Paclitaxel (or taxol, PtX), are powerful and commonly used anti-neoplastic agents for the treatment of several malignancies. PtX triggers cell death, mainly through a mitotic arrest following the activation of the spindle assembly checkpoint (SAC). Cells treated with PtX slowly slip from this mitotic block and die by mitotic catastrophe. However, cancer cells can acquire or are intrinsically resistant to this drug, posing one of the main obstacles for PtX clinical effectiveness. In order to override PtX resistance and increase its efficacy, we investigated both the enhancement of mitotic slippage and the block of mitotic exit.to test these opposing strategies, we used physiological hyperthermia (Ht) to force exit from PtX-induced mitotic block and the anaphase-promoting complex/cyclosome (APC/C) inhibitor, protAMe, to block mitotic exit. We observed that application of Ht on PtX-treated cells forced mitotic slippage, as shown by the rapid decline of cyclin B levels and by microscopy analysis. Similarly, Ht induced mitotic exit in cells blocked in mitosis by other antimitotic drugs, such as Nocodazole and the Aurora A inhibitor MLN8054, indicating a common effect of Ht on mitotic cells. On the other hand, protAMe prevented mitotic exit of PtX and MLN8054 arrested cells, prolonged mitosis, and induced apoptosis. In addition, we showed that protAMe prevented Ht-mediated mitotic exit, indicating that stress-induced APC/C activation is necessary for Ht-induced mitotic slippage.Finally, Ht significantly increased PtX cytotoxicity, regardless of cancer cells' sensitivity to PtX, and this activity was superior to the combination of PtX with pro-tAMe. Our data suggested that forced mitotic exit of cells arrested in mitosis by anti-mitotic drugs, such as PtX, can be a more successful anticancer strategy than blocking mitotic exit by inactivation of the APC/C.

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“…It has been shown that BI-2536 has potent tumoricidal activity against cancer cells, particularly those harboring mutations in TP53 (44-47). BI-2536 was the subject of several clinical trials in patients with cancers of the lung, breast, ovaries, and uterus (48)(49)(50)(51)(52)(53). Although it showed evidence of efficacy in cancer patients, its development was abandoned after phase II trials revealed unacceptable toxicity (grade 4 neutropenia) at subtherapeutic doses.…”

Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hymentioning

confidence: 99%

Remote loading of preencapsulated drugs into stealth liposomes

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Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

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Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

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Cited by 97 publications

References 17 publications

Effects of the Polo-like-kinase-1-inhibitor BI2536 in squamous cell carcinoma cell lines of the head and neck

Effects of the Polo-like-kinase-1-inhibitor BI2536 in squamous cell carcinoma cell lines of the head and neck

Targeting mitotic exit with hyperthermia or APC/C inhibition to increase paclitaxel efficacy

Remote loading of preencapsulated drugs into stealth liposomes

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