Taxanes: A New Class of Antitumor Agents

Huizing, Manon; Misser, V. H. Sewberath; Pieters, Rob; Huinink, W.W. ten Bokkel; Veenhof, C. H. N.; Vermorken, Jan B.; Pinedo, H.M.; Beijnen, Jos H.

doi:10.3109/07357909509031919

Cited by 246 publications

(122 citation statements)

References 85 publications

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“…Although NF-B is generally thought of as a survival factor that prevents cell death (42,58,59), there is also contrary evidence (60 -62). Additional experiments from another laboratory reveal that the super-repressor IB form did not sensitize cells to paclitaxel-induced death, 3 , but it did sensitize cells to TNF-␣, a DNA-damaging agent, and another chemotherapy (42). Fig.…”

Section: Dominant-inhibitory Mutants Of Jnk1 and Mekk1 Suppressmentioning

confidence: 99%

“…Paclitaxel (Taxol) is a new generation of chemotherapeutic drug that is effective against malignant non-small cell lung (1,2), prostate (3,4), and breast cancer (5), with the most encouraging effects observed in cancer chemotherapy-refractory ovarian cancer (6). Paclitaxel exhibited significant antitumor activity against human ovarian cancer in a nude mouse model (6).…”

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Paclitaxel (Taxol)-induced Gene Expression and Cell Death Are Both Mediated by the Activation of c-Jun NH2-terminal Kinase (JNK/SAPK)

Lee¹,

Li²,

Templeton³

et al. 1998

Journal of Biological Chemistry

177

118

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Paclitaxel (Taxol) is a new generation of chemotherapeutic drug that is effective against malignant non-small cell lung (1, 2), prostate (3, 4), and breast cancer (5), with the most encouraging effects observed in cancer chemotherapy-refractory ovarian cancer (6). Paclitaxel exhibited significant antitumor activity against human ovarian cancer in a nude mouse model (6). Furthermore, paclitaxel significantly inhibited the angiogenic response induced by tumor cell supernatant in mice (7,8). The primary mechanism of action of paclitaxel is attributed to its ability to bind microtubules and to prevent their disassembly. However, the effect of paclitaxel exceeds that of conventional microtubule-disrupting agents, and there is increasing evidence that paclitaxel has multiple cellular effects in addition to the blockage of mitosis (9 -15).One of the effects of paclitaxel is to alter gene expression. In murine macrophages, paclitaxel can induce the expression of a series of lipopolysaccharide-inducible cytokines, such as IL 1

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Section: Dominant-inhibitory Mutants Of Jnk1 and Mekk1 Suppressmentioning

confidence: 99%

mentioning

confidence: 99%

Paclitaxel (Taxol)-induced Gene Expression and Cell Death Are Both Mediated by the Activation of c-Jun NH2-terminal Kinase (JNK/SAPK)

Lee¹,

Li²,

Templeton³

et al. 1998

Journal of Biological Chemistry

177

118

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“…First, it is a widely used anticancer agent (20) that has markedly improved the survival of patients (21,22). Notwithstanding this success, Taxol elicits resistance and, even more so than most chemotherapeutic agents, lacks significant activity against MDR tumors (10,23,24), thus providing a formidable and important challenge for evaluating strategies for overcoming MDR.…”

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confidence: 99%

Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters

Dubikovskaya¹,

Thorne

Pillow³

et al. 2008

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

224

213

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Many cancer therapeutic agents elicit resistance that renders them ineffective and often produces cross-resistance to other drugs. One of the most common mechanisms of resistance involves P-glycoprotein (Pgp)-mediated drug efflux. To address this problem, new agents have been sought that are less prone to inducing resistance and less likely to serve as substrates for Pgp efflux. An alternative to this approach is to deliver established agents as molecular transporter conjugates into cells through a mechanism that circumvents Pgp-mediated efflux and allows for release of free drug only after cell entry. Here we report that the widely used chemotherapeutic agent Taxol, ineffective against Taxol-resistant human ovarian cancer cell lines, can be incorporated into a releasable octaarginine conjugate that is effective against the same Taxolresistant cell lines. It is significant that the ability of the Taxol conjugates to overcome Taxol resistance is observed both in cell culture and in animal models of ovarian cancer. The generality and mechanistic basis for this effect were also explored with coelenterazine, a Pgp substrate. Although coelenterazine itself does not enter cells because of Pgp efflux, its octaarginine conjugate does so readily. This approach shows generality for overcoming the multidrug resistance elicited by small-molecule cancer chemotherapeutics and could improve the prognosis for many patients with cancer and fundamentally alter search strategies for novel therapeutic agents that are effective against resistant disease.ovarian cancer ͉ Pgp ͉ Taxol ͉ imaging ͉ luciferase

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“…Les nanoparticules utilisées assurent une certaine gastrorésistance ; elles ne libèrent pas leur contenu en milieu acide et permettent, au contraire, sa libération lente dans les milieux aqueux proches de la neutralité [27,28]. Particulièrement intéressant est le fait que les niveaux plasmatiques de paclitaxel obtenus avec les nanoparticules pégylées sont plus élevés que la concentration minimale considérée comme thérapeutique (environ 85 ng/ml [37]). Les résultats obtenus au cours de ces travaux montrent clairement que la pharmacocinétique du paclitaxel est influencée par la masse moléculaire du PEG utilisé.…”

Section: Discussion Et Conclusionunclassified

Nanoparticules mucopénétrantes : véhicules pour l’administration orale du paclitaxel

Zabaleta

Calleja

Espuelas

et al. 2013

Annales Pharmaceutiques Françaises

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RésuméLe paclitaxel est un agent anticancéreux utilisé en solution pour perfusion intraveineuse dans le traitement de différents types de cancer. Dans les dernières années, de nombreuses stratégies ont été proposées pour le développement d'une formulation orale de cet anticancéreux. Toutefois, la faible solubilité aqueuse du paclitaxel et le fait qu'il soit un substrat de la pglycoprotéine intestinale et du complexe enzymatique cytochrome P450 compliquent énormément le problème. Dans ce travail, des nanoparticules pégylées avec des propriétés mucopénétrantes ont été développées pour acheminer le paclitaxel jusqu'à la surface des entérocytes. Des particules présentant une taille moyenne d'environ 180 nm et un contenu en paclitaxel proche de 15% ont été préparées. Une étude pharmacocinétique chez la souris a montré que les nanoparticules permettent d'obtenir des niveaux plasmatiques efficaces et soutenus du paclitaxel pendant 3 jours. Au total, la biodisponibilité relative orale du paclitaxel, encapsulé dans des nanoparticules pégylées avec du PEG 2000, est proche du 85%. Chez la souris, sur un modèle de tumeur sous-cutanée, ces mêmes nanoparticules administrées par voie orale, une fois tous les trois jours, ont permis d'obtenir une efficacité similaire à celle offerte par le médicament commercialisé administré par voie intraveineuse journellement pendant 9 jours. L'ensemble des résultats tend à démontrer que les nanoparticules développées sont capables de traverser la couche du mucus intestinal et d'atteindre, ainsi, la surface des entérocytes. Les molécules de PEG favorisent l'adhésion des particules à la surface des cellules, évitent la métabolisation du paclitaxel et accroissent son absorption. Mots-clés : nanoparticules, paclitaxel, orale, poly (éthylène glycol), libération contrôlée SummaryPaclitaxel is an anticancer drug used as solution for perfusion for the treatment of certain types of cancers. In the last years, a number of strategies have been proposed for the development of an oral formulation of this drug. However, this task is quite complicated due to the poor aqueous solubility of paclitaxel as well as the fact that this compound is substrate of the intestinal P-glycoprotein and the cytochrome P450 enzymatic complex. In this work, we have developed pegylated nanoparticles with muco-penetrating properties in order to conduct paclitaxel till the surface of the enterocyte. These nanoparticles displayed a size of about 180 nm and a drug loading close to 15% by weight. The pharmacokinetic study in mice has shown that these nanoparticles were capable to offer therapeutic plasma levels of paclitaxel up to 72 hours. In addition, the oral relative bioavailability of paclitaxel when loaded in nanoparticles pegylated with poly(ethylene glycol) 2000 (PEG) was found to be 85%. In a subcutaneous model of tumour in mice, these pegylated nanoparticles administered orally every 3 days have demonstrated a similar efficacy than Taxol administered intravenously every day during 9 days. 3All of these results suggested ...

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Taxanes: A New Class of Antitumor Agents

Cited by 246 publications

References 85 publications

Paclitaxel (Taxol)-induced Gene Expression and Cell Death Are Both Mediated by the Activation of c-Jun NH2-terminal Kinase (JNK/SAPK)

Paclitaxel (Taxol)-induced Gene Expression and Cell Death Are Both Mediated by the Activation of c-Jun NH2-terminal Kinase (JNK/SAPK)

Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters

Nanoparticules mucopénétrantes : véhicules pour l’administration orale du paclitaxel

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