Paclitaxel (Taxol) is a potent anti-neoplastic and anti-mitotic taxane compound used in cancer chemotherapy. Paclitaxel binds to the N-terminus of β-tubulin and and stabilizes microtubules arresting the cell cycle at the G2/M phase. The microtubule damage induces apoptosis through a JNK-dependent pathway followed by a JNK-independent pathway, perhaps related to the activation of protein kinase A (PKA) or of Raf-1 kinase, resulting in phosphorylation of Bcl-2. Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of microtubules during cell division. The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes, a process normally activated during mitosis. The binding site for paclitaxel has been identified on the beta-tubulin subunit. In vitro and in vivo studies have demonstrated that paclitaxel is extensively metabolised by the liver to 3 primary metabolites.
|Cell lines||human neonatal dermal microvascular ECs (HMVECs), human umbilical vein ECs (HUVECs), human umbilical artery ECs (HUAVECs), normal human astrocytes (NHAs), normal human dermal fibroblasts (NHDFs), normal human epidermal keratinocytes (NHEKs|
|Preparation method||Cells including human neonatal dermal microvascular ECs (HMVECs), human umbilical vein ECs (HUVECs), human umbilical artery ECs (HUAVECs), normal human astrocytes (NHAs), normal human dermal fibroblasts (NHDFs), normal human epidermal keratinocytes (NHEKs), human mammary epithelial cells (HMEpCs), human prostate epithelial cells (PrEpCs) and human umbilical artery smooth muscle cells (UASMCs) are cultured. Cell proliferations are performed in 96-well plates using cells between passages 6 and 12. Cells are seeded at 3000–5000 cells/well and allowed to attach for 4 hours. Paclitaxel, diluted in culture medium, is added in quadruplicate wells and the cells ae incubated for 3 days before MTS reagents are added to quantitate the live cells in each well.|
|Incubation time||72 h|
|Animal models||nude athymic mice with BC-V and BC-ER tumors|
|Formulation||Dissolved in absolute ethanol with an equal volume of cremophor and diluted 1:4 with sterile physiological saline before use|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL|
Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules.
Peltier S, et al. Pharm Res. 2006 Jun;23(6):1243-50. PMID: 16715372.
Cytotoxic studies of paclitaxel (Taxol) in human tumour cell lines.
Liebmann JE, et al. Br J Cancer. 1993 Dec;68(6):1104-9. PMID: 7903152.
Clinical pharmacokinetics of paclitaxel.
Sonnichsen DS, et al. Clin Pharmacokinet. 1994 Oct;27(4):256-69. PMID: 7834963.
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