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Paclitaxel (also known as NSC-125973; BMS-181339-01; trade name taxol; Anzatax; Asotax; Bristaxol) is a highly potent microtubule polymer stabilizer (mitotic inhibitor that stabilizes the polymerization of tubulin) with an IC50 of 0.1 pM in human endothelial cells. Paclitaxel has shown potent and a broad spectrum of antineoplastic activities, and has been extensively used in the treatment of various cancers. It is a natural product isolated from the Pacific yew tree Taxus brevifolia that has anticancer activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2.
Physicochemical Properties
| Molecular Formula | C47H51NO14 |
| Molecular Weight | 853.91 |
| Exact Mass | 853.33 |
| Elemental Analysis | C, 66.11; H, 6.02; N, 1.64; O, 26.23 |
| CAS # | 33069-62-4 |
| Related CAS # | Paclitaxel-d5;1129540-33-5;Paclitaxel-d5 (benzoyloxy);1261254-56-1; 33069-62-4; 186040-50-6 (ceribate); 263351-82-2 (Poliglumex); 117527-50-1 (Paclitaxel-Succinic acid) |
| PubChem CID | 36314 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 957.1±65.0 °C at 760 mmHg |
| Melting Point | 213 °C (dec.)(lit.) |
| Flash Point | 532.6±34.3 °C |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C |
| Index of Refraction | 1.637 |
| LogP | 7.38 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 14 |
| Rotatable Bond Count | 14 |
| Heavy Atom Count | 62 |
| Complexity | 1790 |
| Defined Atom Stereocenter Count | 11 |
| SMILES | O=C(C1=CC=CC=C1)N[C@@H](C2=CC=CC=C2)[C@H](C(O[C@@H]3C(C)=C([C@@H](OC(C)=O)C([C@@]4(C)[C@]([C@@](CO5)(OC(C)=O)[C@@]5([H])C[C@@H]4O)([H])[C@@H]6OC(C7=CC=CC=C7)=O)=O)C(C)(C)[C@@]6(O)C3)=O)O |
| InChi Key | RCINICONZNJXQF-MZXODVADSA-N |
| InChi Code | InChI=1S/C47H51NO14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57H,22-24H2,1-6H3,(H,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1 |
| Chemical Name | (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-hydroxy-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxete-6,12b-diyl diacetate |
| Synonyms | NSC 125973; BMS 181339-01; NSC-125973; BMS181339-01; NSC125973; BMS-181339-01; Trade name: Taxol; Taxol Konzentrat; Anzatax; Asotax; Bristaxol; Praxel; TAX.P88XT4IS4D; Paclitaxel; Taxol A; Yewtaxan; Genaxol; Plaxicel; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Microtubule; tubulin polymerization; tubulin stabilizer |
| ln Vitro |
In the G2/M phase of the cell cycle, paclitaxel (20 nM; 48 h) causes programmed cell death and arrest [1]. A prolonged rise in p53 levels is induced by paclitaxel (20 nM; 48 hours). The anticancer agent, taxol, stabilizes tubulin polymerization, resulting in arrest at the G2/M phase of the cell cycle and apoptotic cell death. However, the molecular mechanism of this growth inhibition and apoptosis is poorly understood. In this study, we used MCF-7 and MDA-MB-231 human breast carcinoma cells which have different estrogen receptor (ER) and tumor suppressor p53 statuses to examine the mechanisms of taxol-induced growth inhibition and apoptosis. Treatment of the cells with taxol resulted in a time-dependent inhibition of cell viability, which was accompanied by an accumulation of cells at G2/M and the sub-G1 apoptotic region, determined by flow cytometric analysis. Furthermore, chromatin condensation, DNA ladder formation and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) in both cell lines were observed following treatment with taxol, indicating the occurrence of apoptotic cell death. Western blot analysis using whole cell lysates from MCF-7 and MDA-MB-231 cells treated with taxol demonstrated that taxol treatment inhibited expression of cyclin A and cyclin B1 proteins in a time-dependent manner. The inhibitory effects of taxol on cell growth and apoptosis induced by taxol were also associated with the downregulation of Wee1 kinase expression and a marked induction in the activity of the cyclin-dependent kinase inhibitor, p21WAF/CIP1. Furthermore, taxol elevated p21 promoter activity in both cell lines. These findings suggest that taxol-induced G2/M arrest and apoptosis in human breast carcinoma cells is mediated through the ER- and p53-independent upregulation of p21 [1]. Both tumor cell lines treated with pulsed paclitaxel exposures exhibited a significant number of cells undergoing apoptosis, however many fewer cells were arrested at the G2/M-phase of the cell cycle when compared to the continuous paclitaxel exposures. Short exposures to paclitaxel also induced the phosphorylation and degradation of IkappaB-alpha, which in turn caused the activation of NF-kappaB in both cell lines. Parthenolide was found to inhibit paclitaxel-induced activation of the NF-kappaB/IkappaB signal pathway as well as apoptotic cell death. Conclusion: These findings suggest that paclitaxel-induced apoptosis might occur independent of a prior G2/M-phase arrest and be mediated or regulated by the NF-kappaB/IkappaB signal pathway[2]. To address the controversy regarding efficacy of paclitaxel in the presence of the anti-apoptotic protein Bcl-2, we investigated calcium stored in the endoplasmic reticulum as a potential factor. Our results showed that the ER calcium store is a common target for both paclitaxel and Bcl-2 protein. Paclitaxel directly associates with the endoplasmic reticulum to stimulate the release of calcium into the cytosol, contributing to the induction of apoptosis. However, Bcl-2 expression suppresses the cell's pro-apoptotic response of endoplasmic reticulum calcium release, thus inhibiting susceptibility of cancer cells to undergo apoptosis. Depending upon dosage, a paclitaxel-induced stimulatory effect can overcome the Bcl-2-mediated inhibitory effect on endoplasmic reticulum calcium release, thus attenuating the resistance of Bcl-2 to apoptosis. Our finding is the first to demonstrate that endoplasmic reticulum calcium plays a key role in the efficacy of paclitaxel in the presence of Bcl-2, thus providing insight into the complex but crucial paclitaxel-calcium-Bcl-2 relationship, which may impact breast cancer treatment[4]. |
| ln Vivo |
In the low-paclitaxel group, paclitaxel (1–20 mg/kg; intraperitoneal injection; once every two days, 5 cycles total) significantly increased the risk of liver metastasis while having minimal influence on the growth of the underlying tumor. Here we report that a low dose of paclitaxel enhances metastasis of breast cancer cells to the liver in mouse models. We used microarray analysis to investigate gene expression patterns in invasive breast cancer cells treated with low or clinically relevant high doses of paclitaxel. We also investigated the effects of low doses of paclitaxel on cell migration, invasion and metastasis in vitro and in vivo. The results showed that low doses of paclitaxel promoted inflammation and initiated the epithelial-mesenchymal transition, which enhanced tumor cell migration and invasion in vitro. These effects could be reversed by inhibiting NF-κB. Furthermore, low doses of paclitaxel promoted liver metastasis in mouse xenografts, which correlated with changes in estrogen metabolism in the host liver. Collectively, these findings reveal the paradoxical and dose-dependent effects of paclitaxel on breast cancer cell activity, and suggest that increased consideration be given to potential adverse effects associated with low concentrations of paclitaxel during treatment [3]. The purpose of the present study was to test the prediction that the unique manifestation of chemotherapeutic-induced peripheral neuropathy (CIPN) would be reflected in a specific pattern of changes in the regulation of the intracellular Ca(2+) concentration ([Ca(2+)]i) in subpopulations of cutaneous neurons. To test this prediction, we characterized the pattern of changes in mechanical nociceptive threshold associated with paclitaxel administration (2mg/kg, iv, every other day for four days), as well as the impact of target of innervation and paclitaxeltreatment on the regulation of [Ca(2+)]i in subpopulations of putative nociceptive and non-nociceptive neurons. Neurons innervating the glabrous and hairy skin of the hindpaw as well as the thigh were identified with retrograde tracers, and fura-2 was used to assess changes in [Ca(2+)]i. Paclitaxel was associated with a persistent decrease in mechanical nociceptive threshold in response to stimuli applied to the glabrous skin of the hindpaw, but not the hairy skin of the hindpaw or the thigh. However, in both putative nociceptive and non-nociceptive neurons, resting [Ca(2+)]i was significantly lower in neurons innervating the thigh after treatment. The magnitude of the depolarization-evoked Ca(2+) transient was also lower in putative non-nociceptive thigh neurons. More interestingly, while paclitaxel had no detectable influence on either resting or depolarization-evoked Ca(2+) transients in putative non-nociceptive neurons, in putative nociceptive neurons there was a subpopulation-specific decrease in the duration of the evoked Ca(2+) transient that was largely restricted to neurons innervating the glabrous skin. These results suggest that peripheral nerve length alone, does not account for the selective distribution of CIPN symptoms. Rather, they suggest the symptoms of CIPN reflect an interaction between the toxic actions of the therapeutic and unique properties of the neurons deleteriously impacted[6]. |
| Enzyme Assay |
In Vitro Tubulin Polymerization Assay[8] Tubulin was prepared as described before. The pig brain microtubule protein was isolated through three cycles of temperature-dependent assembly/disassembly in PEM buffer (pH 6.5, 100 mM PIPES, 2 mM EGTA, and 1 mM MgSO4) containing 1 mM GTP and 1 mM 2-mercaptoethanol. Tubulin was prepared from the microtubule protein by phosphocellulose chromatography and stored at −70 °C. Tubulin was mixed with indicated concentrations of test compounds in PEM buffer (100 mM PIPES, 1 mM MgCl2, and 1 mM EGTA) containing 1 mM GTP and 5% glycerol. Microtubule polymerization was monitored by a spectrophotometer at 340 nm. The plateau absorbance values were used for calculations. |
| Cell Assay |
Apoptosis Analysis[1] Cell Types: MCF-7, MDA-MB-231 cells Tested Concentrations: 20 nM Incubation Duration: 48 hrs (hours) Experimental Results: Induced programmed cell death. Cell Cycle Analysis[1] Cell Types: MCF-7, MDA-MB -231 cells Tested Concentrations: 20 nM Incubation Duration: 48 hrs (hours) Experimental Results: >60% of MCF-7 cells and 50% of MDA-MB-231 cells were in the G2/M phase following 24 h treament. Western Blot Analysis[1] Cell Types: MCF-7 cells (harboring wild-type p53) Tested Concentrations: 20 nM Incubation Duration: 48 hrs (hours) Experimental Results: Induced a consistent increase in the level of p53. |
| Animal Protocol |
Animal/Disease Models: MDA-231 xenograft-bearing mice[3] Doses: 1, 20 mg/kg Route of Administration: intraperitoneal (ip)injection; five cycles (1 time/2 days) Experimental Results: Liver metastases were obviously induced in the low-PTX (1 mg /kg) group with little influence on primary tumor growth compared with high-PTX group.《hr Paclitaxel treatment[6] One week following the DiI injection, rats were anesthetized with isofluorane and injected into the tail vein with 2 mg/kg paclitaxel or its vehicle (1:1:23, cremophor EL:ethanol:0.9% saline). The tail vein injection was repeated three more times every other day for a total of four injections. Primary tumor growth and metastasis detection in vivo[3] Specific pathogen free (SPF) nude mice were used. MDA-231 cells (1 × 106) were subcutaneously transplanted. After the formation of primary tumors (diameter > 5 mm), the mice were randomly grouped (10 mice per group) and different doses of PTX (paclitaxel) were diluted with normal saline and administrated by intraperitoneal injection (1 time/2 days). After five cycles of treatment, the mice were euthanized. The primary tumor growth and metastatic intensities were then measured, and images were captured. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the maximum plasma concentration (Cmax) is 195 ng/mL, while the AUC is 6300 ng•h/mL. In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. 227 to 688 L/m^2 [apparent volume of distribution at steady-state, 24 hour infusion] 21.7 L/h/m2 [Dose 135 mg/m2, infusion duration 24 h] 23.8 L/h/m2 [Dose 175 mg/m2, infusion duration 24 h] 7 L/h/m2 [Dose 135 mg/m2, infusion duration 3 h] 12.2 L/h/m2 [Dose 175 mg/m2, infusion duration 3 h] Paclitaxel bound to nanoparticles of the serum protein albumin is delivered via endothelial transport mediated by albumin receptors, and the resulting concentration of paclitaxel in tumor cells is increased compared with that achieved using an equivalent dose of conventional paclitaxel. Like conventional paclitaxel, albumin-bound paclitaxel has a large volume of distribution. Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, the volume of distribution averaged 632 L/sq m. The volume of distribution of albumin-bound paclitaxel 260 mg/sq m by 30-minute IV infusion was 53% larger than the volume of distribution of conventional paclitaxel 175 mg/sq m by 3-hour IV infusion. /Paclitaxel (albumin-bound)/ Following IV administration, paclitaxel is widely distributed into body fluids and tissues. Paclitaxel has a large volume of distribution that appears to be affected by dose and duration of infusion. Following administration of paclitaxel doses of 135 or 175 mg/sq m by IV infusion over 24 hours in patients with advanced ovarian cancer, the mean apparent volume of distribution at steady state ranged from 227-688 L/sq m. The steady-state volume of distribution ranged from 18.9-260 L/sq m in children with solid tumors or refractory leukemia receiving paclitaxel 200-500 mg/sq m by 24-hour IV infusion. Paclitaxel does not appear to readily penetrate the CNS, but paclitaxel has been detected in ascitic fluid following IV infusion of the drug. It is not known whether paclitaxel is distributed into human milk, but in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug. For the dose range 80-375 mg/sq m, increase in dose of albumin-bound paclitaxel was associated with a proportional increase in AUC.354 The duration of infusion did not affect the pharmacokinetic disposition of albumin-bound paclitaxel. Following 30-minute or 3-hour IV infusion of albumin-bound paclitaxel 260 mg/sq m, the peak plasma concentration averaged 18,741 ng/mL. /Paclitaxel (albumin-bound)/ Peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) following IV administration of paclitaxel exhibit marked interindividual variation. Plasma concentrations of paclitaxel increase during continuous IV administration of the drug and decline immediately following completion of the infusion. Following 24-hour IV infusion of paclitaxel at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 195 or 365 ng/mL, respectively; the increase in dose (30%) was associated with a disproportionately greater increase in peak plasma concentration (87%), but the increase in AUC was proportional. When paclitaxel was administered by continuous IV infusion over 3 hours at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 2.17 or 3.65 ug/mL, respectively; the increase in dose (30%) was associated with disproportionately greater increases in peak plasma concentration (68%) and AUC (89%). For more Absorption, Distribution and Excretion (Complete) data for TAXOL (8 total), please visit the HSDB record page. Metabolism / Metabolites Hepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4. Paclitaxel is extensively metabolized in the liver. Metabolism of paclitaxel to its major metabolite, 6alpha-hydroxypaclitaxel, is mediated by cytochrome P-450 isoenzyme CYP2C8,1 185 187 202 354 while metabolism to 2 of its minor metabolites, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel, is catalyzed by CYP3A4. The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24 hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by MS (fast atom bombardment and desorption chemical ionization) and (1)H NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3 of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol. To investigate how taxane's substituents at C3' affect its metabolism, ... the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3' position /was compared/. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4'' (M1) and C6alpha (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by (1)H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4''-hydroxycephalomannine was generated predominantly by CYP3A4 and 6alpha-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6alpha for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6alpha to C4'', and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4''-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4''-hydroxylation, whereas paclitaxel adopted an orientation favoring 3'-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V(m). Our results demonstrate that relatively minor modification of taxane at C3' has major consequence on the metabolism. Hepatic. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6a-hydrox-ypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6a, 3’-p-dihydroxypaclitaxel, by CYP3A4. Route of Elimination: In 5 patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Half Life: When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours. Biological Half-Life When a 24 hour infusion of 135 mg/m^2 is given to ovarian cancer patients, the elimination half=life is 52.7 hours. 5.3-17.4 hours after 1 and 6 hour infusions at dosing levels of 15-275 mg/sq m Following IV infusion of paclitaxel over periods ranging from 6-24 hours in adults with malignancy, plasma concentrations of paclitaxel appeared to decline in a biphasic manner in some studies, with an average distribution half-life of 0.34 hours and an average elimination half-life of 5.8 hours. However, additional studies, particularly those in which paclitaxel is administered over shorter periods of infusion, show that the drug exhibits nonlinear pharmacokinetic behavior. In patients receiving paclitaxel 175 mg/sq m administered by 3-hour IV infusion, the distribution half-life averages 0.27 hours and the elimination half-life averages 2.33 hours. Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, ... terminal half-life albumin-bound paclitaxel was about 27 hours. ... /Paclitaxel (albumin-bound)/ |
| Toxicity/Toxicokinetics |
Hepatotoxicity Paclitaxel has been associated with serum aminotransferase elevations in 7% to 26% of patients, but values greater than 5 times the upper limit of normal (ULN) in only 2% of those receiving the highest doses. Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur. The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation. Paclitaxel has not been linked convincingly to instances of delayed, idiosyncratic clinically apparent liver injury with jaundice. However, the hypersensitivity reactions that occur with infusions of paclitaxel can be severe and accompanied by acute hepatic necrosis. The liver injury may be relatively mild and anicteric (Case 1), but can also be severe with rapid onset of multiorgan failure and death. At least one instance of acute liver failure following a hypersensitivity reaction to paclitaxel has been published in the literature and recent modifications of the product labels for paclitaxel and docetaxel mention the occurrence of toxic deaths following severe infusion reactions. Because paclitaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be reliably attributed to paclitaxel rather than to other specific agents. Furthermore, paclitaxel in combination with other anticancer agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome or sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury. Likelihood score: D (possible cause of acute hepatic necrosis associated with a hypersensitivity reaction to the initial infusions). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Most sources consider breastfeeding to be contraindicated during maternal antineoplastic drug therapy. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence. Some have suggested a breastfeeding abstinence period of 6 to 10 days, but more recent pharmacokinetic modeling using a worst-case scenario suggests that 6 days would be adequate to minimize both systemic and gut toxicity after the colostral phase. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant than typical mothers. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 9 women who received a taxane-containing regimen, 7 had breastfeeding difficulties. Protein Binding 89%-98% bound to plasma protein. The presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. |
| References |
[1]. Paclitaxel-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells. Oncol Rep. 2012 Dec;28(6):2163-9. [2]. Paclitaxel-induced apoptosis may occur without a prior G2/M-phase arrest. Anticancer Res. 2004 Jan-Feb;24(1):27-36. [3]. Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model. FEBS J. 2016 Aug;283(15):2836-52. [4]. Paclitaxel attenuates Bcl-2 resistance to apoptosis in breast cancer cells through an endoplasmic reticulum-mediated calciumrelease in a dosage dependent manner. Biochem Biophys Res Commun. 2013 Feb 13. pii: S0006-291X(13)00259-3. [5]. Low dose paclitaxel reduces S100A4 nuclear import to inhibit invasion and hematogenous metastasis of cholangiocarcinoma. Cancer Res. 2016 Jun 21. [6]. Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model. FEBS J. 2016 Jun 16. [7]. Sensory neuron subpopulation-specific dysregulation of intracellular calcium in a rat model of chemotherapy-induced peripheral neuropathy. Neuroscience. 2015 Aug 6;300:210-8. [8]. E7080 enhances the antitumor effects of paclitaxel in anaplastic thyroid cancer. Am J Cancer Res. 2017 Apr 1;7(4):903-912. |
| Additional Infomation |
Paclitaxel can cause developmental toxicity, female reproductive toxicity and male reproductive toxicity according to state or federal government labeling requirements. Taxol appears as needles (from aqueous methanol) or fine white powder. An anti-cancer drug. Paclitaxel is a tetracyclic diterpenoid isolated originally from the bark of the Pacific yew tree, Taxus brevifolia. It is a mitotic inhibitor used in cancer chemotherapy. Note that the use of the former generic name 'taxol' is now limited, as Taxol is a registered trade mark. It has a role as a microtubule-stabilising agent, a metabolite, a human metabolite and an antineoplastic agent. It is a tetracyclic diterpenoid and a taxane diterpenoid. It is functionally related to a baccatin III. Paclitaxel is a chemotherapeutic agent marketed under the brand name Taxol among others. Used as a treatment for various cancers, paclitaxel is a mitotic inhibitor that was first isolated in 1971 from the bark of the Pacific yew tree which contains endophytic fungi that synthesize paclitaxel. It is available as an intravenous solution for injection and the newer formulation contains albumin-bound paclitaxel marketed under the brand name Abraxane. Paclitaxel is a Microtubule Inhibitor. The physiologic effect of paclitaxel is by means of Microtubule Inhibition. Paclitaxel is an antineoplastic agent which acts by inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer. Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of clinically apparent acute liver injury. Paclitaxel has been reported in Aspergillus ochraceopetaliformis, Aspergillus versicolor, and other organisms with data available. Paclitaxel is a compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2). (NCI04) Nab-paclitaxel is a Cremophor EL-free, albumin-stabilized nanoparticle formulation of the natural taxane paclitaxel with antineoplastic activity. Paclitaxel binds to and stabilizes microtubules, preventing their depolymerization and so inhibiting cellular motility, mitosis, and replication. This formulation solubilizes paclitaxel without the use of the solvent Cremophor, thereby permitting the administration of larger doses of paclitaxel while avoiding the toxic effects associated with Cremophor. A cyclodecane isolated from the bark of the Pacific yew tree, TAXUS brevifolia. It stabilizes microtubules in their polymerized form leading to cell death. ABI-007 (Abraxane) is the latest attempt to improve upon paclitaxel, one of the leading chemotherapy treatments. Both drugs contain the same active agent, but Abraxane is delivered by a nanoparticle technology that binds to albumin, a natural protein, rather than the toxic solvent known as Cremophor. It is thought that delivering paclitaxel with this technology will cause fewer hypersensitivity reactions and possibly lead to greater drug uptake in tumors. Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a US National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol. Later it was discovered that endophytic fungi in the bark synthesize paclitaxel. See also: Paclitaxel Ceribate (is active moiety of); Paclitaxel Poliglumex (is active moiety of); 7-Acetyltaxol (annotation moved to). Drug Indication Used in the treatment of Kaposi's sarcoma and cancer of the lung, ovarian, and breast. Abraxane® is specfically indicated for the treatment of metastatic breast cancer and locally advanced or metastatic non-small cell lung cancer. FDA Label Apealea in combination with carboplatin is indicated for the treatment of adult patients with first relapse of platinumâsensitive epithelial ovarian cancer , primary peritoneal cancer and fallopian tube cancer . Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas. Abraxane in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy. Pazenir monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. Pazenir in combination with carboplatin is indicated for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy. Paxene is indicated for the treatment of patients with: ⢠advanced AIDS-related Kaposi's sarcoma (AIDS-KS) who have failed prior liposomal anthracycline therapy; ⢠metastatic carcinoma of the breast (MBC) who have failed, or are not candidates for standard anthracycline-containing therapy; ⢠advanced carcinoma of the ovary (AOC) or with residual disease (> 1 cm) after initial laparotomy, in combination with cisplatin as first-line treatment; ⢠metastatic carcinoma of the ovary (MOC) after failure of platinum-containing combination therapy without taxanes as second-line treatment; ⢠non-small cell lung carcinoma (NSCLC) who are not candidates for potentially curative surgery and/or radiation therapy, in combination with cisplatin. Limited efficacy data supports this indication (see section 5. 1). Treatment of soft tissue sarcoma Treatment of solid malignant tumours Mechanism of Action Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive. Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication. ... Taxol induces tubulin polymerization and forms extremely stable and nonfunctional microtubules. Taxol has demonstrated broad activity in preclinical screening studies, and antineoplastic activity has been observed in several classically refractory tumors. These tumors include cisplatin resistant ovarian carcinoma in phase II trials and malignant melanoma and non-small cell lung carcinoma in phase I studies. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (2.44 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.. Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30 mg/mL Solubility in Formulation 5: 10 mg/mL (11.71 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 6: 10 mg/mL (11.71 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.1711 mL | 5.8554 mL | 11.7108 mL | |
| 5 mM | 0.2342 mL | 1.1711 mL | 2.3422 mL | |
| 10 mM | 0.1171 mL | 0.5855 mL | 1.1711 mL |