Tasidotin hydrochloride (ILX651)
(Synonyms: TASIDOTIN盐酸盐,ILX651) 目录号 : GC33178
Tasidotin hydrochloride (ILX651) 是抗有丝分裂肽 dolastatin 15 的肽类似物，作为微管组装和微管动力学的抑制剂。
Cas No.:623174-20-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | MDA-MB-435 and HS 578-T breast carcinoma cells are grown in 25 mL of medium in Corning 75-cm2 culture flasks. For monolayer cells, when the cells are at near confluence, the medium is exchanged for 15 mL of fresh medium containing the indicated concentration of 0.1 μM [3H]Tasidotin, and the incubation continues for the indicated time. Monolayer cells are harvested by scraping them from the surface of the culture flask. For suspension cells, when the cells are in log phase and at approximately 106 cells/mL, the [3H]Tasidotin is added at the indicated concentration, and the incubation continued for the indicated time as specified in individual experiments. Suspension cells are harvested by centrifugation. Both types of cells are washed twice with PBS, pH 7.2. The cells are resuspended in 0.5 mL of water and disrupted by 10 s periods of sonication at 28 W, followed by 10 s pauses, for a total of 1 min. Protein content and radiolabel of all cell extracts are determined[1]. |
Cell experiment: | Growth inhibition is determined by the microculture tetrazolium method. Briefly, cells are seeded in 96 well flat-bottomed microtiter plates at a density of 500 cells per well in 100 μL of medium. After overnight incubation, 100 μL of medium containing Tasidotin are added to achieve specified final concentrations and a final volume of 200 μL/well. At 120 h, the relative metabolic activities of treated and untreated cells are measured by mitochondrial conversion of MTT to formazine. At the completion of the drug treatment, 250 μg of MTT are added to each well and incubated at 37°C, 5% CO2 for 6 h. Formazine crystals are dissolved in DMSO and absorbance at 595 nm is measured on a VERSAmax spectrophotometer. Absorbance values are normalized to the values obtained for the vehicle-treated cells to determine the percentage of survival. The IC50 is defined as the concentration at which absorbance of the treated cells is 50% that of the controls[2]. |
Animal experiment: | Mice[2] CB17 female scid-/- mice are treated with Tasidotin daily for 5 days via i.p. injection starting on day 1 every 21 days for two cycles. Five non–tumor-bearing mice are assigned to each treatment group. Mice are treated with either 70, 80, 90, or 100 mg/kg/d Tasidotin. A toxic event is defined as weight loss ≥20% of the animal's weight at the time of randomization or death. The maximally tolerated dose (MTD) is defined as the highest dose at which no toxicity occurred. |
References: [1]. Bai R, et al. Intracellular activation and deactivation of Tasidotin, an analog of dolastatin 15: correlation with cytotoxicity. Mol Pharmacol. 2009 Jan;75(1):218-26. | |
Tasidotin hydrochloride is a peptide analog of the antimitotic depsipeptide dolastatin 15, as an inhibitor of microtubule assembly and microtubule dynamics.
Compared with other breast carcinoma lines, relatively low amounts of Tasidotin enters NCI/ADR-RES cells, consistent with Tasidotin's also being a P-glycoprotein substrate. Of the remaining lines, the greatest difference in sensitivity to Tasidotin is between the more sensitive MDA-MB-435 line and the less sensitive HS 578-T line. The IC50 values in the two lines are 4 and 200 nM, respectively[1]. The IC50 in Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, and synovial sarcoma lines ranges from 2 to 320 nM. In the SK-ES1 and RH30 cell lines, Tasidotin induces a G2-M arrest that persists for 48 h after Tasidotin is washed from the cells. In vitro, more than half the cells are in the early or late phase of apoptosis 48 h after treatment with Tasidotin. Following treatment for 24 h with 160 nM Tasidotin, the RH30 line and SK-ES1 line each shows an accumulation of cells in the G2-M phase. At hour 24, nearly all the RH30 cells are in the G2-M phase[2].
In vivo, a significant increase in apoptotic nuclei is apparent in xenograft tumors harvested within 24 h after a 5-day course of Tasidotin. Mice treated with 100 mg/kg have a mean weight loss of >20% with no return to their baseline starting weight, and one mouse dies before the second treatment course. The mice treated with 90 mg/kg/d Tasidotin have a mean weight loss of <16% following each 5-day treatment of Tasidotin[2].
[1]. Bai R, et al. Intracellular activation and deactivation of Tasidotin, an analog of dolastatin 15: correlation with cytotoxicity. Mol Pharmacol. 2009 Jan;75(1):218-26. [2]. Garg V, et al. Preclinical analysis of Tasidotin HCl in Ewing's sarcoma, rhabdomyosarcoma, synovial sarcoma, and osteosarcoma. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5446-54.
| Cas No. | 623174-20-9 | SDF | |
| 别名 | TASIDOTIN盐酸盐,ILX651 | ||
| Canonical SMILES | [H]Cl.O=C(N1CCC[C@H]1C(NC(C)(C)C)=O)[C@H]2N(C([C@H](C(C)C)N(C([C@H](C(C)C)NC([C@H](C(C)C)N(C)C)=O)=O)C)=O)CCC2 | ||
| 分子式 | C32H59ClN6O5 | 分子量 | 643.3 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.5545 mL | 7.7724 mL | 15.5448 mL |
| 5 mM | 0.3109 mL | 1.5545 mL | 3.109 mL |
| 10 mM | 0.1554 mL | 0.7772 mL | 1.5545 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
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2.
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Phase I and pharmacokinetic study of Tasidotin hydrochloride (ILX651), a third-generation dolastatin-15 analogue, administered weekly for 3 weeks every 28 days in patients with advanced solid tumors
Clin Cancer Res 2006 Sep 1;12(17):5207-15.PMID:16951240DOI:10.1158/1078-0432.CCR-06-0179.
Purpose: To determine the safety, tolerability, and pharmacokinetics and to seek preliminary evidence of anticancer activity of tasidotin (ILX651), a novel dolastatin analogue, when administered as a 30-minute i.v. infusion weekly for 3 weeks every 4 weeks. Experimental design: Thirty patients with advanced solid malignancies were treated with 82 courses at six dose levels ranging from 7.8 to 62.2 mg/m2 weekly, initially according to an accelerated dose-escalation scheme, which evolved into a Fibonacci scheme as a relevant degree of toxicity was observed. Plasma and urine were sampled to characterize the pharmacokinetic behavior of tasidotin. Results: A high incidence of neutropenia complicated by fever (one patient), or precluding treatment on day 15 (three patients), was the principal toxicity of tasidotin, at doses above 46.8 mg/m2. At all dose levels, nonhematologic toxicities were generally mild to moderate and manageable. Grade 3 toxicities included diarrhea and vomiting (one patient each). Drug-induced neurosensory symptoms were mild and there was no evidence of cardiovascular toxicity, which has been previously associated with other dolastatins. Tasidotin pharmacokinetics were mildly nonlinear, whereas metabolite kinetics were linear. A patient with non-small cell lung carcinoma experienced a minor response, and a patient with hepatocellular carcinoma had stable disease lasting 11 months. Conclusions: The recommended dose for phase II studies of tasidotin administered on this schedule is 46.8 mg/m2. The mild myelosuppression and manageable nonhematologic toxicities at the recommended dose, the evidence of antitumor activity, and the unique mechanistic aspects of tasidotin warrant further disease-directed evaluations on this and alternative schedules.
Mechanism of action of the microtubule-targeted antimitotic depsipeptide tasidotin (formerly ILX651) and its major metabolite tasidotin C-carboxylate
Cancer Res 2007 Apr 15;67(8):3767-76.PMID:17440090DOI:10.1158/0008-5472.CAN-06-3065.
Tasidotin (ILX-651), an orally active synthetic microtubule-targeted derivative of the marine depsipeptide dolastatin-15, is currently undergoing clinical evaluation for cancer treatment. Tasidotin inhibited proliferation of MCF7/GFP breast cancer cells with an IC(50) of 63 nmol/L and inhibited mitosis with an IC(50) of 72 nmol/L in the absence of detectable effects on spindle microtubule polymer mass. Tasidotin inhibited the polymerization of purified tubulin into microtubules weakly (IC(50) approximately 30 micromol/L). However, it strongly suppressed the dynamic instability behavior of the microtubules at their plus ends at concentrations approximately 5 to 10 times below those required to inhibit polymerization. Its major actions were to reduce the shortening rate, the switching frequency from growth to shortening (catastrophe frequency), and the fraction of time the microtubules grew. In contrast with all other microtubule-targeted drugs thus far examined that can inhibit polymerization, tasidotin did not inhibit the growth rate. In contrast to stabilizing plus ends, tasidotin enhanced microtubule dynamic instability at minus ends, increasing the shortening length, the fraction of time the microtubules shortened, and the catastrophe frequency and reducing the rescue frequency. Tasidotin C-carboxylate, the major intracellular metabolite of tasidotin, altered dynamic instability of purified microtubules in a qualitatively similar manner to tasidotin but was 10 to 30 times more potent. The results suggest that the principal mechanism by which tasidotin inhibits cell proliferation is by suppressing spindle microtubule dynamics. Tasidotin may be a relatively weak prodrug for the functionally active tasidotin C-carboxylate.
Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite
AAPS J 2007 Dec 14;9(3):E378-87.PMID:18170985DOI:10.1208/aapsj0903045.
The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after single-dose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-C-carboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX- and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute approximately 17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX- and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-C-carboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efflux from cells into plasma was the rate-limiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug.
A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors
Clin Cancer Res 2005 Nov 1;11(21):7807-16.PMID:16278403DOI:10.1158/1078-0432.CCR-05-0909.
Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of the dolastatin-15 analogue, tasidotin (ILX651), when administered i.v. daily for 5 days every 3 weeks. Experimental design: Thirty-six patients with advanced solid tumors received a total of 114 courses through eight dose levels ranging from 2.3 to 36.3 mg/m(2). Pharmacokinetic samples were collected in cycle 1. Results: Neutropenia was the principal dose-limiting toxicity at 36.3 mg/m(2)/d along with grade 3 ileus and elevated aspartate amino transaminase/alanine amino transaminase (n = 1). At the maximum tolerated dose, 27.3 mg/m(2), 4 of 14 patients experienced dose-limiting grade 4 neutropenia. The other principal toxicities consisted of mild-to-moderate elevated transaminases, alopecia, fatigue, and nausea. One patient with melanoma metastatic to liver and bone treated at 15.4 mg/m(2)/d experienced a complete response and received 20 courses of tasidotin. Two other patients with melanoma had mixed responses of cutaneous metastases at 27.3 mg/m(2)/d associated with either stable or progressive visceral disease. In addition, nine patients had stable disease. There was no accumulation of tasidotin following repeated daily dosing. Tasidotin decayed from plasma in a biphasic fashion with a half-life of <45 minutes in most cases. Conclusion: The maximum tolerated dose and recommended phase II dose for tasidotin when administered on this schedule was 27.3 mg/m(2)/d. The favorable toxicity profile of tasidotin compared with other antitubulin agents (particularly the lack of severe cumulative neuropathy, peripheral edema, and fatigue), the observed antitumor activity of tasidotin, and its novel mechanism of action support further disease-directed evaluations of this agent on this 5-day schedule every 3 weeks.
Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors
Clin Cancer Res 2005 Nov 1;11(21):7825-33.PMID:16278405DOI:10.1158/1078-0432.CCR-05-0058.
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. Patients and methods: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m(2). Pharmacokinetic samples were collected during the first course. Results: Neutropenia was the principal DLT at the 45.7 mg/m(2)/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m(2), experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of < or =55 minutes, and approximately 11% was excreted unchanged in the urine. Conclusion: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m(2). The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.