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Purity: ≥98%
Palifosfamide (also known as Isophosphoramide mustard; IPM; ZIO201), a synthetic mustard compound and the active metabolite of ifosfamide, is a novel DNA alkylator with antitumor activity. Palifosfamide, an active metabolite of ifosfamide, cross-links DNA irreversibly through GC base pairs, forming irreversible 7-atom inter-strand cross-links that inhibit DNA replication and cause cell death. Palifosfamide is covalently linked to the amino acid lysine for stability. This agent does not metabolize to acrolein or chloroacetaldehyde, which are metabolites linked to bladder and central nervous system toxicities, unlike ifosfamide. Additionally, palifosfamide may be able to overcome the tumor resistance associated with ifosfamide because it does not require activation by aldehyde dehydrogenase.
| Targets |
Palifosfamide lysine (ZIO-201) is a stable form of the drug. In vitro, palifosfamide lysine exhibits wide activity in sarcoma lines. Except for OS222 (IC50=31.5 μM), the IC50 for most cell lines ranges from 2.25 to 6.75 μM[1].
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| ln Vitro |
Palifosfamide lysine (ZIO-201) is a stable form of the drug. In vitro, palifosfamide lysine exhibits wide activity in sarcoma lines. Except for OS222 (IC50=31.5 μM), the IC50 for most cell lines ranges from 2.25 to 6.75 μM[1].
Palifosfamide lysine demonstrated cytotoxic activity against a panel of pediatric sarcoma cell lines in vitro, as measured by MTT assay. The IC50 values for most cell lines ranged from 0.5 to 1.5 µg/ml (2.25–6.75 µM). The exceptions were the OS222 osteosarcoma cell line, which had a higher IC50 of 7 µg/ml (31.5 µM). Cytotoxicity was similar for both single-day and three-consecutive-day treatment schedules for most lines. [1] |
| ln Vivo |
In the OS31, OS33, and RMS xenografts, as well as in the control group, tumor growth inhibition is observed. This leads to a statistically significant difference in event-free survival. It has been observed that the OS31 xenograft exhibits differential gene expression of ALDH3A1 but not ALDH1A1[1]. Mice treated with stabilized palifosfamide exhibit over 80% growth suppression of MX-1 tumors, with 17% exhibiting full antitumor responses. In mice, antitumor activity is equivalent through both routes, and oral bioavailability in rats ranges from 48-73% of parenteral administration. Complete tumor regression is achieved in 62-75% of mice when palifosfamide-tris and docetaxelor doxorubicin are administered according to optimal regimens[2].
In SCID mice bearing osteosarcoma xenografts, intravenous administration of palifosfamide lysine at its maximum tolerated dose (MTD, 100 mg/kg/day for 3 days) significantly inhibited tumor growth and increased event-free survival (EFS) in both cyclophosphamide (CPA)-sensitive (OS33) and CPA-resistant (OS31) tumors. [1] Palifosfamide lysine also demonstrated significant anti-tumor activity and improved EFS in a rhabdomyosarcoma (RH30) xenograft model. [1] In an Ewing's sarcoma (SKES-1) xenograft model, palifosfamide lysine treatment resulted in a brief early decrease in tumor growth, but the effect was not sustained, and overall differences in tumor volume or EFS were not statistically significant. [1] The CPA-resistant OS31 xenograft exhibited high ALDH3A1 enzyme activity (100 mIU/mg protein) and mRNA expression, while the CPA-sensitive OS33 xenograft showed negligible activity (3 mIU/mg protein). The activity of palifosfamide lysine against the OS31 tumor suggests it can overcome ALDH-mediated oxazaphosphorine resistance. [1] |
| Cell Assay |
Phosphate buffered saline (PBS) is used to dissolve palifosfamide. Approximately 500 cells per well in 100 μL of media are plated in 96-well microtiter plates. Cells are treated with increasing concentrations of palifosfamide lysine in separate plates either as a single day treatment or three consecutive days of treatment, with fresh drug added each day, following a 24-hour incubation period at 37°C. The plates are incubated with 5% CO2 at 37°C for 72 hours. After 72 hours, each well receives 250 μg of MTT, and it is incubated for 6 hours at 37°C. After mitochondria of viable cells convert MTT to formazine crystals, the crystals are dissolved in 100 μL of dimethyl sulfoxide. The wavelength of optical density is 595 nm[2].
Cytotoxicity (MTT) Assay: Cells were plated in 96-well plates at approximately 500 cells per well. After 24 hours, cells were treated with increasing concentrations of palifosfamide lysine. Treatment schedules included either a single dose or three consecutive daily doses, with fresh drug added each day. Following a 72-hour incubation, MTT reagent was added to each well and incubated for 6 hours. The formazan crystals formed by viable cells were dissolved, and the optical density was measured at 595 nm. Cell viability was calculated relative to vehicle-treated controls, and the IC50 was determined. [1] |
| Animal Protocol |
Mice: The study uses female CB17 SCID mice. Mice are randomized into treatment and control groups (5-8 mice/group) for each tumor line once the tumors have grown to a size of 50–150 mm3. For six weeks, 150 mg/kg of cyclophosphamide is given intraperitoneally once a week. Serial tumor volumes are measured over the next six weeks after palifosfamide lysine is injected intravenously for three days in a row at the highest tolerated dose of 100 mg/kg. The experiment concludes with the sacrifice of the mice[2].
Maximum Tolerated Dose (MTD) Determination: Female CB17 SCID mice (5-6 weeks old) received intravenous injections of palifosfamide lysine (dissolved in phosphate-buffered saline) daily for three consecutive days at doses ranging from 50 to 250 mg/kg. The MTD was defined as the highest dose causing no toxicity (weight loss ≥20% or death) in 3 out of 3 mice, which was determined to be 100 mg/kg/day. [1] Efficacy Studies in Xenograft Models: Mice were subcutaneously implanted with tumor fragments (OS31, OS33) or cells suspended in Matrigel (RH30, SKES-1). When tumors reached 50-150 mm³, mice were randomized into control and treatment groups. The treatment group received a single course of palifosfamide lysine intravenously at 100 mg/kg/day for three consecutive days. Tumor volumes were measured serially for 6 weeks. An event was defined as a relative tumor volume exceeding four times the initial volume or death. Event-free survival and tumor volume differences were analyzed statistically. [1] |
| Toxicity/Toxicokinetics |
In mice, the dose-limiting toxicities of palifamide lysine were myelosuppression and renal tubular damage. At the maximum tolerated dose (MTD, 100 mg/kg/day for 3 consecutive days), the mean weight loss was less than 15%, and the weight returned to baseline within 4 weeks. At doses above 100 mg/kg were extremely toxic, resulting in weight loss of more than 20% or death. [1] Compared to the prodrug ifosfamide, palifamide does not produce toxic metabolites such as acrolein (associated with hemorrhagic cystitis) or chloroacetaldehyde (associated with encephalopathy), and theoretically has a better toxicity profile. [1]
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| References |
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| Additional Infomation |
Ifosfamide mustard is a phosphatidyl diamide compound. Palifosfamide (ZIO-201) is a proprietary stable metabolite of ifosfamide. Ifosfamide has been shown to be effective in treating testicular cancer, sarcoma, and lymphoma at high doses. Palifosfamide is a synthetic mustard-like compound with potential antitumor activity. As the active metabolite of ifosfamide, palifosfamide enhances stability by covalently linking to the amino acid lysine, irreversibly alkylating and cross-linking GC base pairs in DNA, leading to irreparable 7-atom interchain cross-links; thereby inhibiting DNA replication and causing cell death. Unlike ifosfamide, this drug is not metabolized to acrolein or chloroacetaldehyde, which are metabolites associated with bladder and central nervous system toxicity. Furthermore, because palifosfamide does not require aldehyde dehydrogenase activation, it may overcome tumor resistance induced by ifosfamide.
Drug indications Studied for the treatment of cancer/tumor (not specified), lymphoma (not specified) and sarcoma. Mechanism of action After metabolic activation, palifamide can be alkylated or bound to a variety of intracellular molecular structures (including nucleic acids). Its cytotoxic effects are mainly attributed to cross-linking of DNA and RNA chains and inhibition of protein synthesis. Palifoamide lysine (ZIO-201) is a stable direct-acting form of the active metabolite of ifosfamide, designed to bypass hepatic metabolic activation. [1] A key advantage is its potential to overcome resistance mediated by overexpression of aldehyde dehydrogenases (ALDH), such as ALDH1A1 and ALDH3A1, which inactivate intermediate metabolites of prodrugs such as ifosfamide and cyclophosphamide. [1] Studies have shown that pallicyclophosphamide lysine has broad preclinical activity against childhood sarcomas (osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma) and may be effective against oxaphosphonate-resistant tumors. [1] |
| Molecular Formula |
C₄H₁₁CL₂N₂O₂P
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| Molecular Weight |
221.02
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| Exact Mass |
219.993
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| Elemental Analysis |
C, 28.08; H, 6.48; Cl, 20.72; N, 12.28; O, 23.38; P, 9.05
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| CAS # |
31645-39-3
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| Related CAS # |
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| PubChem CID |
100427
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
341.5±52.0 °C at 760 mmHg
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| Melting Point |
106-107ºC
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| Flash Point |
160.4±30.7 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.498
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| LogP |
-1.05
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
11
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| Complexity |
134
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=P(NCCCl)(NCCCl)O
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| InChi Key |
BKCJZNIZRWYHBN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C4H11Cl2N2O2P/c5-1-3-7-11(9,10)8-4-2-6/h1-4H2,(H3,7,8,9,10)
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| Chemical Name |
bis(2-chloroethylamino)phosphinic acid
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (13.57 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 30.0 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: ≥ 3 mg/mL (13.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 30.0 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. View More
Solubility in Formulation 3: ≥ 3 mg/mL (13.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (45.24 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5245 mL | 22.6224 mL | 45.2448 mL | |
| 5 mM | 0.9049 mL | 4.5245 mL | 9.0490 mL | |
| 10 mM | 0.4524 mL | 2.2622 mL | 4.5245 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02375204 | Active Recruiting |
Drug: ifosfamide Drug: cisplatin |
Teratoma Germinoma |
Alliance for Clinical Trials in Oncology |
August 5, 2015 | Phase 3 |
| NCT03016871 | Active Recruiting |
Drug: Ifosfamide Drug: Etoposide |
Recurrent Hodgkin Lymphoma Refractory Hodgkin Lymphoma |
City of Hope Medical Center | April 24, 2017 | Phase 2 |
| NCT01959698 | Active Recruiting |
Drug: Ifosfamide breakfast Drug: Etoposide |
CD20 Positive Stage I Diffuse Large B- Cell Lymphoma |
Roswell Park Cancer Institute | April 17, 2014 | Phase 1 |
| NCT01873326 | Active Recruiting |
Drug: Ifosfamide Drug: Cisplatin |
Germ Cell Tumors | Memorial Sloan Kettering Cancer Center |
June 2013 | Phase 2 |
| NCT04665765 | Active Recruiting |
Drug: Ifosfamide Drug: Etoposide |
Recurrent Diffuse Large B- Cell Lymphoma Refractory Diffuse Large B- Cell Lymphoma |
City of Hope Medical Center | January 18, 2021 | Phase 2 |
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