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Evofosfamide (TH-302)
Catalog No.S2757 Synonyms: Evofosfamide
For research use only.
Evofosfamide (TH-302) is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM, demonstrates 270-fold enhanced cytotoxicity under hypoxia versus their potency under aerobic conditions, stable to cytochrome P450 metabolism.
CAS No. 918633-87-1
Selleck's Evofosfamide (TH-302) has been cited by 2 Publications
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Biological Activity
| Description | Evofosfamide (TH-302) is selective hypoxia-activated prodrug targeting hypoxic regions of solid tumors with IC50 of 19 nM, demonstrates 270-fold enhanced cytotoxicity under hypoxia versus their potency under aerobic conditions, stable to cytochrome P450 metabolism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| In vitro |
TH-302 is selectively potent under hypoxia and stable to liver microsomes. Substitution of the chlorine with bromine on the phosphorus mustard in 3b increases the potency by 10-fold and maintaines the high hypoxic selectivity [Hypoxia cytotoxicity ratio (HCR) = 270]. In both human lung cancer H460 cells and human colon cancer HT29 cells, potent cytotoxicity of TH-302 is observed under N2. TH-302 inhibits H460 cells and HT29 cells with IC90 of 0.1 μM and 0.2 μM, respectively. [1] TH-302 shows much enhanced potency in H460 spheroids compared to H460 monolayer cells under normoxia. [2] TH-302 exhibits potent cytotoxicity to MM cells with hypoxic selectivity and dose dependency. TH-302 can induce G0/G1 cell-cycle arrest under hypoxic conditions. The effect of TH-302 on cell-cycle machinery is mediated by down-regulating cyclin D1/2/3, CDK4/6, p21cip-1, p27kip-1, and pRb expression, whereas CDK2 expression remained undisturbed. TH-302 can induce dose-dependent apoptosis in both human and murine MM cells in hypoxic conditions. TH-302-activated apoptosis is mediated through down-regulating the antiapoptotic proteins BCL-2 and BCL-xL, as well as up-regulating the expression of cleaved proapoptotic protein caspase-3, -8, and -9 and poly ADP-ribose polymerase. In contrast to the hypoxia-specific toxicity, TH-302 shows very low toxicity in normoxic condition, even at high concentrations. [3] |
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| Cell Data |
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| In vivo | TH302 inhibits primary tumor growth by 41% on day 25 after implantation, whereas TH302 plus gemcitabine (a nucleoside analog) inhibits primary tumor growth by 96% on day 25. [1] When TH-302 is administered at 6.25, 12.5, 25, or 50 mg/kg in the H460 NSCLC xenograft model QD × 5/wk × 2 wks (once a day for 5 days per week for 2 weeks) i.p., the tumor growth inhibition at Day 22 is 43%, 51%, 75%, and 89%, respectively. TH-302 at 100 mg/kg shows a decrease in blood cell counts 3 days after treatment end, but is totally recovered 7 days post-treatment. TH-302 under all tested regimens exhibits efficacy metrics ranging from 58% to 89% tumor growth inhibition. TH-302 induced cell killing is breathing oxygen concentration dependent, with the greatest cytotoxicity occurring when the tumor-bearing mice are exposed to low oxygen concentrations. Tumor growth is significantly reduced by TH-302 in animals breathing 10% O2 compared with 95% O2 breathing. After TH-302 treatment, the pimonidazole-positive area is significantly decreased at 48 hours after dosing (6.3 % in vehicle vs. 1.8 % in the TH-302 treatment group). [4] |
Protocol (from reference)
| Cell Research:[1] |
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| Animal Research:[4] |
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| References |
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Solubility (25°C)
|
In vitro |
DMSO |
90 mg/mL
(200.42 mM) |
| Water |
10 mg/mL
warmed (22.26 mM) |
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| Ethanol |
'90 mg/mL
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In vivo |
Add solvents to the product individually and in order |
30 mg/mL |
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Information
| Molecular Weight | 449.04 | ||
|---|---|---|---|
| Formula | C9H16Br2N5O4P |
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| CAS No. | 918633-87-1 | ||
| Storage | 3 years | -20°C | powder |
| 2 years | -80°C | in solvent | |
| Smiles | CN1C(=CN=C1[N+](=O)[O-])COP(=O)(NCCBr)NCCBr | ||
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
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Clinical Trial Information
| NCT Number | Recruitment | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|---|
| NCT02020226 | Unknown status | Drug: TH-302 | Solid Tumors | Threshold Pharmaceuticals | November 2013 | Phase 1 |
| NCT01833546 | Completed | Drug: Evofosfamide|Drug: Gemcitabine | Solid Tumor|Pancreatic Cancer | Merck KGaA Darmstadt Germany|Threshold Pharmaceuticals | April 18 2013 | Phase 1 |
(data from https://clinicaltrials.gov, updated on 2021-09-06)
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