Etoposide Phosphate | CAS#117091-64-2 | Eposin | Etopophos

MedKoo Cat#: 100320 | Name: Etoposide Phosphate

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Etoposide phosphate is a phosphate salt of a semisynthetic derivative of podophyllotoxin. Etoposide binds to the enzyme topoisomerase II, inducing double-strand DNA breaks, inhibiting DNA repair, and resulting in decreased DNA synthesis and tumor cell proliferation. Cells in the S and G2 phases of the cell cycle are most sensitive to this agent.

Chemical Structure

Etoposide Phosphate

CAS#117091-64-2

Theoretical Analysis

MedKoo Cat#: 100320

Name: Etoposide Phosphate

CAS#: 117091-64-2

Chemical Formula: C29H33O16P

Exact Mass: 668.1506

Molecular Weight: 668.54

Elemental Analysis: C, 52.10; H, 4.98; O, 38.29; P, 4.63

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Synonym

Eposin Etopophos Vepesid VP16. US brand name: Etopophos. Abbreviation: ETOP.

IUPAC/Chemical Name

[4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-2,6-dimethoxyphenyl] dihydrogen phosphate

InChi Key

LIQODXNTTZAGID-OCBXBXKTSA-N

InChi Code

InChI=1S/C29H33O16P/c1-11-38-9-20-27(42-11)23(30)24(31)29(43-20)44-25-14-7-17-16(40-10-41-17)6-13(14)21(22-15(25)8-39-28(22)32)12-4-18(36-2)26(19(5-12)37-3)45-46(33,34)35/h4-7,11,15,20-25,27,29-31H,8-10H2,1-3H3,(H2,33,34,35)/t11-,15+,20-,21-,22+,23-,24-,25-,27-,29+/m1/s1

SMILES Code

O=P(O)(OC1=C(OC)C=C([C@H](C2=C3C=C4OCOC4=C2)[C@@]5([H])C(OC[C@]5([H])[C@@H]3O[C@H]6[C@H](O)[C@@H](O)[C@]7([H])O[C@H](C)OC[C@@]7([H])O6)=O)C=C1OC)O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

According to http://en.wikipedia.org/wiki/Etoposide, Etoposide phosphate (brand names: Eposin, Etopophos, Vepesid, VP-16) is a cancer drug. It inhibits the enzyme topoisomerase II, which unwinds DNA, and by doing so causes DNA strands to break. Cancer cells are less able to repair this damage than healthy cells. It is used as a form of chemotherapy for cancers such as Ewing's sarcoma, lung cancer, testicular cancer, lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme. It is often given in combination with other drugs. It is also sometimes used in a conditioning regimen prior to a bone marrow or blood stem cell transplant. Its chemical make-up derives from podophyllotoxin, a toxin found in the American Mayapple. The name "VP-16"likely comes from a compounding of the last name of the chemists who performed early work on the drug (von Wartburg and von Kuhn) and podophyllotoxin[1]. Another chemist who was integral in the development of podophyllotoxin-based chemotherapeutics was Hartmann F. StÃ¤helin. DRUG DESCRIPTION ETOPOPHOS (etoposide phosphate) for Injection is an antineoplastic agent which is available for intravenous infusion as a sterile lyophile in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate is a water soluble ester of etoposide (commonly known as VP-16), a semi-synthetic derivative of podophyllotoxin. The water solubility of etoposide phosphate lessens the potential for precipitation following dilution and during intravenous administration.

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Etoposide phosphate (VP-16, VP-16213) is a semisynthetic derivative of podophyllotoxin, which inhibits DNA synthesis via topoisomerase II inhibition activity.

In vitro activity:

In RIN-m5F cells (a β-cell-derived cell line), the number of viable cells was significantly decreased after 24h of etoposide treatment and underwent mitochondria-dependent apoptotic signals accompanied by mitochondrial dysfunction, and increases in the population of sub-G1 hypodiploid cells and apoptotic cells, caspase-3 activity, and the activation of caspase cascades. Etoposide also increased the phosphorylation levels of glycogen synthase kinase (GSK)-3α/β in treated RIN-m5F cells. Pretreatment with LiCl, a GSK-3 inhibitor, prevented etoposide-induced mitochondria-dependent apoptosis and GSK-3 protein phosphorylation in RIN-m5F cells. Furthermore, exposure of the cells to etoposide induced the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase (ERK)1/2 but not p38-MAPK. Reference: Toxicol In Vitro. 2016 Oct;36:142-152. https://linkinghub.elsevier.com/retrieve/pii/S0887-2333(16)30147-3

In vivo activity:

Of C57B1/6 mice injected with 10(6) Lewis lung cancer (3LL) cells followed by treatment with a single 50 mg/kg dose of etoposide (VP-16), 60% survived over 60 days, in contrast to untreated control mice which died within 30 days. Approximately 40% of surviving mice rejected a subsequent challenge with 3LL. Their splenocytes protected naive mice injected with 3LL. To test if VP-16 treatment produced alterations in 3LL cells, which induce host immunity, leading to tumor rejection, C57B1/6 mice were injected with 3LL cells that had survived an 80-90% lethal concentration of VP-16 in vitro. These cells killed 75% of recipient mice but 60% of the surviving mice rejected challenge with 3LL. Splenocytes harvested from tumor-rejecting mice protected naive mice injected with 3LL. Reference: Cancer Chemother Pharmacol. 2001 Oct;48(4):327-32. https://dx.doi.org/10.1007/s002800100357

Preparing Stock Solutions

The following data is based on the product molecular weight 668.54 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Lee KI, Su CC, Yang CY, Hung DZ, Lin CT, Lu TH, Liu SH, Huang CF. Etoposide induces pancreatic β-cells cytotoxicity via the JNK/ERK/GSK-3 signaling-mediated mitochondria-dependent apoptosis pathway. Toxicol In Vitro. 2016 Oct;36:142-152. doi: 10.1016/j.tiv.2016.07.018. Epub 2016 Jul 27. PMID: 27473919. 2. Slater LM, Stupecky M, Sweet P, Osann K, Eklof A, Arquilla ER. Etoposide induction of tumor immunity in Lewis lung cancer. Cancer Chemother Pharmacol. 2001 Oct;48(4):327-32. doi: 10.1007/s002800100357. PMID: 11710634.

In vitro protocol:

In vivo protocol:

1. Slater LM, Stupecky M, Sweet P, Osann K, Eklof A, Arquilla ER. Etoposide induction of tumor immunity in Lewis lung cancer. Cancer Chemother Pharmacol. 2001 Oct;48(4):327-32. doi: 10.1007/s002800100357. PMID: 11710634.

1: Schacter L. Etoposide phosphate: what, why, where, and how? Semin Oncol. 1996 Dec;23(6 Suppl 13):1-7. PMID: 8996569. 2: Witterland AH, Koks CH, Beijnen JH. Etoposide phosphate, the water soluble prodrug of etoposide. Pharm World Sci. 1996 Oct;18(5):163-70. doi: 10.1007/BF00820727. PMID: 8933576. 3: Pringle NR, Gilbar PJ, Grewal GD. Immediate severe hypersensitivity reaction to etoposide phosphate: Case report and review of the literature. J Oncol Pharm Pract. 2022 Jun;28(4):1019-1023. doi: 10.1177/10781552211073345. Epub 2022 Jan 17. PMID: 35037804. 4: Budman DR. Early studies of etoposide phosphate, a water-soluble prodrug. Semin Oncol. 1996 Dec;23(6 Suppl 13):8-14. PMID: 8996570. 5: Hande KR. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer. 1998 Sep;34(10):1514-21. doi: 10.1016/s0959-8049(98)00228-7. PMID: 9893622. 6: Stockton WM, Nguyen T, Zhang L, Dowling TC. Etoposide and etoposide phosphate hypersensitivity in children: Incidence, risk factors, and prevention strategies. J Oncol Pharm Pract. 2020 Mar;26(2):397-405. doi: 10.1177/1078155219858390. Epub 2019 Jul 18. PMID: 31315549. 7: Brooks JP, Azmy V, Thompson A, Luon D, Prozora SD, Price C, Hsu FI. Etoposide phosphate for pediatric orthopedic malignancies after intravenous etoposide hypersensitivity. J Oncol Pharm Pract. 2020 Jan;26(1):228-231. doi: 10.1177/1078155219836478. Epub 2019 Mar 18. PMID: 30885040. 8: Srinivas R, Satterlee A, Wang Y, Zhang Y, Wang Y, Huang L. Theranostic etoposide phosphate/indium nanoparticles for cancer therapy and imaging. Nanoscale. 2015 Nov 28;7(44):18542-18551. doi: 10.1039/c5nr04509f. Epub 2015 Oct 22. PMID: 26489694; PMCID: PMC4670036. 9: Sambasivan K, Mahmoud S, Kokache A, Seckl M, Savage P. Hypersensitivity reactions to etoposide phosphate. J Oncol Pharm Pract. 2014 Apr;20(2):158-60. doi: 10.1177/1078155213488015. Epub 2013 Jun 4. PMID: 23740378. 10: Greco FA, Hainsworth JD. Etoposide phosphate or etoposide with cisplatin in the treatment of small cell lung cancer: randomized phase II trial. Lung Cancer. 1995 Jun;12 Suppl 3:S85-95. doi: 10.1016/s0169-5002(10)80022-4. PMID: 7551961. 11: Cotteret C, Rousseau J, Zribi K, Schlatter J. Severe hypersensitivity reaction to etoposide phosphate: A case report. Clin Case Rep. 2020 Aug 6;8(9):1821-1823. doi: 10.1002/ccr3.2732. PMID: 32983504; PMCID: PMC7495780. 12: Simon N, Barnoud D, Bruno B, Vasseur M, Béné J, Odou P. Should we replace etoposide phosphate by etoposide for allogeneic hematopoetic stem-cell transplantation in children? Pediatr Blood Cancer. 2018 Jul;65(7):e27039. doi: 10.1002/pbc.27039. Epub 2018 Mar 12. PMID: 29528186. 13: Mummaneni V, Kaul S, Igwemezie LN, Newell DR, Porter D, Thomas H, Calvert AH, Winograd B, Barbhaiya RH. Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters. J Pharmacokinet Biopharm. 1996 Aug;24(4):313-25. doi: 10.1007/BF02353515. PMID: 9044163. 14: Greco FA, Hainsworth JD. Clinical studies with etoposide phosphate. Semin Oncol. 1996 Dec;23(6 Suppl 13):45-50. PMID: 8996575. 15: Canel C, Moraes RM, Dayan FE, Ferreira D. Podophyllotoxin. Phytochemistry. 2000 May;54(2):115-20. doi: 10.1016/s0031-9422(00)00094-7. PMID: 10872202. 16: Trissel LA, Martinez JF, Simmons M. Compatibility of etoposide phosphate with selected drugs during simulated Y-site injection. J Am Pharm Assoc (Wash). 1999 Mar-Apr;39(2):141-5. doi: 10.1016/s1086-5802(16)30488-0. PMID: 10079649. 17: Hu JL, Xu G, Lei L, Zhang WL, Hu Y, Huang AL, Cai XF. Etoposide phosphate enhances the acetylation level of translation elongation factor 1A in PLC5 cells. Z Naturforsch C J Biosci. 2012 May-Jun;67(5-6):327-30. doi: 10.1515/znc-2012-5-613. PMID: 22888539. 18: Zhang Y, Trissel LA. Physical and chemical stability of etoposide phosphate solutions. J Am Pharm Assoc (Wash). 1999 Mar-Apr;39(2):146-50. doi: 10.1016/s1086-5802(16)30489-2. PMID: 10079650. 19: de Jong RS, Slijfer EA, Uges DR, Mulder NH, de Vries EG. Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile. Br J Cancer. 1997;76(11):1480-3. doi: 10.1038/bjc.1997.581. PMID: 9400945; PMCID: PMC2228182. 20: de Jong RS, Mulder NH, Uges DR, Kaul S, Winograd B, Sleijfer DTh, Groen HJ, Willemse PH, van der Graaf WT, de Vries EG. Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide. Br J Cancer. 1997;75(11):1660-6. doi: 10.1038/bjc.1997.282. PMID: 9184183; PMCID: PMC2223531.