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Oxaliplatin

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Oxaliplatin

Oxaliplatin
Systematic (IUPAC) name
[(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II)
Clinical data
Trade names Eloxatin
AHFS/Drugs.com
MedlinePlus
Pregnancy cat.
Legal status
Routes Intravenous
Pharmacokinetic data
Bioavailability Complete
Half-life ~10 - 25 minutes[1]
Excretion Renal
Identifiers
CAS number  YesY
ATC code L01
PubChem
DrugBank
ChemSpider  N
UNII  N
KEGG  YesY
ChEMBL  N
PDB ligand ID 1PT (, )
Chemical data
Formula C8H14N2O4Pt 
Mol. mass 397.2858 g/mol
 N   

Oxaliplatin (pronounced ox-ally-plat-in), marketed as Eloxatin by Sanofi, is a platinum-based antineoplastic agent used in cancer chemotherapy.[2]

History

Oxaliplatin was discovered in 1976 at Nagoya City University by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm and developed as an advanced colorectal cancer treatment. Debio licensed the drug to Sanofi-Aventis in 1994. It gained European approval in 1996 (initially in France) and approval by the U.S. Food and Drug Administration in 2002. Generic oxaliplatin was first approved in the United States in August 2009.[3] In 2010, Sanofi regained exclusivity protection for the drug until August 2012.[4]

Structure and mechanism

The compound features a square planar platinum(II) center. In contrast to cisplatin and carboplatin, oxaliplatin features the bidentate ligand 1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group.

According to in vivo studies, oxaliplatin fights carcinoma of the colon through non-targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA,[5] which prevent DNA replication and transcription, causing cell death.

Clinical use

Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid and 5-fluorouracil in a combination known as FOLFOX. Oxaliplatin has been compared with other platinum compounds used for advanced cancers, such as cisplatin and carboplatin.

Advanced colorectal cancer

In clinical studies, oxaliplatin by itself has modest activity against advanced colorectal cancer.[6] When compared with just 5-fluorouracil and folinic acid administered according to the de Gramont regimen, a FOLFOX4 regime produced no significant increase in overall survival, but did produce an improvement in progression-free survival, the primary end-point of the phase III randomized trial.[7]

Adjuvant treatment of colorectal cancer

After and/or before[8] the curative resection of colorectal cancer, chemotherapy based on 5-fluorouracil and folinic acid reduces the risk of relapse. The benefit is clinically relevant when cancer has spread to locoregional lymph nodes or penetrated through the wall of the rectum or colon (stage III, Dukes C). The addition of oxaliplatin improves relapse-free survival, but data on overall survival have not yet been published in extenso.

When cancer has not spread to the locoregional lymph nodes, nor penetrated through the wall of the rectum or colon (stage II, Dukes B) the benefit of chemotherapy is marginal and the decision on whether to give adjuvant chemotherapy should be carefully evaluated by discussing with the patient the realistic benefits and the possible toxic side effects of treatment. This is even more relevant when the oncologist proposes treatment with oxaliplatin.

Adverse effects

Side-effects of oxaliplatin treatment can potentially include:

In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women.[10]

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.[9]

Patent information

Eloxatin is covered by patent numbers 5338874 (Expiry Apr 07,2013), 5420319 (Expiry Aug 08,2016), 5716988 (Expiry Aug 07,2015) and 5290961 (Expiry Jan 12, 2013) (see Electronic Orange Book patent info for Eloxatin).[12] Exclusivity code I-441, which expired on Nov 04, 2007, is for use combination with infusional 5-FU/LV for adjuvant treatment stage III colon cancer patients who have undergone complete resection primary tumor-based on improvement in disease free survival with no demonstrated benefit overall survival after 4 years. Exclusivity code NCE, New Chemical Entity, expired on Aug 09, 2007.[12]

References

  1. ^ Ehrsson H, Wallin I, Yachnin J (2002). "Pharmacokinetics of oxaliplatin in humans". Medical Oncology 19 (4): 261–265.  
  2. ^ The status of platinum anticancer drugs in the clinic and in clinical trials Dalton Transactions, 2010, 39, 8113-8127
  3. ^ "Generic Eloxatin availability".  
  4. ^ "Top 10 best-selling cancer drugs: Eloxatin–$1.2 billion". FiercePharma. 15 May 2012. Retrieved 20 April 2014. 
  5. ^ Graham, Joanne; Mushin, Mohamed; Kirkpatrick, Peter (January 2004). "Oxaliplatin". Nature Reviews Drug Discovery 3 (1): 11–2.  
  6. ^ Becouarn Y, Ychou M, Ducreux M et al. (1998). "Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers". J Clin Oncol 16 (8): 2739–44.  
  7. ^ De Gramont A, Figer A, Seymour M et al. (2000). "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer". J Clin Oncol 18 (16): 2938–47.  
  8. ^ National Cancer Institute, Rectal Cancer Treatment (PDQ®)
  9. ^ a b Pasetto LM, D'Andrea MR, Rossi E, Monfardini S (August 2006). "Oxaliplatin-related neurotoxicity: how and why?". Crit. Rev. Oncol. Hematol. 59 (2): 159–68.  
  10. ^ a b Chay WY, Chew L, Yeoh TT, Tan MH (May 2010). "An association between transient hypokalemia and severe acute oxaliplatin-related toxicity predominantly in women". Acta Oncol 49 (4): 515–7.  
  11. ^ http://www.drugs.com/sfx/oxaliplatin-side-effects.html
  12. ^ a b Orange Book. accessdata.fda.gov. URL: http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021759&Product_No=001&table1=OB_Rx. Accessed on: July 22, 2007.

External links

  • Oxaliplatin - Official web site of manufacturer.
  • Oxaliplatin Prescribing Information - Official prescribing information.
  • NCI Drug Information Summary on Oxaliplatin

Additional sources

  • Graham J, Mushin M, Kirkpatrick P (2004). "Oxaliplatin" (PDF). Nat Rev Drug Discov 3 (1): 11–2.  
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