Oxaliplatin: Wikis

  
  

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Oxaliplatin
Systematic (IUPAC) name
(R,R)-1,2-diaminocyclohexane(ethanedioate-O,O)platinum
Identifiers
CAS number 63121-00-6
ATC code L01XA03
PubChem 77994
DrugBank APRD00186
Chemical data
Formula C 8H14N2O4Pt 
Mol. mass 397.2858 g/mol
Pharmacokinetic data
Bioavailability Complete
Metabolism  ?
Half life ~10 - 25 minutes [1]
Excretion Renal
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes Intravenous

Oxaliplatin is a platinum-based cancer chemotherapy drug. [2] [3] These drugs are usually classified as alkylating agents, although they are not capable of actually adding alkyl groups to DNA and simply work by a similar mechanism.

Oxaliplatin is typically administered with fluorouracil and leucovorin in a combination known as FOLFOX for the treatment of colorectal cancer. Oxaliplatin is marketed by Sanofi-Aventis under the trademark Eloxatin or by Medac GmbH under the trademark Oxaliplatin Medac. There are generic equivalents on the market now [4]

Contents

History

Oxaliplatin was discovered in 1976 at Nagoya City University by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 over the drug 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. Eloxatin gained European approval in 1996 (firstly in France) and approval by the U.S. Food and Drug Administration (FDA) in 2002.

Chemistry

The compound has a 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.

Mechanism of action

The cytotoxicity of platinum compounds is thought to result from inhibition of DNA synthesis in cancer cells. [2][5] In vivo studies showed that Oxaliplatin has anti-tumor activity against colon carcinoma through its (non-targeted) cytotoxic effects.

Clinical use

Oxaliplatin has been compared with other platinum compounds (Cisplatin, Carboplatin) in advanced cancers (gastric, ovarian).

Advanced colorectal cancer

In clinical studies, Oxaliplatin by itself has modest activity against advanced colorectal cancer[6]. It has been extensively studied in combination with Fluorouracil and Folinic Acid (a combination known as FOLFOX). When compared with Fluorouracil and Folinic Acid administered according to the "De Gramont regimen" there was no significant increase in overall survival with the FOLFOX regimen (specifically, FOLFOX4), but progression-free survival, the primary end-point of the phase III randomized trial, was improved with FOLFOX.[7]

Adjuvant treatment of colorectal cancer

After the curative resection of colorectal cancer, chemotherapy based on Fluorouracil and folinic acid reduces the risk of relapse. The benefit is clinically relevant when cancer has spread to locoregional lymph nodes (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 (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.

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.[8]

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).[9] 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, expires on Aug 09, 2007.[9]

External links

References

  1. ^ Ehrsson H, Wallin I, Yachnin J. Medical Oncology. 2002; 19:251-265.
  2. ^ a b Samantha L. Kerr, Tamer Shoeib and Barry L. Sharp A study of oxaliplatin–nucleobase interactions using ion trap electrospray mass spectrometry Analytical and Bioanalytical Chemistry; Vol. 391, Number 6 (July 2008) doi:10.1007/s00216-008-2128-3
  3. ^ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  4. ^ Generic Oxaliplatin Approved
  5. ^ Micromedex, accessed 08.2008
  6. ^ Becouarn Y, Ychou M, Ducreux M, et al. 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 1998; 16(8):2739-44. PMID 9704726.
  7. ^ de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18(16):2938-47. PMID 10944126
  8. ^ a b Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: how and why? Crit Rev Oncol Hematol. 2006 Aug;59(2):159-68. Pub. June 27, 2006. PMID 16806962.
  9. ^ 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.

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