Oxaliplatin

Oxaliplatin

Systematic (IUPAC) name
[(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II)
Clinical data
Trade names	Eloxatin
AHFS/Drugs.com	monograph
MedlinePlus	a607035
Pregnancy cat.	?
Legal status	?
Routes	Intravenous
Pharmacokinetic data
Bioavailability	Complete
Half-life	~10 - 25 minutes[1]
Excretion	Renal
Identifiers
CAS number	63121-00-6 Y
ATC code	L01XA03
PubChem	CID 77994
DrugBank	APRD00186
ChemSpider	8062727 N
UNII	04ZR38536J N
KEGG	D01790 Y
ChEMBL	CHEMBL414804 N
Chemical data
Formula	C8H14N2O4Pt
Mol. mass	397.2858 g/mol
N(what is this?)  (verify)

Oxaliplatin is a coordination complex that is used in cancer chemotherapy^[2]. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups (they function by a similar mechanism).^[3]

Preparation and structure

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. Eloxatin gained European approval in 1996 (firstly in France) and approval by the U.S. Food and Drug Administration (FDA) in 2002.

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.

Mechanism of action

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

Clinical use

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] 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.^[5] 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.^[6]

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:

• Neuropathy, (both an acute, reversible sensitivity to cold and numbness in the hands and feet and a chronic, possibly irreversible foot/leg, hand/arm numbness, often with deficits in proprioception)^[7]
• Fatigue
• Nausea, vomiting, and/or diarrhea
• Neutropenia
• Ototoxicity (hearing loss)
• Extravasation if Oxaliplatin leaks from the infusion vein it may cause severe damage to the connective tissues.
• Hypokalemia, which is more common in women than men^[8]

In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women.^[8]

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin.^[7]

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, expired on Aug 09, 2007.^[9]

References

1. ^ Ehrsson H, Wallin I, Yachnin J (2002). "Pharmacokinetics of oxaliplatin in humans". Medical Oncology 19 (4): 261–265. doi:10.1385/MO:19:4:261. PMID 12512920. 
2. ^ The status of platinum anticancer drugs in the clinic and in clinical trials Dalton Transactions, 2010, 39, 8113-8127
3. ^ Yongwon Jung and Stephen J. Lippard (2007). "Direct Cellular Responses to Platinum-Induced DNA Damage". Chem. Rev. 107 (5): 1387–1407. doi:10.1021/cr068207j. PMID 17455916. 
4. ^ Generic Oxaliplatin Approved
5. ^ 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. PMID 9704726. 
6. ^ 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. PMID 10944126. 
7. ^ ^{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. doi:10.1016/j.critrevonc.2006.01.001. PMID 16806962. 
8. ^ ^{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. doi:10.3109/02841860903464015. PMID 20092386. 
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.

External links

• Oxaliplatin - Official web site of manufacturer.
• Oxaliplatin Prescribing Information - Official prescribing information.
• Virtual Cancer Centre: Oxaliplatin/Eloxatin
• 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. doi:10.1038/nrd1287. PMID 14756144. http://www.dresources.com/nature/ntr_0104.pdf.