Oxaliplatin
Encyclopedia
Oxaliplatin is a coordination complex that is used in cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

. These platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...

-based drugs are usually classified as alkylating agents
Alkylating antineoplastic agent
An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group to DNA.The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring....

, although they are not actually alkylating groups (they function by a similar mechanism).

Preparation and structure

Oxaliplatin was discovered in 1976 at Nagoya City University
Nagoya City University
, abbreviated to , is one of the public universities in Japan. The main campus is located in Mizuho-ku, Nagoya City. Other three campuses are also located in the city.- History :...

 by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 in 1979. Oxaliplatin was subsequently in-licensed by Debiopharm
Debiopharm
Debiopharm Group™ is a global biopharmaceutical group of companies comprising Debiopharm S.A., Debio R.P. S.A. , Debioclinic S.A. and the two financial arms Debiomanagement S.A. and Debioinnovation S.A...

 and developed as an advanced colorectal cancer treatment. Debio licensed the drug to Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...

 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
Square planar
The square planar molecular geometry in chemistry describes the stereochemistry that is adopted by certain chemical compounds...

 platinum(II) center. In contrast to cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...

 and carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...

, oxaliplatin features the bidentate ligand 1,2-diaminocyclohexane in place of the two monodentate
Denticity
Denticity refers to the number of atoms in a single ligand that bind to a central atom in a coordination complex. In many cases, only one atom in the ligand binds to the metal, so the denticity equals one, and the ligand is said to be monodentate...

 ammine ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...

s. 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
Fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...

 and leucovorin in a combination known as FOLFOX
FOLFOX
FOLFOX is a chemotherapy regimen for treatment of colorectal cancer, made up of the drugs* FOL– Folinic acid * F – Fluorouracil * OX – Oxaliplatin - FOLFOX4 :...

 for the treatment of colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....

. Oxaliplatin is marketed by Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...

 under the trademark Eloxatin or by Medac GmbH under the trademark Oxaliplatin Medac. There are generic equivalents on the market now 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. 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.

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
    Proprioception
    Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...

    )
  • Fatigue
    Fatigue (physical)
    Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

  • Nausea
    Nausea
    Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

    , vomiting
    Vomiting
    Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

    , and/or diarrhea
    Diarrhea
    Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

  • Neutropenia
    Neutropenia
    Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...

  • Ototoxicity
    Ototoxicity
    Ototoxicity is damage to the ear , specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based...

     (hearing loss)
  • Extravasation
    Extravasation
    Extravasation is the accidental administration of intravenously infused medicinal drugs into the surrounding tissue, either by leakage , or direct exposure...

     if Oxaliplatin leaks from the infusion vein it may cause severe damage to the connective tissues.
  • Hypokalemia
    Hypokalemia
    Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...

    , which is more common in women than men


In addition, some patients may experience an allergic reaction
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

 to platinum-containing drugs. This is more common in women.

Oxaliplatin has less ototoxicity and nephrotoxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...

than cisplatin and carboplatin.

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). 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.

External links

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