Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (

platinum-based antineoplastic Platinum-based antineoplastic drugs (informally called platins) are chemotherapeutic agents used to treat cancer. They are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. ...

class) used to treat

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

. It is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

. Common side effects include

numbness Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli. In everyday speech this is generally referred to as num ...

, feeling tired, nausea, diarrhea, and low blood cell counts. Other serious side effects include

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

. Use in

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

is known to harm the baby. Oxaliplatin is in the

family of medications. It is believed to work by blocking the duplication of DNA. Oxaliplatin was patented in 1976 and approved for medical use in 1996. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...

Medical uses

Oxaliplatin is used for treatment of

, typically along with

folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to tr ...

(leucovorin) and

fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreat ...

in a combination known as FOLFOX or along with

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Comm ...

in a combination known as

CAPOX CAPOX (also called XELOX) is a chemotherapy regimen consisting of capecitabine (trade name Xeloda) combined with oxaliplatin. Xelox regime operates in 3-week cycles, usually with 8 cycles in total; Xeloda is orally taken for twice daily for two we ...

XELOX CAPOX (also called XELOX) is a chemotherapy regimen consisting of capecitabine (trade name Xeloda) combined with oxaliplatin. Xelox regime operates in 3-week cycles, usually with 8 cycles in total; Xeloda is orally taken for twice daily for two we ...

Advanced colorectal cancer

Oxaliplatin by itself has modest activity against advanced colorectal cancer. When compared with just

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...

and

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 Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

, the primary end-point of the phase III randomized trial.

Adjuvant treatment of colorectal cancer

After and/or before the curative resection of colorectal cancer, chemotherapy based on 5-fluorouracil and folinic acid reduces the risk of relapse.

Adverse effects

Side-effects of oxaliplatin treatment can potentially include: *

Neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

leading to

chemotherapy-induced peripheral neuropathy Chemotherapy-induced peripheral neuropathy (CIPN) is a nerve-damaging side effect of antineoplastic agents in the common cancer treatment, chemotherapy. CIPN afflicts between 30% and 40% of patients undergoing chemotherapy. Antineoplastic agents ...

, a progressive, enduring and often irreversible tingling numbness, intense pain and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs, often with deficits in

proprioception Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neurons ...

. This chronic neuropathy may also be preceded by a transient acute neuropathy occurring at the time of infusion and associated with excitation of voltage-gated Na⁺ channels. *

Fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

, or

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

(low number of a type of white blood cells) *

Ototoxicity Ototoxicity is the property of being toxic to the ear (''oto-''), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, ...

(hearing loss) *

Extravasation __NOTOC__ Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the ...

if oxaliplatin leaks from the infusion vein it may cause severe damage to the connective tissues. *

Hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

(low blood potassium), which is more common in women than men * Persistent

hiccups A hiccup (scientific name ''singultus'', from a Latin word meaning "to catch one's breath while sobbing"; also spelled hiccough) is an involuntary contraction (myoclonic jerk) of the diaphragm that may repeat several times per minute. The hic ...

Rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...

In addition, some patients may experience an

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

to platinum-containing drugs. This is more common in women. Oxaliplatin has less ototoxicity and

nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...

than cisplatin and carboplatin.

Structure and mechanism

The compound features a

square planar The square planar molecular geometry in chemistry describes the stereochemistry (spatial arrangement of atoms) that is adopted by certain chemical compounds. As the name suggests, molecules of this geometry have their atoms positioned at the corne ...

platinum(II) center. In contrast to other drugs of the

class of drugs

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...

and

carboplatin Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used b ...

, oxaliplatin features the bidentate ligand ''trans''-1,2-diaminocyclohexane in place of the two

monodentate In coordination chemistry, denticity () refers to the number of donor groups in a given ligand that bind to the central metal atom in a coordination complex. In many cases, only one atom in the ligand binds to the metal, so the denticity equals ...

ammine

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

s. It also features a bidentate

oxalate Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl o ...

group. The three-dimensional structure of the molecule has been elucidated by X-ray crystallography, although the presence of pseudosymmetry in the crystal structure has caused confusion in its interpretation. According to ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' studies, oxaliplatin fights

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

of the colon through non-targeted

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occur ...

in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA, which prevent DNA replication and transcription, causing cell death.

History

Oxaliplatin was discovered in 1976 at

Nagoya City University , abbreviated to , is a public university in Japan. The main campus (Kawasumi) is located in Mizuho-ku, Nagoya City. Other three campuses (Yamanohata, Tanabe-dori and Kita Chikusa) are also located in the city. Nagoya City University has been r ...

by Professor Yoshinori Kidani, who was granted U.S. Patent 4,169,846 in 1979. Oxaliplatin was subsequently in-licensed by

Debiopharm Debiopharm is a family-owned biopharmaceutical company active in drug development and manufacturing of proprietary drugs, diagnostics, and investments, headquartered in Lausanne, Switzerland. It was founded in 1979 by Rolland-Yves Mauvernay.

and developed as an advanced colorectal cancer treatment.

licensed the drug to

Sanofi-Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...

in 1994. It gained European approval in 1996 (initially in France) and approval by the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

in 2002.

Generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...

oxaliplatin was first approved in the United States in August 2009. Patent disputes caused generic production to stop in 2010, but it restarted in 2012.

Patent information

Eloxatin was covered by patent numbers 5338874 (expired Apr 07, 2013), 5420319 (expired Aug 08, 2016), 5716988 (expired Aug 07, 2015) and 5290961 (expired Jan 12, 2013) (see Electronic Orange Book patent info for Eloxatin).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. 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.

References

External links

* * {{Portal bar, Medicine Coordination complexes Platinum(II) compounds Ammine complexes Oxalato complexes Platinum-based antineoplastic agents World Health Organization essential medicines Wikipedia medicine articles ready to translate Sanofi