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| Pronunciation | /dʒɛmˈsaɪtəbiːn/ |
| Trade names | Gemzar, others[1] |
| Other names | 2', 2'-difluoro 2'deoxycytidine, dFdC |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intravenous |
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| Protein binding | <10% |
| Eliminationhalf-life | Short infusions: 32–94 minutes Long infusions: 245–638 minutes |
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| ECHA InfoCard | 100.124.343 |
| Chemical and physical data | |
| Formula | C9H11F2N3O4 |
| Molar mass | 263.201 g·mol−1 |
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Gemcitabine, sold under the brand nameGemzar, among others,[1] is achemotherapy medication used to treatcancers.[3] It is used to treattesticular cancer,[4]breast cancer,ovarian cancer,non-small cell lung cancer,pancreatic cancer, andbladder cancer.[3][5] It is administered byintravenous infusion.[3] It acts against neoplastic growth, and it inhibits the replication ofOrthohepevirus A, the causative agent ofHepatitis E, through upregulation ofinterferon signaling.[6]
Common side effects includebone marrow suppression, liver and kidney problems,nausea,fever,rash,shortness of breath, mouth sores,diarrhea, neuropathy, andhair loss.[3] Use duringpregnancy will likely result infetal harm.[3] Gemcitabine is in thenucleoside analog family of medication.[3] It works by blocking the creation of newDNA, which results in cell death.[3]
Gemcitabine was patented in 1983 and was approved for medical use in 1995.[7] Generic versions were introduced in Europe in 2009 and in the US in 2010.[8][9] It is on theWHO Model List of Essential Medicines.[10]
Gemcitabine treats variouscarcinomas. It is used as a first-line treatment alone forpancreatic cancer, and in combination withcisplatin for advanced or metastaticbladder cancer and advanced or metastaticnon-small cell lung cancer. It is used as a second-line treatment in combination withcarboplatin forovarian cancer and in combination withpaclitaxel forbreast cancer that is metastatic or cannot be surgically removed.[11][12][13]
It is usedoff-label to treatcholangiocarcinoma[14] and otherbiliary tract cancers.[15]
Taking gemcitabine can also affect fertility in men and women, sex life, and menstruation. Women taking gemcitabine should not become pregnant, and pregnant and breastfeeding women should not take it.[16]
As of 2014, drug interactions had not been studied.[12][11]
Gemcitabine is achemotherapy drug that works by killing any cells that are dividing.[11] Cancer cells divide rapidly and so are targeted at higher rates by gemcitabine, but many essential cells also divide rapidly, including cells in skin, the scalp, the stomach lining, and bone marrow, resulting in adverse effects.[17]: 265
The gemcitabine label carries warnings that it can suppress bone marrow function and causeloss of white blood cells,loss of platelets, andloss of red blood cells, and that it should be used carefully in people with liver, kidney, or cardiovascular disorders. People taking it should not take live vaccines. The warning label also states it may causeposterior reversible encephalopathy syndrome, that it may causecapillary leak syndrome, that it may cause severe lung conditions likepulmonary edema,pneumonia, andadult respiratory distress syndrome, and that it may harm sperm.[11][18]
More than 10% of users develop adverse effects, including difficulty breathing, low white and red blood cells counts, low platelet counts, vomiting and nausea,elevated transaminases, rashes and itchy skin, hair loss, blood and protein in urine, flu-like symptoms, andedema.[11][16]
Common adverse effects (occurring in 1–10% of users) include fever, loss of appetite, headache, difficulty sleeping, tiredness, cough, runny nose, diarrhea, mouth and lip sores, sweating, back pain, and muscle pain.[11]
Thrombotic thrombocytopenic purpura (TTP) is a rare but serious side effect that been associated with particular chemotherapy medications including gemcitabine. TTP is a blood disorder and can lead tomicroangipathic hemolytic anemia (MAHA), neurologic abnormalities, fever, and renal disease.[19]
Gemcitabine ishydrophilic and must be transported into cells via molecular transporters fornucleosides (the most common transporters for gemcitabine areSLC29A1, SLC28A1, and SLC28A3).[20][21] After entering the cell, gemcitabine is first modified by attaching aphosphate to it, and so it becomes gemcitabine monophosphate (dFdCMP).[20][21] This is therate-determining step that is catalyzed by theenzymedeoxycytidine kinase (DCK).[20][21] Two more phosphates are added by other enzymes. After the attachment of the three phosphates gemcitabine is finally pharmacologically active as gemcitabine triphosphate (dFdCTP).[20][22]
After being thricephosphorylated, gemcitabine can masquerade asdeoxycytidine triphosphate and is incorporated into new DNA strands being synthesized as the cellreplicates.[3][20][21]
When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to "masked chain termination" because gemcitabine is a "faulty" base, but due to its neighboring native nucleoside it eludes the cell's normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cell's DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.[3][20][21]
The form of gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the enzymeribonucleotide reductase (RNR), which is needed to create new DNA nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which also increases uptake of gemcitabine.[3][20][21][23]
Gemcitabine is a syntheticpyrimidinenucleosideprodrug—anucleoside analog in which thehydrogenatoms on the 2' carbon ofdeoxycytidine are replaced byfluorine atoms.[3][24][25]
The synthesis described and pictured below is the original synthesis done in theEli Lilly Company labs. Synthesis begins withenantiopure D-glyceraldehyde (R)-2 as the starting material which can made from D-mannitol in 2–7 steps. Then fluorine is introduced by a "building block" approach usingethyl bromodifluoroacetate. Then, Reformatsky reaction under standard conditions will yield a 3:1 anti/syn diastereomeric mixture, with one major product. Separation of the diastereomers is carried out via HPLC, thus yielding the anti-3 gemcitabine in a 65% yield.[24][25] At least two other full synthesis methods have also been developed by different groups.[25]
Gemcitabine was first synthesized in Larry Hertel's lab atEli Lilly and Company during the early 1980s. It was intended as anantiviral drug, but preclinical testing showed that it killed leukemia cellsin vitro.[26]
During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival rate significantly, and it was approved in the UK in 1995[11] and approved by the FDA in 1996 for pancreatic cancers.[5] In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved for metastatic breast cancer.[5]
European labels were harmonized by the EMA in 2008.[27]
By 2008, Lilly's worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009.[28] The first generic launched in Europe in 2009,[8] and patent challenges were mounted in the US which led to invalidation of a key Lilly patent on its method to make the drug.[29][30] Generic companies started selling the drug in the US in 2010 when the patent on the chemical itself expired.[30][9] Patent litigation in China made headlines there and was resolved in 2010.[31]
As of 2017, gemcitabine was marketed under many brand names worldwide: Abine, Accogem, Acytabin, Antoril, axigem, Bendacitabin, Biogem, Boligem, Celzar, Citegin, Cytigem, Cytogem, Daplax, DBL, Demozar, Dercin, Emcitab, Enekamub, Eriogem, Fotinex, Gebina, Gemalata, Gembin, Gembine, Gembio, Gemcel, Gemcetin, Gemcibine, Gemcikal, Gemcipen, Gemcired, Gemcirena, Gemcit, Gemcitabin, Gemcitabina, Gemcitabine, Gemcitabinum, Gemcitan, Gemedac, Gemflor, Gemful, Gemita, Gemko, Gemliquid, Gemmis, Gemnil, Gempower, Gemsol, Gemstad, Gemstada, Gemtabine, Gemtavis, Gemtaz, Gemtero, Gemtra, Gemtro, Gemvic, Gemxit, Gemzar, Gentabim, Genuten, Genvir, Geroam, Gestredos, Getanosan, Getmisi, Gezt, Gitrabin, Gramagen, Haxanit, Jemta, Kalbezar, Medigem, Meditabine, Nabigem, Nallian, Oncogem, Oncoril, Pamigeno, Ribozar, Santabin, Sitagem, Symtabin, Yu Jie, Ze Fei, and Zefei.[1]
Because it is clinically valuable and is only useful when delivered intravenously orintravesically, methods to reformulate it so that it can be given by mouth have been a subject of research.[32][33][34]
Research intopharmacogenomics andpharmacogenetics has been ongoing. As of 2014, it was not clear whether or not genetic tests could be useful in guiding dosing and which people respond best to gemcitabine.[20] However, it appears that variation in the expression of proteins (SLC29A1,SLC29A2,SLC28A1, and SLC28A3) used for transport of gemcitabine into the cell lead to variations in its potency. Similarly, the genes that express proteins that lead to its inactivation (deoxycytidine deaminase,cytidine deaminase, andNT5C) and that express its other intracellular targets (RRM1,RRM2, andRRM2B) lead to variations in response to the drug.[20] Research has also been ongoing to understand how mutations in pancreatic cancers themselves determine response to gemcitabine.[35]
It has been studied as a treatment forKaposi's sarcoma, a common cancer in people withAIDS which is uncommon in the developed world but not uncommon in the developing world.[36]
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