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Trofosfamide Synthesis Essay

Clinical data
Trade names Cytosar-U
  • AU:D
  • US:D (Evidence of risk)
Routes of
Injectable (intravenous injection or infusion, intrathecal, or subcutaneously)
ATC codeL01BC01(WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 20% oral
Protein binding 13%
Metabolism Liver
Biological half-life biphasic: 10 min, 1–3 hr
Excretion Renal

IUPAC name

  • 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
CAS Number147-94-4 Y
DrugBankDB00987 Y
ChemSpider6017 Y
KEGGD00168 Y
PDB ligand ID AR3 (PDBe, RCSB PDB)
ECHA InfoCard100.005.188
Chemical and physical data
Molar mass 243.217 g/mol
3D model (Jmol)Interactive image


  • O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@@H]2O)CO


  • InChI=1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1 Y

Cytarabine or cytosine arabinoside (Cytosar-U or Depocyt) is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia (AML) and non-Hodgkin lymphoma.[1] It is also known as ara-C (arabinofuranosyl cytidine).[2] It kills cancer cells by interfering with DNA synthesis.

It is called cytosine arabinoside because it combines a cytosine base with an arabinose sugar. Cytosine normally combines with a different sugar, deoxyribose, to form deoxycytidine, a component of DNA. Certain sponges, where it was originally found, use arabinoside sugars to form a different compound (not part of DNA). Cytosine arabinoside is similar enough to human cytosine deoxyribose (deoxycytidine) to be incorporated into human DNA, but different enough that it kills the cell. This mechanism is used to kill cancer cells. Cytarabine is the first of a series of cancer drugs that altered the sugar component of nucleosides. Other cancer drugs modify the base.[3]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]

Medical uses

Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas,[5] where it is the backbone of induction chemotherapy.

Cytarabine also possesses antiviral activity, and it has been used for the treatment of generalised herpesvirus infection. However, cytarabine is not very selective in this setting and causes bone marrow suppression and other severe side effects. Therefore, ara-C is not a useful antiviral agent in humans because of its toxic profile[6] and actually it is used mainly for the chemotherapy of hematologic cancers.

Cytarabine is also used in the study of the nervous system to control the proliferation of glial cells in cultures, the amount of glial cells having an important impact on neurons.

One of the unique toxicities of cytarabine is cerebellar toxicity when given in high doses, which may lead to ataxia. Cytarabine may cause granulocytopenia and other impaired body defenses, which may lead to infection, and thrombocytopenia, which may lead to hemorrhage.

Toxicity: leukopenia, thrombocytopenia, anemia, GI disturbances, stomatitis, conjunctivitis, pneumonitis, fever, and dermatitis, palmar-plantar erythrodysesthesia. Rarely, myelopathy has been reported after high dose or frequent intrathecal Ara-C administration.[7]

When used in protocols designated as high dose, cytarabine can cause cerebral and cerebellar dysfunction, ocular toxicity, pulmonary toxicity, severe GI ulceration and peripheral neuropathy (rare).

To prevent the side effects and improve the therapeutic efficiency, various derivatives of these drugs (including amino acid, peptide, fatty acid and phosphates) have been evaluated, as well as different delivery systems.[8]

Mechanism of action

Cytosine arabinoside interferes with the synthesis of DNA. It is an antimetabolic agent with the chemical name of 1β-arabinofuranosylcytosine. Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphate, which damages DNA when the cell cycle holds in the S phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication for mitosis, are therefore most affected. Cytosine arabinoside also inhibits both DNA[9] and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis.

When used as an antiviral, cytarabine functions by inhibiting deoxycytidine use.[10]

Cytarabine is rapidly deaminated in the body into the inactive uracil derivative and therefore is often given by continuous intravenous infusion.


Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at the University of California, Berkeley.[11]

It was approved by the United StatesFood and Drug Administration in June 1969, and was initially marketed in the U.S. by Upjohn under the trade name Cytosar-U.

Brand names

  • Cytosar-U
  • Tarabine PFS (Pfizer)
  • Depocyt (longer-lasting liposomal formulation)
  • AraC


  1. Wang WS, Tzeng CH, Chiou TJ, et al. (June 1997). "High-dose cytarabine and mitoxantrone as salvage therapy for refractory non-Hodgkin's lymphoma". Jpn. J. Clin. Oncol. 27 (3): 154–7. doi:10.1093/jjco/27.3.154. PMID 9255269. 
  2. Ogbomo H, Michaelis M, Klassert D, Doerr HW, Cinatl J (December 2008). "Resistance to cytarabine induces the up-regulation of NKG2D ligands and enhances natural killer cell lysis of leukemic cells". Neoplasia. 10 (12): 1402–10. PMC 2586691. PMID 19048119. 
  3. Feist, Patty (April 2005). "A Tale from the Sea to Ara C". 
  4. "WHO Model List of EssentialMedicines"(PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. Pigneux A, Perreau V, Jourdan E, et al. (October 2007). "Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results". Haematologica. 92 (10): 1327–34. doi:10.3324/haematol.11068. PMID 18024370. 
  6. Lauter, CB.; Bailey, EJ.; Lerner, AM. (Nov 1974). "Assessment of cytosine arabinoside as an antiviral agent in humans.". Antimicrob Agents Chemother. 6 (5): 598–602. doi:10.1128/aac.6.5.598. PMID 15825312. 
  7. Watterson J, Toogood I, Nieder M, et al. (December 1994). "Excessive spinal cord toxicity from intensive central nervous system-directed therapies". Cancer. 74 (11): 3034–41. doi:10.1002/1097-0142(19941201)74:11<3034::AID-CNCR2820741122>3.0.CO;2-O. PMID 7954266. 
  8. Chhikara BS, Parang K (2010). "Development of cytarabine prodrugs and delivery systems for leukemia treatment". Expert Opinion on Drug Delivery. 7 (12): 1399–1414. doi:10.1517/17425247.2010.527330. 
  9. Perry, Michael J. (2008). The Chemotherapy source book. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 80. ISBN 0-7817-7328-8. 
  10. Lemke, Thomas L.; Williams, David H.; Foye, William O. (2002). Foye's principles of medicinal chemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 963. ISBN 0-683-30737-1. 
  11. Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN 0-471-89979-8. 

External links

This article is issued from Wikipedia - version of the 11/10/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.

2.1.1. In Vitro Evidence for the Antineoplastic Effects of Metformin

In vitro experimentation suggests a plausible repositioning of metformin in the field of gynecologic oncology. Metformin is known to decrease the proliferative capacity and clonogenicity of breast cancer cell lines, regardless of p53 status and the status of estrogen and ErbB2 (elsewhere also referred to as Her-2/neu) receptors [62]. In the latter study, metformin negatively influenced the expression or the activity of various cell cycle- and cell growth-regulatory molecules exemplified by E2F1, MAPK, AKT and mTOR. Low-dose metformin was reported to display a selective cytotoxicity over cancer stem cells (CSCs) in breast cancer types with different genetic background [63]. This finding pays further credit to the validity of CSC theory. The suppressive effects of metformin on the biosynthetic pathway of estrogens both in breast cancer cells [64] and in adipocytes in breast tissue [65] underline its multi-level anti-cancer function encompassing the targeting of pathways operating not only in malignant elements themselves but also in stromal cells in the tumor microenvironment [29,66]. Unfortunately, recent evidence suggests that the prolonged exposure of estrogen receptor (ER)-positive human breast cancer cells to metformin upregulates AKT/Snail1, suppresses ER and renders these cells tolerant to the toxicity of both metformin and tamoxifen; a phenomenon known as “cross-resistance”, irrespective of AMPK stimulation [67]. In ovarian cancer cells metformin has been found to exert cytostatic effects [68]. Consistent with data demonstrating the ability of metformin to eliminate ovarian CSCs [69], it was reported that low-dose metformin restrains the self-renewing capacity of CD44/CD117-positive ovarian CSCs as well as the expression of epithelial-to-mesenchymal transition (EMT) markers in vitro [70]. Besides, irrespective of ER status, metformin exerts anti-EMT effects on 17β-estradiol-treated human endometrial adenocarcinoma cells via engaging a βKlotho/ERK-dependent pathway. These effects partially depend on AMPKα [71].

Metformin displays antitumor properties not only in studies using breast cancer and ovarian cancer cells, but also in a series of experiments with other types of malignant cells. In human pancreatic cancer cells metformin acts in a cytostatic manner. Drug-induced cytostasis in these cells coincides with an alteration in the expression profile of microRNAs and cell cycle-modulatory molecules [72]. On the other hand, non-small cell lung cancer (NSCLC) cells relay on Nemo-like kinase (NLK) for their stemness and their ability to proliferate and metformin has been found to inhibit this kinase, thereby suppressing both NSCLC cell proliferation and stemness [73]. LKB1 seems to be dispensable for the anti-proliferative activity of metformin in NSCLC cells [51]. The finding that in NSCLC H1299 cells metformin counteracts the biosynthetic processes that depend on mitochondrial reactions [50] propelled the suggestion of the “substrate limitation” model (Figure 1), as mentioned above.

Head and neck cancer (HNC) encompasses different pathological entities including nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC), with HNSCC patients running the risk to develop second primary esophageal squamous cell carcinoma (ESCC) [74]. Metformin has actually been demonstrated to exhibit antitumor activity both in HNC cells and in studies assessing its antineoplastic properties in esophageal cancer in vitro. Significantly, the expression of the organic cation transporter 3 (OCT3) which mediates the uptake of metformin into HNSCC cells is necessary for the drug-induced growth suppression via the inhibition of the mTOR pathway [75]. In esophageal adenocarcinoma (EAC) or nasopharyngeal carcinoma cells the antitumorigenicity of metformin is associated with the modulation of the expression of cell cycle-regulatory proteins [76] and DNA repair factors [77], respectively. On ESCC cells, metformin exerts cytostatic effects in an AMPK-dependent fashion [78].

Metformin, apart from its growth-inhibitory properties has also been reported to affect cancer cell viability. Actually, metformin triggers apoptosis in vitro, i.e., in gastric [79], pancreatic [80], colon cancer [47] and salivary adenocarcinoma cells [81]. P53-null colon cancer cells are presumed to be susceptible to metformin-induced apoptosis owing to their inability to undergo the metabolic alterations imposed by metformin in the absence of p53 which is a crucial controller of various aspects of metabolism [47]. This finding is of great importance because it highlights the therapeutic potential of metformin in the treatment of p53-deficient tumors. Further, metformin in combination with the glycolytic inhibitor 2-deoxyglucose (2-DG) makes the prostate cancer cell’s life/death decision scale to tilt towards apoptosis whereas metformin or 2-DG alone exert minor cytotoxicity [82]. Similarly, 2-DG potentiates the toxic effects of metformin in thyroid cancer cells [83]. In prostate cancer cells metformin also negatively modulates lipogenesis; an anabolic route which is a key characteristic of tumor cells [84]. These studies pave the road for the maximal exploitation of metabolic modulators including metformin in cancer therapeutics. Metformin promotes the apoptosis of quiescent B-cell chronic lymphocytic leukemia (CLL) cells. Also, this drug prevents CLL cells from entering the cell cycle upon their stimulation through co-culture with CD40L-positive fibroblasts [85]. In highly invasive C4-2B cells metformin in conjunction with simvastatin evokes necrosis, thereby circumventing the resistance to apoptosis characterizing these prostate cancer cells [58]. In hepatocellular carcinoma (HCC) cells metformin functions as a radiosensitizer via increasing oxidative stress [86] while in osteosarcoma cells metformin potentiates the cytotoxic effects of cisplatin [87].

Besides, metformin influences the migratory/metastatic activity of various cancer cells. Metformin can possibly inhibit the metastatic potential of prostate cancer cells through upregulating miR30a that, in turn, prevents an EMT program mediated by its target SOX4 [88]. The invasive and migratory potential of prostate cancer cells is also decreased by metformin in prostate cancer cell via the impairment of the insulin-like growth factor 1 receptor (IGF-1R) axis [89]. The metformin-induced suppression of the EMT has been described in thyroid cancer cells, too. In this case, this metformin’s function has been attributed to its ability to inhibit the kinase mTOR [90]. In addition, metformin dampens the proliferative as well as the invasive potential of MG63 osteosarcoma cells and counteracts their stemness [91]. The invasiveness of B16F10 mouse melanoma cells is decreased by metformin due to up-regulation of E-cadherin expression [92].

2.1.2. Pre-Clinical In Vivo Evidence for the Antineoplastic Effects of Metformin

There is a considerable amount of in vivo evidence of the preclinical anti-neoplastic activities of metformin, as presented immediately below. Data from an animal model of mammary tumor virus (MMTV)-ErbB2 tumorigenesis underscore the preventive antitumor function of metformin, since it selectively inhibits the proliferation of a specific cellular subpopulation which is being incriminated for tumor initiation; those with the CD61(high)/CD49f(high) immunophenotype. Importantly, the “Achilles heel” of the tumor-initiating cells (TIC)/CSC-rich tumorspheres was shown to be the elevated ErbB2 whose expression is ablated by metformin [93]. A similar CSC-killing activity was reported for metformin in ErbB2-positive mouse xenografts where metformin-mediated toxicity towards human CD44+/CD24−/low breast CSCs is associated with sensitization to the humanized anti-ErbB2 monoclonal antibody trastuzumab [94]. Of note, metformin displays antitumor synergy with several conventional chemotherapeutic agents aside from trastuzumab. In addition, it does not only prevent tumor initiation as mentioned above, but also it prevents the relapse of cancer [33]. Moreover, metformin prolongs the survival of murine ErbB2 transgenes [95] and exhibits chemosensitizing properties in breast cancer cell line xenografts [63]. Also, metformin in synergy with everolimus restrains the growth of tumors from xenografts of HCC1428 breast cancer cells [96].

Pre-clinical, in vivo evidence for the antitumor properties of metformin has been also provided for glioblastoma [97], esophageal cancer [76,78,98] as well as prostate cancer [89], ovarian cancer [68] and salivary gland adenocarcinoma [81] in mouse models. In fact, metformin inhibits the growth of ESCC xenograft mouse models; an event which is molecularly associated with the upregulation of Cip/Kip family members that are known to perturb cell cycle progression [78]. Significantly, metformin inhibits the growth of human pancreatic cancer xenografts, possibly due to the ablation of the crosstalk among an insulin receptor (IR) and G protein-coupled receptors (GPCRs), in an AMPK-dependent manner [99

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