Altretamine
{{Short description|Chemical compound}}
{{Drugbox
| verifiedrevid = 456682333
| drug_name =
| IUPAC_name = N2,N2,N4,N4,N6,N6-Hexamethyl-1,3,5-triazine-2,4,6-triamine
| image = Altretamine.svg
| width = 180
| alt = Skeletal formula of altretamine
| image2 = Altretamine-3D-balls.png
| width2 = 180
| alt2 = Ball-and-stick model of the altretamine molecule
| tradename = Hexalen
| Drugs.com = {{drugs.com|monograph|altretamine}}
| MedlinePlus = a601200
| licence_US = Altretamine
| pregnancy_AU = D
| pregnancy_US = D
| legal_AU = S4
| legal_CA = Rx-only
| legal_US = Rx-only
| routes_of_administration = Oral (capsules)
| protein_bound = 94%
| metabolism = Extensive liver
| metabolites = Pentamethylmelamine, tetramethylmelamine
| elimination_half-life = 4.7–10.2 hours
| IUPHAR_ligand = 7112
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 645-05-6
| ATC_prefix = L01
| ATC_suffix = XX03
| PubChem = 2123
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00488
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2038
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = Q8BIH59O7H
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02841
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 24564
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1455
| synonyms = 2,4,6-Tris(dimethylamino)-1,3,5-triazine
| C=9 | H=18 | N=6
| smiles = n1c(nc(nc1N(C)C)N(C)C)N(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H18N6/c1-13(2)7-10-8(14(3)4)12-9(11-7)15(5)6/h1-6H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UUVWYPNAQBNQJQ-UHFFFAOYSA-N
}}
Altretamine (trade name Hexalen), also called hexamethylmelamine, is an antineoplastic agent. It was approved by the U.S. FDA in 1990.
Uses
It is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with cisplatin and/or alkylating agent-based combination.{{cite web|title=Hexalen (altretamine) Capsule. Human Prescription Drug Label|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8456a8db-a7f6-4bc0-86be-e9c8c374140b |website=dailymed.nlm.nih.gov |publisher=Eisai Inc.|access-date=24 August 2016}}
It is not considered a first-line treatment,{{cite journal | vauthors = Keldsen N, Havsteen H, Vergote I, Bertelsen K, Jakobsen A | title = Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study | journal = Gynecologic Oncology | volume = 88 | issue = 2 | pages = 118–122 | date = February 2003 | pmid = 12586589 | doi = 10.1016/S0090-8258(02)00103-8 }} but it can be useful as salvage therapy.{{cite journal | vauthors = Chan JK, Loizzi V, Manetta A, Berman ML | title = Oral altretamine used as salvage therapy in recurrent ovarian cancer | journal = Gynecologic Oncology | volume = 92 | issue = 1 | pages = 368–371 | date = January 2004 | pmid = 14751188 | doi = 10.1016/j.ygyno.2003.09.017 }} It also has the advantage of being less toxic than other drugs used for treating refractory ovarian cancer.{{cite journal | vauthors = Malik IA | title = Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer | journal = Japanese Journal of Clinical Oncology | volume = 31 | issue = 2 | pages = 69–73 | date = February 2001 | pmid = 11302345 | doi = 10.1093/jjco/hye012 }}
Mechanism
The precise mechanism by which altretamine exerts its anti-cancer effect is unknown but it is classified by MeSH as an alkylating antineoplastic agent.{{cite journal | vauthors = Damia G, D'Incalci M | title = Clinical pharmacokinetics of altretamine | journal = Clinical Pharmacokinetics | volume = 28 | issue = 6 | pages = 439–448 | date = June 1995 | pmid = 7656502 | doi = 10.2165/00003088-199528060-00002 | s2cid = 28375029 }}
This unique structure is believed to damage tumor cells through the production of the weakly alkylating species formaldehyde, a product of CYP450-mediated N-demethylation. Administered orally, altretamine is extensively metabolized on first pass, producing primarily mono- and didemethylated metabolites. Additional demethylation reactions occur in tumor cells, releasing formaldehyde in situ before the drug is excreted in the urine. The carbinolamine (methylol) intermediates of CYP450-mediated metabolism also can generate electrophilic iminium species that are capable of reacting covalently with DNA guanine and cytosine residues as well as protein. Iminium-mediated DNA cross-linking and DNA-protein interstrand cross-linking, mediated through both the iminium intermediate and formaldehyde, have been demonstrated, although the significance of DNA cross-linking on altretamine antitumor activity is uncertain.{{cite book| veditors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry |date=2008 |publisher=Lippincott Williams & Wilkins |location=Philadelphia |isbn=978-0-7817-6879-5 |edition=6th }}
Side effects
Interactions
Combination with pyridoxine (vitamin B6) decreases neurotoxicity but has been found to reduce the effectiveness of an altretamine/cisplatin regime.{{cite journal | vauthors = Wiernik PH, Yeap B, Vogl SE, Kaplan BH, Comis RL, Falkson G, Davis TE, Fazzini E, Cheuvart B, Horton J | display-authors = 6 | title = Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group | journal = Cancer Investigation | volume = 10 | issue = 1 | pages = 1–9 | year = 1992 | pmid = 1735009 | doi = 10.3109/07357909209032783 }} MAO inhibitor can cause severe orthostatic hypotension when combined with altretamine; and cimetidine can increase its elimination half-life and toxicity.
See also
References
{{reflist|30em}}
{{Chemotherapeutic agents}}
{{Use dmy dates|date=April 2017}}