Altretamine

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Altretamine
Skeletal formula of altretamine
Ball-and-stick model of the altretamine molecule
Names
Pronunciational tret' a meen[1]
Trade namesHexalen
Other namesHexamethylmelamine, 2,4,6-Tris(dimethylamino)-1,3,5-triazine
  • N2,N2,N4,N4,N6,N6-Hexamethyl-1,3,5-triazine-2,4,6-triamine
Clinical data
Drug classAlkylating agent[1]
Main usesOvarian cancer[1]
Side effectsNausea, vomiting, diarrhea, hair loss, bone marrow suppression, peripheral nerve problems, rash[1]
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
use
By mouth (capsules)
External links
AHFS/Drugs.comMonograph
US NLMAltretamine
MedlinePlusa601200
Legal
License data
Legal status
Pharmacokinetics
Protein binding94%
MetabolismExtensive liver
MetabolitesPentamethylmelamine, tetramethylmelamine
Elimination half-life4.7–10.2 hours
Chemical and physical data
FormulaC9H18N6
Molar mass210.285 g·mol−1
3D model (JSmol)
  • n1c(nc(nc1N(C)C)N(C)C)N(C)C
  • InChI=1S/C9H18N6/c1-13(2)7-10-8(14(3)4)12-9(11-7)15(5)6/h1-6H3 checkY
  • Key:UUVWYPNAQBNQJQ-UHFFFAOYSA-N checkY

Altretamine, sold under the brand name Hexalen, is a medication used to treat ovarian cancer.[1] Specifically it is used for advanced disease when other treatments are not effective.[1] It is taken by mouth.[1]

Common side effects include nausea, vomiting, diarrhea, hair loss, bone marrow suppression, peripheral nerve problems, and rash.[1] Other side effects may include mood disorders and further cancer.[2] Use in pregnancy may harm the baby.[2] It is an alkylating agent.[1]

Altretamine was approved for medical use in the United States in 1990.[1] As of 2022 it is not commercially available in the United States.[3]

Medical uses

It is indicated for use as a single agent in the palliative treatment of people with persistent or recurrent ovarian cancer following first-line therapy with cisplatin and/or alkylating agent-based combination.[4]

It is not considered a first-line treatment,[5] but it can be useful as salvage therapy.[6] It also has the advantage of being less toxic than other drugs used for treating refractory ovarian cancer.[7]

Side effects

Side effects include nausea, vomiting, anemia and peripheral sensory neuropathy.[8]

Interactions

Combination with pyridoxine (vitamin B6) decreases neurotoxicity but has been found to reduce the effectiveness of an altretamine/cisplatin regime.[9] MAO inhibitor can cause severe orthostatic hypotension when combined with altretamine; and cimetidine can increase its elimination half-life and toxicity.[8]

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.[10]

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.[11]

See also

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 "Altretamine". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 6 May 2021. Retrieved 14 January 2022.
  2. 2.0 2.1 "Altretamine Monograph for Professionals". Drugs.com. Archived from the original on 26 January 2021. Retrieved 14 January 2022.
  3. "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov. Archived from the original on 27 August 2021. Retrieved 14 January 2022.
  4. "Hexalen (altretamine) Capsule. Human Prescription Drug Label". dailymed.nlm.nih.gov. Eisai Inc. Archived from the original on 28 August 2016. Retrieved 24 August 2016.
  5. Keldsen N, Havsteen H, Vergote I, Bertelsen K, Jakobsen A (2003). "Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study". Gynecol. Oncol. 88 (2): 118–22. doi:10.1016/S0090-8258(02)00103-8. PMID 12586589.
  6. Chan JK, Loizzi V, Manetta A, Berman ML (2004). "Oral altretamine used as salvage therapy in recurrent ovarian cancer". Gynecol. Oncol. 92 (1): 368–71. doi:10.1016/j.ygyno.2003.09.017. PMID 14751188.
  7. Malik IA (2001). "Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer". Jpn. J. Clin. Oncol. 31 (2): 69–73. doi:10.1093/jjco/hye012. PMID 11302345.
  8. 8.0 8.1 Drugs.com: Altretamine Monograph Archived 26 January 2021 at the Wayback Machine
  9. Wiernik, P. H.; Yeap, B.; Vogl, S. E.; Kaplan, B. H.; Comis, R. L.; Falkson, G.; Davis, T. E.; Fazzini, E.; Cheuvart, B.; Horton, J. (1992). "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". Cancer Investigation. 10 (1): 1–9. doi:10.3109/07357909209032783. PMID 1735009.
  10. Damia G, D'Incalci M (1995). "Clinical pharmacokinetics of altretamine". Clinical Pharmacokinetics. 28 (6): 439–48. doi:10.2165/00003088-199528060-00002. PMID 7656502.
  11. Lemke, Thomas L.; Williams, David A., eds. (2008). Foye's Principles of Medicinal Chemistry (6th ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 978-0-7817-6879-5.

External links

Identifiers: