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Altretamine

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Altretamine
Skeletal formula of altretamine
Ball-and-stick model of the altretamine molecule
Systematic (IUPAC) name
N2,N2,N4,N4,N6,N6-hexamethyl-1,3,5-triazine-2,4,6-triamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a601200
  • AU: D
  • US: D (Evidence of risk)
Pharmacokinetic data
Protein binding 94%
Half-life 4.7-10.2 hours
Identifiers
645-05-6 7pxY
L01XX03
PubChem CID 2123
DrugBank DB00488 7pxY
ChemSpider 2038 7pxY
UNII Q8BIH59O7H 7pxY
KEGG D02841 7pxY
ChEBI CHEBI:24564 7pxY
ChEMBL CHEMBL1455 7pxY
Chemical data
Formula C9H18N6
210.28 g/mol
 14pxY (what is this?)  (verify)

Altretamine (also hexalen) is an antineoplastic agent. It was approved by the FDA in 1990.

Uses

It is used to treat refractory ovarian cancer.

It is not considered a first-line treatment,[1] but it can be useful as salvage therapy.[2] It also has the advantage of being less toxic than other drugs used for treating refractory ovarian cancer.[3]

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.[4] 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.[5]

Side effects

Side effects include nausea, vomiting, anemia and peripheral sensory neuropathy.[6]

Interactions

Combination with pyridoxine (vitamin B6) decreases neurotoxicity but has been found to reduce the effectiveness of an altretamine/cisplatin regime.[7] MAO inhibitor can cause severe orthostatic hypotension when combined with altretamine; and cimetidine can increase its elimination half-life and toxicity.[6]

See also

References

  1. 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. PMID 12586589. doi:10.1016/S0090-8258(02)00103-8. 
  2. 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. PMID 14751188. doi:10.1016/j.ygyno.2003.09.017. 
  3. Malik IA (2001). "Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer". Jpn. J. Clin. Oncol. 31 (2): 69–73. PMID 11302345. doi:10.1093/jjco/hye012. 
  4. Damia G, D'Incalci M (1995). "Clinical pharmacokinetics of altretamine". Clinical pharmacokinetics 28 (6): 439–48. PMID 7656502. doi:10.2165/00003088-199528060-00002. 
  5. "Foy`s principles of Medical chemistry", edited by Thomas L. Lemke, sixth edition, 2008, pages=1162, ISBN=978-0-7817-6879-5.
  6. 6.0 6.1 Drugs.com: Altretamine Monograph
  7. 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. PMID 1735009. doi:10.3109/07357909209032783.  edit