Altretamine

Altretamine
Clinical data
Trade names	Hexalen
Other names	2,4,6-Tris(dimethylamino)-1,3,5-triazine
AHFS/Drugs.com	Monograph
MedlinePlus	a601200
License data	US FDA: Altretamine;
Pregnancy; category	AU: D ; US: D (Evidence of risk) ;
Routes of; administration	Oral (capsules)
ATC code	L01XX03 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only) ; CA: ℞-only ; US: ℞-only ;
Pharmacokinetic data
Protein binding	94%
Metabolism	Extensive liver
Metabolites	Pentamethylmelamine, tetramethylmelamine
Elimination half-life	4.7–10.2 hours
Identifiers
	IUPAC name N2,N2,N4,N4,N6,N6-Hexamethyl-1,3,5-triazine-2,4,6-triamine;
CAS Number	645-05-6 ;
PubChem CID	2123;
IUPHAR/BPS	7112;
DrugBank	DB00488 ;
ChemSpider	2038 ;
UNII	Q8BIH59O7H;
KEGG	D02841 ;
ChEBI	CHEBI:24564 ;
ChEMBL	ChEMBL1455 ;
CompTox Dashboard (EPA)	DTXSID4022579 ;
ECHA InfoCard	100.010.391
Chemical and physical data
Formula	C9H18N6
Molar mass	210.285 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES n1c(nc(nc1N(C)C)N(C)C)N(C)C;
	InChI InChI=1S/C9H18N6/c1-13(2)7-10-8(14(3)4)12-9(11-7)15(5)6/h1-6H3 ; Key:UUVWYPNAQBNQJQ-UHFFFAOYSA-N ;
	(verify)

Altretamine (trade name Hexalen) 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.[1]

It is not considered a first-line treatment,[2] but it can be useful as salvage therapy.[3] It also has the advantage of being less toxic than other drugs used for treating refractory ovarian cancer.[4]

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.[5]

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.[6]

Side effects

Side effects include nausea, vomiting, anemia and peripheral sensory neuropathy.[7]

Interactions

Combination with pyridoxine (vitamin B₆) decreases neurotoxicity but has been found to reduce the effectiveness of an altretamine/cisplatin regime.[8] MAO inhibitor can cause severe orthostatic hypotension when combined with altretamine; and cimetidine can increase its elimination half-life and toxicity.[7]

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References

"Hexalen (altretamine) Capsule. Human Prescription Drug Label". dailymed.nlm.nih.gov. Eisai Inc. Retrieved 24 August 2016.
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.
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.
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.
Damia G, D'Incalci M (1995). "Clinical pharmacokinetics of altretamine". Clinical Pharmacokinetics. 28 (6): 439–48. doi:10.2165/00003088-199528060-00002. PMID 7656502.
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.
Drugs.com: Altretamine Monograph
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.

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[1] "Hexalen (altretamine) Capsule. Human Prescription Drug Label". dailymed.nlm.nih.gov. Eisai Inc. Retrieved 24 August 2016.

[pmid12586589-2] 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.

[pmid14751188-3] 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.

[pmid11302345-4] 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.

[pmid7656502-5] Damia G, D'Incalci M (1995). "Clinical pharmacokinetics of altretamine". Clinical Pharmacokinetics. 28 (6): 439–48. doi:10.2165/00003088-199528060-00002. PMID 7656502.

[6] 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.

[Drugs.com-7] Drugs.com: Altretamine Monograph

[8] 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.