altretamine

Altretamine
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
Pregnancy cat.	AU: D; US: D;
Legal status	AU: Prescription Only (S4); CA: ℞-only; US: ℞-only;
Pharmacokinetic data
Protein binding	94%
Half-life	4.7-10.2 hours
Identifiers
CAS number	645-05-6
ATC code	L01XX03
PubChem	CID 2123
DrugBank	DB00488
ChemSpider	2038
UNII	Q8BIH59O7H
KEGG	D02841
ChEBI	CHEBI:24564
ChEMBL	CHEMBL1455
Chemical data
Formula	C9H18N6
Mol. mass	210.28 g/mol
	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 ;
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関: hexamethylmelamine

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/12/25 08:49:30」(JST)

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[Wiki en表示]

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]

References

^ 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.
^ "Foy`s principles of Medical chemistry", edited by Thomas L. Lemke, sixth edition, 2008, pages=1162, ISBN=978-0-7817-6879-5.
^ ^a ^b 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. edit

UpToDate Contents

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In vivo Antitumor Activity of Hexamethylmelamine against Human Breast, Stomach and Colon Carcinoma Xenografts

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NAID 10008069617