Altretamine

Chemical properties

White Solid

Originator

Hexastat,Roger Bellon,France,1979

The Uses of Altretamine

An antitumor agent which also acts as a chemosterilant for male houseflies and other insects. Antineoplastic.

The Uses of Altretamine

antimalarial

The Uses of Altretamine

As experimental insect chemosterilant.

What are the applications of Application

Altretamine is an antineoplastic

Indications

For use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.

Background

An alkylating agent proposed as an antineoplastic. It also acts as a chemosterilant for male houseflies and other insects.

Definition

A hexamethyl-2,4,6- triamine derivative of 1,3,5-triazine.

Indications

Although both DNA and RNA synthesis are inhibited in cells exposed to hexamethylmelamine (Hexalen), the molecular mechanisms of these effects are not known.

Manufacturing Process

50 g of hexamethylolmelamine-hexamethyl ether in 950 cc methanol are hydrogenated, at 90°C to 100°C, in the presence of 2 g Raney nickel with 100 atmospheres excess pressure of hydrogen in a steel autoclave holding 2 L until the absorption of hydrogen is terminated. After the catalyst has been filtered off with suction, the methanol is distilled off. As a result, 23.1 g (86% of the theoretical) of crude hexamethylmelamine are formed having a melting point of 158°C to 162°C. After recrystallization from methanol, the pure product is obtained having a melting point of 168°C.

brand name

Hexalen (Millot Laboratories, France).

Therapeutic Function

Antitumor

General Description

Colorless crystalline solid. Insoluble in water.

General Description

Altretamine is available in 50-mg capsules for oraladministration as a second-line treatment for ovarian cancer.The mechanism of action has not been firmly established, althoughthe spectrum of activity is similar to that for otheralkylating agents; however, cross-resistance is not seen.Cytotoxicity has been correlated with metabolism to give thecarbinolamines, which may form imines capable of crosslinking,or decompose to give formaldehyde, which may reactwith nucleophiles on DNA or proteins. The agent is well absorbedupon oral administration, well distributed, and highly(90%) plasma protein bound. The agent is extensively metabolizedin the liver by CYP to give demethylated metabolites via the previously mentioned carbinolamines. Elimination occursprimarily in the urine as mostly demethylated metaboliteswith a terminal elimination half-life of 4 to 10 hours.Myleosuppression and nausea/vomiting are dose-limitingtoxicities. Other adverse effects include lethargy, agitation,hallucinations, skin rash, and elevations in transaminase levels,flulike symptoms, abdominal cramps, and diarrhea.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Altretamine neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

Hazard

Toxic.

Mechanism of action

Hexamethylmelamine is readily absorbed after oral administration, with peak plasma levels achieved after 1 hour.The drug is readily metabolized to form a number of demethylated metabolites. Urinary elimination is the primary route of drug excretion.

Pharmacokinetics

Altretamine is a novel antineoplastic agent. The precise mechanism by which altretamine exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, altretamine resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of altretamine and its metabolitics have been negative. Altretamine has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement of cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.

Clinical Use

Hexamethylmelamine is useful for the treatment of ovarian adenocarcinoma and is frequently combined with cyclophosphamide, cisplatin, and doxorubicin in the treatment of this tumor. It also has some activity against small cell lung cancer.

Side Effects

Nausea and vomiting are the major toxicities associated with hexamethylmelamine administration. Myelosuppression and a peripheral neuropathy also may occur.

Metabolism

Not Available

Metabolism

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.