Teniposide

Chemical properties

White Solid

Originator

Vehem,Sandoz,France,1976

The Uses of Teniposide

A labelled semi-synthetic derivative of Podophyllotoxin. Antineoplastic.

The Uses of Teniposide

A semi-synthetic derivative of Podophyllotoxin. Antineoplastic.

The Uses of Teniposide

Teniposide is a podophyllotoxin derivative that causes dose-dependent single- and double-stranded breaks in DNA by inhibiting topoisomerase II. Its cytostatic effects are related to its ability to stabilize the DNA-topoisomerase II complex during DNA replication, inducing DNA damage and cellular apoptosis. Teniposide has been widely used in the treatment of various cancers including, small cell lung cancer, malignant lymphoma, breast cancer, oral squamous cell carcinoma, and acute lymphoblastic leukemia.

Indications

Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia

Background

Teniposide is a semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent cells from entering into the mitotic phase of the cell cycle, and lead to cell death. Teniposide acts primarily in the G2 and S phases of the cycle.

Definition

ChEBI: A furonaphthodioxole that is a synthetic derivative of podophyllotoxin with anti-tumour activity; causes single- and double-stranded breaks in DNA and DNA-protein cross-links and prevents repair by topoisomerase II binding.

What are the applications of Application

Teniposide is a derivative of podophyllotoxin that has shown cytostatic effect & inhibition of topoisomerase II

Indications

Teniposide (VM-26, Vumon) is closely related to etoposide in structure, mechanisms of action and resistance, and adverse effects. It is more lipophilic and approximately threefold more potent than etoposide. Its major uses have been in pediatric cancers, particularly in acute lymphoblastic leukemias.

Manufacturing Process

10 ml of pure thiophene-2-aldehyde and 0.25 g of anhydrous zinc chloride are American Home Products Corporation; British Patent 1,022,642; March 16, 1966
American Home Products Corporation; British Patent 1,022,645; March 16, 1966
Bell, S.C.; British Patent 1,057,492; February 1, 1967; assigned to American Home Products Corporation

brand name

Vumon (Bristol-Myers Squibb).

Therapeutic Function

Antineoplastic

General Description

Teniposide is available in 50-mg ampules with Cremophor ELfor IV administration in the treatment of acute lymphoblasticleukemia (ALL). The agent is more potent as an inhibitor oftopoisomerase II. The pharmacokinetics of teniposide issimilar to that of etoposide; however, the more lipophilic teniposideis more highly protein bound (99%) and less isexcreted unchanged in the urine (10%–20%). There is alsogreater overall metabolism of teniposide; however, CYP3A4-mediated conversion to the active catechol is slower comparedwith etoposide. Elimination occurs primarily in the urine witha terminal elimination half-life of 5 hours.

Biochem/physiol Actions

Teniposide (VM-26) is a Topoisomerase II inhibitor with antitumor activity. Teniposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA, inducing breaks in double stranded DNA and preventing repair.

Pharmacokinetics

Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA.

Clinical Use

Teniposide is used in combination with other agents for the treatment of refractory childhood acute lymphoblastic leukemia.

Safety Profile

Poison by intraperitoneal and subcutaneous routes. An experimental teratogen. Human systemic effects by ingestion and intravenous route: anorexia, nausea or vomiting, leukopenia, agranulocytosis and aplastic anemia of the blood, bone marrow changes, and hair changes. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of SOx.

Synthesis

Teniposide, [5R-(5|á,5a|?,8a|á,9|?)]-9-[4,6-O-(2-thienylmethylene)-|?-D-glucopyranosyl)oxy]- 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4: 6,7]-naphtho[2,3-d]-1,3-dioxol-6(5aH)-one (30.4.9), is basically synthesized by an analogous scheme from 4-benzyloxy-4-desmethylepipodophyllotoxin (30.4.6), which is esterified by 2,3,4,6- tetra-O-acetyl-|?-D-glucose in the presence of boron trifluoride etherate, giving a glycoside 30.4.7. The acetyl and benzyloxycarbonyl protecting groups in this molecule are removed by succesive use of zinc acetate and sodium methoxide, and then by subsequent hydrogen reduction, which forms the diol 30.4.8. The resulting diol is then transformed into the corresponding acetal 2-formylthiophene, which is the desired teniposide (30.4.9) .

Metabolism

storage

Store at -20°C