Topoisomerase II inhibitors

In the 1960s, podophylin derivatives—etoposide and teniposide— were found to have a unique mechanism of action, subsequently identified as inhibition of topoll. Etoposide and teniposide exert their action on topoll by:

♦ Inhibiting the ability of the enzyme to relegate the cleaved DNA complex

♦ Generating high levels of DNA with potentially toxic double-stranded breaks

♦ Promoting mutation

♦ Permanent double-stranded breaks

♦ Illegitimate recombination

Chemically, teniposide only differs from etoposide in the substitution of a thenylidene ring in place of a methyl group. However, teniposide is approximately 10% more potent then etoposide, in terms of both in vitro cytotoxicity and DNA strand breakage, but the difference is less apparent in vivo where teniposide is only 1.5-3 times more potent.

Etoposide and teniposide are poorly water-soluble and are formulated with a number of excipients including polysorbate (etoposide) or cremophor EL (teniposide). Etoposide can be administered by either oral or intravenous routes, teniposide only by intravenous injection. Recently, etoposide phosphate was introduced, a more soluble yet bioequivalent form of etoposide designed to decrease infusion-related toxicity.

Teniposide and etoposide are widely used in treatment of adult and paediatric malignancies. Etoposide has been more broadly used in front-line therapy for:

♦ Small-cell lung cancer

♦ Germ-cell tumours

♦ Kaposi's sarcoma

♦ As part of preoperative regimens for bone marrow transplantation Both agents are used in front-line therapy for childhood cancer, including:

♦ Acute lymphoblastic leukaemia

♦ Neuroblastoma

♦ Rhabdomyosarcoma

The pattern of toxicity is very similar between both agents and includes:

♦ Neutropenia

♦ Infusion-related blood pressure changes

♦ Hypersensitivity reactions

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