Overview:   Etoposide has activity against the following cancer types: Hodgkin's disease, large cell lymphomas, pediatric leukemia, testicular tumors, and lung small cell carcinoma. Both drugs in this category (etoposide and teniposide) have similar mechanisms of action and also target similar tumors.

Mechanism of Action:  Similar to the anthracycline anticancer agents but dissimilar to its parent compound, podophyllotoxin, these agents form complexes with topoisomerase-II and DNA (ternary complex) this preventing re-annealing or ceiling of the break which is associated with topoisomerase-DNA-binding. Normally, there is a transient complex involving topoisomerase covalently linked to the 5' phosphate of the double-stranded DNA break. Accumulation of these DNA breaks promotes cell death.

• Topoisomerase-II is a commonly found enzyme that regulates DNA under-and overwinding and also removes knots and tangles by causing transient double-stranded breaks in the double helix. As suggested above, etoposide is lethal to cells by stabilizing the normally transient covalent enzyme-cleaved DNA complex (the cleavage complex).

  • Normally this complex is just an intermediate in the catalytic cycle of topoisomerase-II. 

    • The topoisomerase-II catalytic cycle is defined by six separate steps. The first step is the binding of topoisomerase-II to DNA. The second step is production of a double-stranded DNA break preceding strand passage. The third step is ATP-dependent strand passage. The fourth step involves DNA break religation followed by ATP hydrolysis (step five). The last step, step six, is dissociation of topoisomerase-II from DNA.

  • Likely sites of etoposide-topoisomerase and etoposide-DNA interactions are described below:

    • Etoposide substituents involved in binding to human topoisomerase IIα⁵

      In this figure the blue region on etoposide may interact with topoisomerase IIα, forming the binary drug-enzyme complex. The moieties in yellow are necessary for drug efficacy but are not substantively involved in binding.  The drug regions shaded in gray may interact with DNA, thus defining the drug-stabilized topoisomerase IIα-DNA cleavage complex. (Figure and description from reference 5, Bender et al, 2008)

• If stabilization of the covalent enzyme-cleaved DNA complex occurs often enough, and accumulation of these damaged elements increase in concentration, a number of adverse cellular consequences may occur including mutagenesis and chromosomal translocations. In addition, recombination/repair pathways are activated; however, if enough breaks occur pathways are activated that lead to cell death. Sometimes chromosomal translocation induced by this process might give rise to certain leukemias.³ 

Therapeutics:

• The primary anti-neoplastic use for etoposide is in management of testicular and small cell lung carcinoma. For treatment of testicular tumors, etoposide is combined with cisplatin and bleomycin; whereas, for small cell lung cancer treatment etoposide is administered along with ifosfamide and cisplatin. Anticancer activity in non-Hodgkin's lymphomas, Kaposi's sarcoma developed in association with AIDS (acquired immunodeficiency syndrome), and acute nonlymphocytic leukemia. Myelosuppression is the primary acute toxicity; moreover, the dose-limiting toxicity for etoposide is leukopenia with white cell count suppression most notable at 10-14 days, tending to recover by about three weeks.¹

• As noted above, individuals with childhood acute lymphoblastic leukemia who have been treated with etoposide may develop, some time later, a form of acute nonlymphocytic leukemia which has been associated with a chromosome 11 translocation at the 11q23 locus. At that site a mixed-lineage leukemia gene appears localized and its gene product regulates pluripotent stem cell proliferation. Etoposide-induced leukemia occurs in a 1-3-year timeframe following the end of treatment. This timeframe can be contrasted with a longer, 4-5 year interval between discontinuation of alkylating anticancer drugs and the appearance of secondary leukemia. Also, in the case of secondary leukemia due to etoposide treatment, there appears to be no myelodysplastic disease observed prior to development of the secondary leukemia.¹

• Etoposide can be administered either intravenously or orally, being incompletely absorbed from the gastrointestinal tract; the oral bioavailability is about 50% with an uncertainty of about 25%. The etoposide crosses the blood brain barrier and is widely distributed in the body with highest concentrations found in the CNS, liver, spleen, and kidneys. Some hepatic metabolism occurs and biliary excretion of unchanged, parent drug and/or metabolites is important in bioelimination. Less than 10% of IV etoposide can be accounted for in urine as metabolites. Hepatic metabolism involves, in part, an O-demethylation reaction catalyzed by the liver microsomal enzyme system in this case utilizing cytochrome P450 3A4 (CYP3A4).

Teniposide is an IV-administered anticancer agent which can be used for treatment of refractory acute lymphocytic leukemia in children. This drug appears to work synergistically with cytarabine. In addition to treatment of childhood acute leukemia (notably monocytic leukemia in infants), teniposide exhibits activity in glioblastoma, neuroblastoma and in brain metastases secondary to small cell lung carcinoma. By contrast to etoposide, a significant fraction of teniposide is excreted by the kidney (45%) and much of that (80%) appears as metabolites.