Introduction: Some anticancer agents are derived from natural products. One example of a toxin extracted from a plant is the basis of two derivatives that are used in contemporary chemotherapy. This toxin is podophyllotoxin which is extracted from the mayapple plant, Podophyllum pelatum. The two derivatives are etoposide (VP-16-213) and teniposide (VM-26).1
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.
Likely sites of etoposide-topoisomerase and etoposide-DNA interactions are described below:
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
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 is noted 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).
Resistance to the effects of etoposide may be due to increased drug efflux caused by an increase in P-glycoprotein transporter.
This change appears associated with an increase (amplification) of the mdr1 gene.
Another possibility to explain etoposide resistance would be reduced expression of topoisomerase-II or an enzyme mutation or, alternatively, a mutation in the p53 tumor suppressor gene, necessary apoptotic pathway element.1
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