Elsevier

European Journal of Cancer

Volume 34, Issue 10, September 1998, Pages 1514-1521
European Journal of Cancer

Clinical Oncology Update
Etoposide: four decades of development of a topoisomerase II inhibitor

https://doi.org/10.1016/S0959-8049(98)00228-7Get rights and content

Abstract

Podophyllin-containing materials have been used as folk medicines for centuries. In the 1950s, scientists began a search to identify a more effective podophyllotoxin derivative. These efforts eventually resulted in the development of a new class of antineoplastic agents which target the DNA unwinding enzyme, topoisomerase II. The history of the development of one of the first identified topoisomerase II inhibitors, etoposide, is reviewed in this paper. Critical developments in etoposide’s mechanism of action, pharmacology and administration schedule are summarised. The clinical benefits of the recently marketed etoposide prodrug, etoposide phosphate (Etopophos®) are also detailed. The current status of other clinically approved anticancer agents which target topoisomerase II is briefly reviewed.

Introduction

DNAtopoisomerases are nuclear enzymes which make transient DNA strand breaks allowing the cell to manipulate the topology of its DNA1, 2. DNA topoisomerases are essential for DNA replication, transcription, chromosomal segregation and DNA recombination. Two major topoisomerase forms are present in all cells: the type I enzyme which makes single-strand cuts in DNA and type II enzymes which cut and pass double-stranded DNA. DNA topoisomerase I was first described in 1971[3]and DNA topoisomerase II in 1976[4]. Several commercially available antineoplastic drugs are now known to be inhibitors of topoisomerase I (irinotecan, topotecan) or topoisomerase II (etoposide, teniposide, doxorubicin, daunorubicin, idarubicin, mitoxantrone). This review will concentrate primarily on the development of etoposide as an antineoplastic agent. Etoposide was the first agent recognised as a topoisomerase II inhibiting anticancer drug. Research on etoposide has helped the understanding of mechanisms by which drugs poison topoisomerase II. Recognition of the relationship of topoisomerase II inhibition and a resulting antineoplastic effect has stimulated development of other agents. Currently available topoisomerase II inhibitors are briefly described.

Section snippets

Historical development

Podophyllotoxins have been used as medications by various cultures for over 1,000 years (Table 1)[5]. In the 19th century, podophyllin was found to be topically effective for skin cancers. In 1946, the antimitotic properties of podophyllin were established[6]. Clinical evaluation of podophyllotoxin and selected derivatives demonstrated modest antineoplastic activity. However, toxicity of podophyllin was prohibitive7, 8. In the 1950s, investigators at Sandoz Pharmaceuticals began synthesising a

Other topoisomerase II targeting antineoplastic agents

In addition to etoposide, five other topoisomerase II targeting antineoplastic agents (teniposide, doxorubicin, daunorubicin, idarubicin and mitoxantrone) have been approved for clinical use in the US by the Food and Drug Administration (Table 8). Other topoisomerase II inhibitors (Table 9) which have demonstrated antitumour activity in animal or clinical studies have not been approved for general clinical use in the US.

Conclusion

Four decades of research have led to the recognition that certain antineoplastic drugs poison topoisomerase II, thereby killing cancer cells. These studies have provided a new target site for drug development. Etoposide, the lead drug in this class, continues to be a widely used agent with activity against a wide range of cancers. It is a standard component of therapy for small cell lung cancer, testicular cancers and lymphomas. Optimal and convenient schedules have been devised over the past

References (72)

  • Leiter J, Downing V, Hartwell J, et al. Damage induced in sarcoma 37 with podophyllin, podophyllotoxin, alpha-peltatin,...
  • H.F Stahelin et al.

    The chemical and biological route from podophyllotoxin glucoside to etoposide: Ninth Cain Memorial Award Lecture

    Cancer Res

    (1991)
  • D.H Johnson et al.

    Current status of etoposide in the management of small cell lung cancer

    Cancer

    (1991)
  • P.A Radice et al.

    Therapeutic trials with VP-16-213 and VM-26: active agents in small cell lung cancer, non-Hodgkin’s lymphomas and other malignancies

    Cancer Treat Rep

    (1979)
  • J Aisner et al.

    Etoposide: current and future status

    Cancer

    (1991)
  • F.M Muggia et al.

    New chemotherapies for ovarian cancer

    Cancer

    (1991)
  • J.A Ajani et al.

    Current strategies in the management of locoregional and metastatic gastric carcinoma

    Cancer

    (1991)
  • G.W Sledge

    Etoposide in the management of metastatic breast cancer

    Cancer

    (1991)
  • R.A Fleming et al.

    Etoposide: an update

    Clin Pharmacy

    (1989)
  • J.D Loike et al.

    Effect of podophyllotoxin and VP-16 on microtubule assembly in vitro and nucleoside transport in HeLa cells

    Biochemistry

    (1976)
  • A.J Wozniak et al.

    DNA damage as a basis for 4-demethylepipodophyllotoxicity

    Cancer Res

    (1983)
  • T.L Schwinghammer et al.

    Cracking of ABS plastic devices used to infuse undiluted etoposide injection

    Am J Hosp Pharm

    (1988)
  • P.J Creaven et al.

    EPEG, a new antineoplastic epipodophyllotoxin

    Clin Pharmacol Ther

    (1975)
  • K.R Hande

    Etoposide pharmacology

    Semin Oncol

    (1992)
  • D’Incalci M, Rossi C, Zucchetti M, et al. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic...
  • P.J Creaven et al.

    PTG, a new antineoplastic epipodophyllotoxin

    Clin Pharmacol Ther

    (1997)
  • Hande KR, Wedlund PJ, Noone RN, et al. Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer...
  • Hande KR, Wolff SN, Greco FA, et al. Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 1990, 8,...
  • S.P Joel et al.

    Predicting etoposide toxicity: relationship to organ function and protein binding

    J Clin Oncol

    (1996)
  • H Minami et al.

    Pharmacodynamic modeling of prolonged administration of etoposide

    Cancer Chemother Pharmacol

    (1996)
  • Joel SP, Ellis P, O’Bymek, et al. Therapeutic monitoring of continuous etoposide in small cell lung cancer. J Clin...
  • M Zucchetti et al.

    Clinical pharmacology of chronic oral etoposide in patients with small cell and non-small cell lung cancer

    Clin Cancer Res

    (1995)
  • Thompson DS, Hainsworth JD, Hande KR, et al. Prolonged administration of low-dose infusional etoposide in patients with...
  • Wolff SN, Grosh WW, Prater K, et al. In vitro pharmacodynamic evaluation of VP-16-213 and implications for...
  • B Drewinko et al.

    Survival and cycle-progression delay of human lymphoma cells in vitro exposed to VP-16-213

    Cancer Treat Rep

    (1976)
  • Heck MMS, Hittelman AN, Eamshaw WC. Differential expression of DNA topoisomerases I and II during the eukaryotic cell...
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