Role of Free Radicals in Etoposide (Vp-16,213) Action
Part of the
Basic Life Sciences
book series (BLSC, volume 49)
Etoposide (VP-16, Figure 1), a semisynthetic derivative of phodophyllotoxin, is clinically active as a single agent and in combination with other antitumor drugs, e.g. adriamycin and cis-platinum. VP-16 has shown promising activity in the treatment of small cell lung carcinoma, testicular tumors and malignant lymphomas1, 2. VP-16 has been shown to induce DNA strand breaks in tumor cells and it is believed that topoisomerase II is the likely intracellular target for this DNA damage3, 4. Although the DNA strand breaking activity of VP-16 has been implicated in its cytotoxicty, the molecular mechanism remains to be defined. For DNA damage and the biological activity, the presence of cellular components and the presence of free hydroxyl group in the C-4′ are essential5 suggesting other factors may also be important in the biochemical mechanism of the drug.
KeywordsElectron Spin Resonance Antitumor Drug Small Cell Lung Carcinoma Testicular Tumor Phenoxy Radical
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
M. Rozencweig, D. D. Von Hoff, J. E. Henney, and F. M. Muggia, VM-26 and VP-16–213: a comparative analysis, Cancer
40: 334 (1977).PubMedCrossRefGoogle Scholar
P.J. Dwyer, B. Leyland-Jones, M. T. Alonso, S. Marsoni, and R.E. Wittes, Etoposide (VP-16–213): current status of an active anticancer drug, N. Engl. J. Med.
, 312: 692 (1985).CrossRefGoogle Scholar
A. J. Wojniac, and W. E. Ross, DNA damage as a basis for 4′-demethylepipodophyllotoxin-9-(4,6-O-ethylene-β-D-glucopyranoside (etoposide) cytotoxicity, Cancer Res
., 43: 120 (1983) .PubMedGoogle Scholar
B. H. Long, S. T. Musial, and M. G. Brattain, Comparison of cytotoxicity and DNA breakage activity of congeners of podophyllotoxin including VP-16–213 and VM-26: a quantative structure-activity relationship, Biochemistry
, 23: 1183 (1984).PubMedCrossRefGoogle Scholar
J. D. Loike, and S. B. Horwitz, Effects of VP-16–213 on the intracellular degradation of DNA in HeLa cells, Biochemistry 15: 5443 (1976).PubMedCrossRefGoogle Scholar
N. Haim, J. Nemec, J. Roman, and B. K. Sinha, In vitro metabolism of etoposide (VP-16–213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins, Biochem. Pharmacol
., 36: 527 (1987).PubMedCrossRefGoogle Scholar
B. K. Sinha, and C. E. Myers, Irreversible binding of etoposide (VP-16–213) to deoxyribonucleic acid and proteins, Biochem. Pharmacol.
, 33 : 3725 (1984).PubMedCrossRefGoogle Scholar
B. K. Sinha, M. A. Trush, and B. Kalayanaraman, Microsomal interactions and inhibition of lipid peroxidation by etoposide (VP-16–213): Implications for mode of action, Biochem. Pharmacol.
, 34: 2036 (1985).PubMedCrossRefGoogle Scholar
B. K. Sinha, M. A. Trush, and B. Kalayanaraman, Free radical metabolism of VP-16 and inhibition of anthracycline-induced lipid peroxidation, Biochem. Pharmacol.
, 32: 3495 (1983).PubMedCrossRefGoogle Scholar
N. Haim, J. Roman, J. Nemec, and B. K. Sinha, Peroxidative free radical formation and O-demethylation of etoposide (VP-16) and teniposide (VM-26), Biochem. Biophys. Res. Commun.
, 135: 215 (1986).PubMedCrossRefGoogle Scholar
A. G. Katki, B. Kalayanaraman, and B. K. Sinha, Interactions of the antitumor drug, etoposide, with reduced thiols in vitro and in vivo, Chem. Biol. Interact
., 62, 237 (1987).PubMedCrossRefGoogle Scholar
© Plenum Press, New York 1988