title: Structure-activity relations, cytotoxicity and topoisomerase II dependent cleavage induced by pendulum ring analogues of etoposide.
abstract: The cytotoxicity of etoposide and its analogues, dihydroxy (DHVP), o-quinone (VP-Q) and o-methyl (VP-OMe), was evaluated in human breast (MCF-7) and HL60 tumour cells. Although less potent than etoposide, both DHVP and VP-Q were cytotoxic to these cells. However, VP-OMe was inactive. Studies with purified topoisomerase II showed that the intensity of DNA cleavage and the pattern of cleavage were similar for DHVP, VP-Q and etoposide. In contrast, the VP-OMe failed to induce DNA cleavage, indicating that the presence of 4'-OH is essential for metabolism, induction of topoisomerase II-mediated DNA cleavage and cytotoxicity of etoposide and its analogues.
authors.affiliation: Biochemical Pharmacology Section, NCI, NIH, Bethesda, MD 20892.
authors.forename: B K
authors.initials: BK
authors.lastname: Sinha
authors.forename: P M
authors.initials: PM
authors.lastname: Politi
authors.forename: H M
authors.initials: HM
authors.lastname: Eliot
authors.forename: D
authors.initials: D
authors.lastname: Kerrigan
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D005047:Etoposide / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D006801:Humans; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects*
chemical_list: D004273:DNA, Neoplasm; D005047:Etoposide; D004250:DNA Topoisomerases, Type II