Abstract：
:Verapamil and a number of other Ca2+ antagonists were found to potentiate DNA damage induced by 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside (VP-16) in L1210 cells in vitro. The potentiating effect of verapamil on DNA single-strand breaks in vitro was concentration dependent, relevant to clinically achieved levels of Ca2+ antagonists, and showed good correlation with enhanced cytotoxicity when VP-16 and Ca2+ antagonists were combined in soft agar colony-forming assays. Onset of verapamil activity was observed within 20 min of addition to cells whether VP-16 had been preincubated with cells or was added simultaneously with the Ca2+ blocker. The presence of the extracellular Ca2+ antagonist was required for potentiation as evidenced by the rapid reversal of increased DNA single-strand breaks when cells were washed free of verapamil. Neither ethyleneglycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid nor the Ca2+ ionophore A23187 altered verapamil potentiation of VP-16-induced DNA damage, suggesting that this Ca2+ antagonist acts by a mechanism other than by inhibition of Ca2+ influx. In isolated L1210 nuclei, verapamil did not enhance VP-16- or 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D- glucopyranoside (VM-26)-induced single-strand breaks suggesting a requirement for the intact cell. Even though VM-26 was 5- to 10-fold more potent than VP-16, verapamil potentiated the DNA damage caused by these two epipodophyllotoxins in L1210 cells to the same extent when these agents were used at equipotent doses. Potency differences between VM-26 and VP-16 were evident in isolated nuclei suggesting that nuclear binding or activation is a more important parameter than were previously reported membrane transport differences. The significance of Ca2+ antagonist potentiation of VP-16-induced DNA damage is discussed in terms of overcoming resistance to epipodophyllotoxins and characterizing more precisely the intracellular disposition, binding, and activation of VP-16.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Yalowich JC,Ross WEsubject
Has Abstractpub_date
1984-08-01 00:00:00pages
3360-5issue
8eissn
0008-5472issn
1538-7445journal_volume
44pub_type
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