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Potentiation of Etoposide-induced DNA Damage by Calcium Antagonists in L1210 Cells in Vitro¹

Clinical Pharmacology Program, Department of Pharmacology, and Division of Medical Oncology, Department of Medicine, University of Florida, Gainesville, Florida 32610

Verapamil and a number of other Ca²⁺ antagonists were found to potentiate DNA damage induced by 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-ß-D-glucopyranoside (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(ß-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-ß-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.

¹ Supported by the Ralph E. Cody Research Grant from the American Cancer Society and Bristol Laboratories, Syracuse, NY.

² To whom requests for reprints should be addressed.

³ Recipient of support from Grant RCDA CA-00537 from the National Cancer Institute.

Received 8/19/83. Accepted 5/ 9/84.

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