Theophylline does not reverse DNA replicon initiation inhibition in human cells resistant to alkylating agent-theophylline killing synergism

Abstract

The human Burkitt's lymphoma cell line BHM fails to show synergistic killing by alkylating agents in the presence of theophylline. Nitrosoureas (BCNU and CNU), a mustard agent (L-phenylalanine mustard), and a platinum coordination complex (cis-diamminedichloroplatinum-II) did not show increased cytotoxicity when cells were treated in the presence of theophylline. Despite varying abilities of the drugs to induce DNA damage in BHM cells (no DNA interstrand cross-linking with nitrosoureas or platinum and significant interstrand cross-linking following L-PAM treatment) theophylline did not alter the pattern of DNA damage. DNA interstrand cross-linking following treatment by L-PAM with theophylline was slightly decreased from that seen with L-PAM alone. All three drugs induced DNA replicon initiation inhibition in BHM cells as measured both by alkaline sucrose gradient sedimentation and pH step alkaline elution. As opposed to cell lines where methylxanthines increase alkylating agent cytotoxicity, theophylline and caffeine failed to reverse the drug-induced replicon initiation inhibition seen in BHM cells. These findings support the hypothesis that the synergistic killing seen in some cell lines with alkylating agents and methylxanthines is due to the reversal of replicon initiation inhibition by the methylxanthines.