Lidocaine potentiation of bleomycin A2 cytotoxicity and DNA strand breakage in L1210 and human A-253 cells.
The survival of cultured L1210 cells exposed to bleomycin A2 (BLM A2) was markedly decreased by coincubation with the local anesthetic lidocaine. The potentiation occurred with concentrations of lidocaine that were nontoxic and was dependent upon both the concentration of lidocaine and BLM A2. A 1000-fold decrease in survival was seen with a 1-h exposure to 8 mM lidocaine and 10 microM BLM A2 compared to incubation with 10 microM BLM A2 alone. Prior exposure to lidocaine did not markedly alter BLM A2 cytotoxicity, while treatment with lidocaine immediately after BLM A2 exposure did, suggesting that increased cellular content of BLM A2 was not the mechanism of enhancement. Furthermore, lidocaine reduced the total amount of cell-associated radioactivity seen after incubation with [3H]BLM A2. The enhancement in L1210 cell cytotoxicity with lidocaine was not specific for the C- and N-terminal moieties of the BLM molecule. Other DNA-interacting antitumor agents, such as etoposide and mitomycin C, did not exhibit biologically significant alterations in their cytotoxicity when coincubated with lidocaine, although cis-diamminedichloroplatinum was significantly more toxic in the presence of lidocaine. The potentiation of BLM A2 cytotoxicity was not unique to murine tumor cells, since it was also seen with cultured human head and neck carcinoma (A-253) cells. Lidocaine did not increase directly BLM A2-induced breakage of DNA in vitro as measured by loss of form I pAT 153 DNA, but it did increase BLM A2-induced DNA strand breaks in intact L1210 cells coincubated with lidocaine and BLM A2. Exposure of L1210 cells to lidocaine after BLM A2 treatment also greatly increased DNA breakage consistent with possible inhibition of DNA repair. In addition, a modest reduction in the in vitro inactivation of BLM A2 by BLM hydrolase was found with lidocaine. We propose that inhibition of BLM metabolism and repair of BLM-induced DNA damage by lidocaine may have a role in the enhanced cytotoxicity.
Lazo
J S
JS
Braun
I D
ID
Meandzija
B
B
Kennedy
K A
KA
Pham
E T
ET
Smaldone
L F
LF
D000818:Animals; D001761:Bleomycin / Q000378:metabolism / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D007939:Leukemia L1210 / Q000473:pathology; D008012:Lidocaine / Q000494:pharmacology*; D051379:Mice
D002147:Calmodulin; D001761:Bleomycin; D005047:Etoposide; D008012:Lidocaine