Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.
The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes significant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF-187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II-mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular pH. Chloroquine, in contrast to etoposide, is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pH-dependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH (pHe) from neutral (pHe = 7.4) to acidic (pHe = 6.0), [3H]chloroquine accumulation was decreased 5-fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia L1210 cells. In parallel, the antagonism exhibited by chloroquine on etoposide cytotoxicity was pHe dependent. Thus, no protection by chloroquine was observed at pHe = 6.5, whereas at pHe = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.
Jensen
P B
PB
Department of Oncology, Finsen Institute, Rigshospitalet, Copenhagen, Denmark.
Sørensen
B S
BS
Sehested
M
M
Grue
P
P
Demant
E J
EJ
Hansen
H H
HH
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D018288:Carcinoma, Small Cell / Q000378:metabolism; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007939:Leukemia L1210 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D000677:Amsacrine; D005047:Etoposide; D002738:Chloroquine; D004250:DNA Topoisomerases, Type II