Inhibitors of topoisomerase II as pH-dependent modulators of etoposide-mediated cytotoxicity.
Chloroquine intercalates into DNA and protects cells against topoisomerase II (topo II) poisons such as etoposide by hindering the DNA cleavage reaction of this target enzyme. Chloroquine, in contrast to etoposide, is a weak base and therefore barely enters the cell when the extracellular fluid is acidic, as is the case in most solid tumors. Such a pH-dependent drug interaction could be useful in targeting the cytotoxicity of topo II poisons toward solid tumors. Unfortunately, antagonistic chloroquine concentrations cannot be reached in vivo because of its unacceptable toxicity. Thus, antagonists with a higher therapeutic index are needed. We report here on the structure-activity relationship of several chloroquine and acridine analogues in a clonogenic assay. There were major differences in the cytotoxicity of the different compounds, with acridines being 50-fold more toxic than the chloroquine analogues. Several compounds were, however, able to antagonize etoposide-mediated cytotoxicity in a pH-dependent manner as chloroquine. Dependency on pH was lost if the aminoalkyl side arm of chloroquine was removed or lengthened by one CH2 whereas pH dependency was strong with hydroxychloroquine. In contrast, the aminoalkyl side arm was clearly dispensable in the acridines because both quinacrine and 9-aminoacridine demonstrated profound pH dependency. The results from clonogenic assay were compared with cellular transport measurements and topo II enzyme inhibition. Compounds with the most marked pH-dependent intracellular accumulation were also the best pH-dependent protectors of etoposide cytotoxicity, clearly supporting the hypothesis that extracellular pH can be used to regulate topo II poisoning.
Langer
S W
SW
Laboratory of Experimental Medical Oncology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark. swlanger@dadlnet.dk
Schmidt
G
G
Sørensen
M
M
Sehested
M
M
Jensen
P B
PB
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide