In an attempt to clarify the role of drug-induced protein-associated DNA breaks 
(i.e., DNA topoisomerase II-mediated DNA cleavage) in the cytotoxic activity of 
doxorubicin and etoposide, their cellular effects were compared in 2 human 
small-cell lung cancer (SCLC) lines, characterized by differential sensitivity 
to DNA topoisomerase II inhibitors. These drugs were selected for comparative 
studies since they are among the most effective agents in the treatment of SCLC. 
H146 and N592 cell lines were obtained from pleural effusion and bone-marrow 
aspirate of pretreated patients, respectively. Both cell lines grew as floating 
aggregates with similar doubling times (30 and 33 hr for N592 and H146 cells, 
respectively). Although, immediately after 1 hr exposure to equitoxic drug 
levels, the extent of DNA cleavage produced by doxorubicin was markedly lower 
than that produced by etoposide, DNA lesions produced by doxorubicin persisted 
and even increased following drug removal. In contrast, an almost complete 
disappearance of etoposide-induced DNA breaks was noted 1 hr after drug removal. 
Resealing of strand breaks was faster in N592 than in H146 cells. These findings 
suggest that reversal of these lesions plays a major role in cell survival 
rather than the occurrence of DNA breaks immediately following drug exposure. 
This observation is consistent with the view that inhibition of DNA re-ligation 
rather than stimulation of DNA cleavage is the critical step for drug action. 
The different response of these cell lines to cytotoxic action of the 
topoisomerase inhibitors is associated with a differential drug effect on DNA 
integrity (detected as DNA double-strand breaks and DNA-protein cross-links). 
However DNA lesions were comparable when cells were exposed to equitoxic drug 
levels. The observation that etoposide-induced DNA breaks were similar in 
isolated nuclei from both cell lines suggests that drug-target interaction is 
modulated in a different manner in the intact cell. As indicated by doxorubicin 
uptake and retention, cellular drug pharmacokinetics do not account for the 
different drug response of the studied SCLC lines, presumably, reflecting a 
different extent of DNA break formation and/or a different cytotoxic consequence 
of DNA damage.