Relationships among tumor responsiveness, cell sensitivity, doxorubicin cellular pharmacokinetics and drug-induced DNA alterations in two human small-cell lung cancer xenografts

Abstract

In an attempt to understand the underlying cellular/biochemical factors of sensitivity/resistance in human small‐cell lung cancer (SCLC), 2 SCLC tumor lines were compared with respect to tumor responsiveness to drug treatment, cell sensitivity, cellular doxorubicin accumulation, and DNA topoisomerase‐II‐mediated DNA cleavage. The tumor lines growing in nude mice with simillar growth characteristics (doubling time around 10 days) were selected since one (POCI tumor) was found to be hypersensitive and the other (POSG tumor) resistant to doxorubicin treatment. The pattern of anti‐tumor, drug response of the doxorubicin‐resistant tumor was atypical (i. e., non‐adherent to the well‐characterized multi‐drug‐resistant phenotype), since it responded to vincristine. The markedly different in vivo tumor response reflected the intrinsic cellular sensitivity to doxorubicin. No correlation was found between cellular drug accumulation and doxorubicin sensitivity following in vitro exposure to the drug. In agreement with this observation, the expression of mdr‐I gene was undetectable in these tumors. Thus, in the POSG tumor, resistance to doxorubicin occurred without expression of the P‐glycoprotein and reduction of cellular drug accumulation. In contrast, the extent of DNA cleavage produced by doxorubicin was markedly higher in the doxorubicin‐hypersensitive than in the doxorubicin‐resistant tumor. These results, taken together with previous observations in SCLC cell lines, support the important role of DNA topoisomerase‐mediated effects in the sensitivity of SCLC to doxorubicin.