Immunohistochemical detection of DNA topoisomerase IIα, P-glycoprotein and multidrug resistance protein (MRP) in small-cell and non small-cell lung cancer

Non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) differ significantly in their clinical response to topoisomerase II alpha (topo-II alpha)-directed drugs, such as etoposide and teniposide, as NSCLC is virtually insensitive to single-agent therapy, while SCLC responds in two-thirds of cases. Preclinical studies have indicated that resistance to topo-II alpha drugs depends on topo-II alpha content and/or activity, the altered-topo-II multidrug resistance phenotype (at-MDR) and/or one of two different drug efflux pumps, P-glycoprotein (P-gp) and the multidrug resistance protein (MRP). Immunohistochemical analysis on paraffin-embedded tissue from 27 cases of untreated NSCLC and 29 cases of untreated SCLC (of which additional tumour biopsies after treatment with topo-II alpha-directed drugs were available in ten cases) yielded the following results: NSCLC had significantly less topo-II alpha than SCLC (P<0.0001), as only 5 out of 27 NSCLC cases had >5% positive cells compared with 28 out of 29 SCLC, and 0 out of 27 NSCLC had >25% positive cells compared with 26 out of 29 SCLC. P-gp was detected in >5% of cells in only 3 out of 27 NSCLC and in 6 out of 29 SCLC, and MRP in 5 out of 27 of NSCLC and 9 out of 29 SCLC. After treatment of patients with SCLC with either etoposide or teniposide, which are topo-II alpha-directed drugs, there was an increase in MRP (P<0.1) and P-gp (P<0.05) positivity, while topo-II alpha decreased (P<0.05). In conclusion, the major difference between untreated NSCLC and SCLC was in topo-II alpha content. In the small series of ten patients treated for SCLC, all three MDR phenotypes appeared to increase.