Immunohistochemical detection of DNA topoisomerase IIalpha, 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 IIalpha (topo-IIalpha)-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-IIalpha drugs depends on topo-IIalpha 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-IIalpha-directed drugs were available in ten cases) yielded the following results: NSCLC had significantly less topo-IIalpha 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-IIalpha-directed drugs, there was an increase in MRP (P < 0.1) and P-gp (P < 0.05) positivity, while topo-IIalpha decreased (P < 0.05). In conclusion, the major difference between untreated NSCLC and SCLC was in topo-IIalpha content. In the small series of ten patients treated for SCLC, all three MDR phenotypes appeared to increase.
Kreisholt
J
J
Department of Pathology, Laboratory Center, Rigshospitalet, Copenhagen, Denmark.
Sorensen
M
M
Jensen
P B
PB
Nielsen
B S
BS
Andersen
C B
CB
Sehested
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis* / Q000378:metabolism; D000951:Antigens, Neoplasm; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D004250:DNA Topoisomerases, Type II / Q000032:analysis* / Q000378:metabolism; D004268:DNA-Binding Proteins; D018432:Drug Resistance, Multiple / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D019450:Genes, MDR / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D004250:DNA Topoisomerases, Type II