Expression of the multidrug resistance-associated protein (MRP) gene in human lung tumours and normal tissue as determined by in situ hybridisation

Thomas, G.A.; Barrand, Margery A.; Stewart, Susan; Rabbits, P.H.; Williams, E. D.; Twentyman, Peter R.

doi:10.1016/0959-8049(94)00290-l

Cited by 50 publications

(30 citation statements)

References 9 publications

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“…In tumour cells, MRP exhibited a membraneous stain. In non-malignant cells, MRP was often seen in superficial bronchial epithelium, however, in contrast to P-gp, MRP was also commonly observed in macrophages and scattered lymphocytes (Figure 4), in agreement with a study using mRNA in situ hybridization (Thomas et al, 1994). In SCLC, after treatment, an increase in the proportion of positive cells was observed in four (Cole et al, 1992;Borst et al, 1993), or changes in their drug target topo-IIa, namely at-MDR (Pommier et al, 1986;Danks et al, 1988).…”

Section: Mrpsupporting

confidence: 91%

“…However, when analysing their frequency in subtypes of NSCLC, it is interesting that both our (Table II) and a previous study (Ota et al, 1995) detected an increased level of MRP in SCC relative to other histological subtypes. This was, however, not the case when an mRNA assay was used (Sugarawa et al, 1995), a result which could be due to admixture of MRP mRNA from macrophages and lymphocytes (Thomas et al, 1994;Figure 4). The highly significant difference in topo-Ila content between untreated SCLC and NSCLC (Tables 1 and 2) is therefore remarkable.…”

Section: Mrpmentioning

confidence: 96%

“…In this respect, a mRNA and/or catalytic assay for topo-Ila should be more dependable as this protein is, for practical purposes, only found in tumour tissue. Both P-gp and MRP have been detected in SCLC and NSCLC, although their clinical importance is still undecided (Volm et al, 1991;Holzmayer et al, 1992;Segawa et al, 1993;Tabata et al, 1993;Abe et al, 1994;Oberli-Schrammli et al, 1994;Peoch et al, 1994;Thomas et al, 1994;Ota et al, 1995;Sugarawa et al, 1995;Beer et al, 1996;Chuman et al, 1996;Giaccone et al, 1996;Narasaki et al, 1996;Nooter et al, 1996;Stammler et al, 1996). In the present study, their incidence was equal in untreated SCLC and NSCLC (Tables 1 and 2), indicating that these drug efflux pumps are not themselves responsible for the very different sensitivities to etoposide in these two diseases.…”

Section: Mrpmentioning

confidence: 99%

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

Kreisholt

Sørensen²,

Pb³

et al. 1998

Br J Cancer

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Summary Non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) differ significantly in their clinical response to topoisomerase lla (topo-lla)-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-lla drugs depends on topo-lIa content and/or activity, the altered-topo-l1 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-lla-directed drugs were available in ten cases) yielded the following results: NSCLC had significantly less topo-lla 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-lla-directed drugs, there was an increase in MRP (P < 0.1) and P-gp (P < 0.05) positivity, while topo-lla decreased (P < 0.05). In conclusion, the major difference between untreated NSCLC and SCLC was in topo-lla content. In the small series of ten patients treated for SCLC, all three MDR phenotypes appeared to increase.

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Section: Mrpsupporting

confidence: 91%

Section: Mrpmentioning

confidence: 96%

Section: Mrpmentioning

confidence: 99%

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

Kreisholt

Sørensen²,

Pb³

et al. 1998

Br J Cancer

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“…Among the known multidrug transporter proteins, P-gp (Gottesman and Pastan, 1993) has been reported to be of minor importance (Doyle, 1993), whereas MRP (Cole et al, 1992) has been considered to play a decisive role in NSCLC chemoresistance. This assumption is based on the fact that several drug-selected lung cancer cell lines display MRP overexpression (review: Loe et al, 1996) and that clinical NSCLC specimens as well as derived cell lines frequently exhibit MRP gene expression (Chuman et al, 1996;Narasaki et al, 1996;Nooter et al, 1996;Ota et al, 1995;Sugawara et al, 1995;Thomas et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells

Berger¹,

Elbling²,

Hauptmann³

et al. 1997

Int. J. Cancer

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“…Expression of MRP has been demonstrated in a variety of solid tumours (Bordow et al, 1994;Thomas et al, 1994;Nooter et al, 1995, 1996a andb;Ota et al, 1995;Endo et al, 1996;Filipits et al, 1996;Kavallaris et al, 1996) and leukaemias (Burger et al, 1994a and b;Schneider et al, 1995). In a previous study (Nooter et al, 1995), we determined the expression ofMRP in normal tissues and in about 370 human tumour biopsies using a quantitative RNAase protection assay and immunohistochemistry (IHC).…”

mentioning

confidence: 99%

The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer

Nooter

Rivière²,

Look³

et al. 1997

Br J Cancer

125

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Summary In the present study, we determined the frequency and intensity of MRP protein expression by monoclonal antibody immunohistochemistry in a series of 259 resected invasive primary breast carcinomas, and we evaluated MRP immunoreactivity in relation to patient and tumour characteristics, relapse-free (RFS) and overall survival (OS). The immunostaining was graded on a semiquantitative scale that ranged from (-) to (+++). Overall, 34% of the tumours were positive for anti-MRP antibody: 19% showed weak cytoplasmic staining (+), 14% had clear cytoplasmic staining (++) and only 1 % of the tumours had a strong cytoplasmic as well as membranous staining (+++). MRP expression was not related to patient's age, menopausal status, tumour size, differentiation grade, oestrogen and progesterone receptor level or lymph node involvement. In an exploratory univariate analysis of all patients, only primary tumour size and number of lymph nodes involved were significantly associated with shortened RFS (P < 0.001 and P < 0.001 respectively) and OS (P = 0.02 and P < 0.001 respectively). In Cox univariate analysis for RFS in subgroups of patients stratified by menopausal status, tumour size, nodal status, adjuvant systemic therapy and oestrogen and progesterone receptor status, MRP expression was associated with increased risk for failure in patients with small tumours (Ti), in node-negative patients and in node-positive patients who received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF); the relative hazard rate (RHR) for relapse was increased in the presence of MRP, with RHR values with 95% confidence limits (CL) of 2.8 (1.2-6.9), 2.1 (1.0-4.2) and 2.8 (0.8-9.9) respectively. In analysis for OS, expression of MRP was also associated with increased risk for failure in patients with small tumours (T1) [RHR (95% CL) 2.3 (0.9-6.0)] and in node-positive patients who received adjuvant systemic chemotherapy with CMF [RHR (95% CL) 3.7 (0.8-17.1)] but not in node-negative patients [RHR (95% CL) 1.1 (0.4-2.6)]. In conclusion, our results show that MRP is frequently overexpressed in primary breast cancer and suggest that MRP expression might be of prognostic significance in the subgroups of patients with the more favourable prognosis, i.e. patients with small tumours and nodenegative patients, as well as in the setting of adjuvant systemic chemotherapy. In primary breast cancer, MRP might be related to altered cell biological behaviour, including a more aggressive phenotype, and resistance to adjuvant systemic chemotherapy.

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Expression of the multidrug resistance-associated protein (MRP) gene in human lung tumours and normal tissue as determined by in situ hybridisation

Cited by 50 publications

References 9 publications

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

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

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells

The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer

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