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Abstract
Expression of the MRP gene has been demonstrated in vitro to be a casual factor in non-P-glycoprotein-mediated multidrug resistance, and is implicated in resistance to a number of the chemotherapeutic agents currently used in the treatment of high-grade transitional cell carcinoma (TCC) of the bladder (doxorubicin, epirubicin and vinblastine). Using a sensitive RT-PCR-based technique, we have quantified MRP mRNA levels in a series of untreated TCC (n=24), normal bladder (n=5) and control tissue and cell line samples. MRP mRNA was widely expressed and detectable in all samples analysed, with considerable (up to 190-fold) variation observed between individual tumour samples. MRP mRNA levels found in TCC samples were lower than those determined for normal peripheral mononucleocyte (2.3-fold) and testis (4.1-fold) samples, previously reported to be high-expressing tissues, and varied over a similar range to that observed in normal bladder samples. Results indicate that MRP mRNA levels in a greater proportion of high-grade (G3) bladder tumours (55%, 6/11) are significantly reduced (P=0.018) compared with low- and moderate-grade (G1/2) bladder tumours (8%, 1/13), and suggest that MRP mRNA levels frequently become reduced as a consequence of tumour progression to advanced, poorly differentiated disease. No correlation was apparent between MRP and MDR1 mRNA levels, thus providing no evidence to suggest common regulation of the two genes. In a limited number of patients, no evidence was found to support a role for MRP mRNA levels as a determinant of response to chemotherapy in patients being uniformly treated with either cisplatin-methotrexate-vinblastine (n=6) or epirubicin-cisplatin-methotrexate (n=4) regimens. Similarly, no overall pattern of altered MRP mRNA expression was observed following chemotherapy in four patients from whom post chemotherapy biopsies were taken. This study provides a useful pilot investigation regarding the level, variation and pattern of MRP mRNA expression in TCC of the bladder, and suggests that further studies to establish the clinical significance of these variations are required.
Highlights
The pooled mean multidrug resistance-associated protein (MRP) mRNA level determined for normal bladder samples was 2.97 (±2.06) x 10, with the levels observed in individual samples varying over a comparable range (31-fold; high, 4.9 x 10-5; low, 1.6 x 10-6; coefficient of variation, 70%) to that observed for bladder tumours
We have demonstrated that MRP mRNA is widely expressed in both transitional cell carcinoma and normal bladder tissue, with quantifiable gene transcripts detectable in all samples analysed, and a considerable level of variation (190-fold) observed between individual untreated bladder tumours
Our results show that the proportion of tumours with low MRP mRNA levels (MRP/18S ratio < 1 x 10-5) iS significantly greater in the high-grade compared with the low- and moderate-grade group (55% vs 8%)
Summary
Tissues and cell linesTCC tumour samples were obtained at presentation by local resection or cystectomy from the primary tumour site. A portion of the sample was sent for histological evaluation of tumour differentiation, and the extent of tumour invasion was assessed according to UICC (1978) criteria by histopathological examination, computerised tomography (CT) scan and bimanual palpation. Care was taken to limit the proportion of tumour sample contaminated by normal tissue. The papillary growth pattern of superficial tumours allowed their routine resection without contamination by underlying normal tissue. Despite their involvement with the underlying lamina propria and muscle, contamination of muscleinvasive tumours with normal tissue was minimised by only selecting material from the protruding tumour mass. It was more difficult to ensure complete elimination of normal tissue from these samples, histological examination indicated an upper limit of 10 -15% contamination by normal tissue. None of the patients described had received prior treatment by chemotherapy
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