Expression of mdr1 was detected in both HxRh12 and HxRh28 tumors, sensitive to VCR, but there was no increase in expression in tumors selected for primary resistance to VCR or L-PAM.
The analysis of MDR1 RNA expression by in situ hybridization which is validated by this study should be useful in the study of normal human tissue and tumor samples expressing the MDR1 gene.
Human breast carcinoma cell levels of MDR-1 (P-glycoprotein) transcripts correlate in vivo inversely and reciprocally with tumor progesterone receptor content.
Only one of 15 (6%) tumors from patients who had not received chemotherapy exhibited high levels of MDR1 transcripts, while 11 of 26 (42%) treated tumors showed high levels of MDR1 expression (Fisher exact test: P = .03).
In situ hybridizations with RNA probes have demonstrated higher levels of expression of mdr-1/Pgp in well-differentiated tumors and in well-differentiated areas in tumors with mixed histologies.
We have characterized the normal human tissue distribution and tumor expression of the human multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) by immunohistochemical staining of frozen tissue sections of human normal and tumor tissues, using three mouse monoclonal antibodies (MAb) which recognize at least two different epitopes of Pgp.
Although drug resistance is a major problem in treatment of ovarian cancer, resistance to the drugs most active against these tumors probably occurs through a mechanism other than expression of the MDR1 gene product.
MDR1 gene expression was found to be increased in 5 out of 29 tumor samples at onset (17%) and in 1 out of 3 at relapse, but none of them expressed both MDR1 and N-myc genes simultaneously.
The frequency of samples without detectable MDR1 expression varied among different types of tumors; MDR1-negative samples were most common among tumor types known to be relatively responsive to chemotherapy.
The results of our study show that the MDR1 gene is expressed in human glial tumors and suggest that the multidrug transporter may contribute to the clinical non-responsiveness of these tumors to chemotherapy.
Characterization of the radiation-pretreated subline showed that overexpression of P-glycoprotein, as determined by immunofluorescence and Mabs C219 and 265/F4, occurred in this tumor.
The human colon cancer cell line HT-29, which grows as an ascitic tumor in athymic NCr-nu/nu nude mice, was made multidrug resistant by infection with an MDR1 (also known as PGY1) retrovirus.
Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor.
Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.
MDR1 and GST-pi expression, which is known to be a marker for adriamycin resistance, was detected in six (66.7%) and seven (77.8%) of the nine clinically resistant tumors, respectively.
Tumours with bimodal DNA distribution showed median values of P-glycoprotein expression of their hyperdiploid cell clones significantly higher than those of their diploid clones and of the tumours with unimodal DNA distribution (P less than 0.005).
For comparison, we used MCF-7ADR human breast cancer cells, which overexpress MDR1 and have also lost the requirement for 17 beta-estradiol supplementation to form tumors in nude mice.