Prediction of Doxorubicin Resistance In Vitro in Myeloma, Lymphoma, and Breast Cancer by P-Glycoprotein Staining

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Abstract
Prior studies have shown that the p-glycoprotein is ac cell membrane efflux pump that is quantitavely increased in expression in multidrug-resistant tumor cell lines. In this study, fresh tumor tissues from patients with multiple myeloma, malignant lymphoma, or metastatic breast cancer were studied immunohistochemically for P-glycoprotein expression and for in vitro sensitivity to doxourbicin. Twenty-six patients who were either previously untreated or in relapse after chemotherapy had tumor specimens submitted that could be evaluated in both assays. The testing was done independently and blindly in separate laboratories instead of our being provided relevant clinical data on the patients. Tumor cells from 12 of the 26 patients (46%) stained positively for P-glycoprotein. Fifteen of the 26 specimens (58%) exhibited drug resistance in vitro. Although only three (21%) of the 14 p-glycoprotein-negative tumors exhibited in vitro resistance to doxourbicin, all 12 fresh tumors that stained positively for P-glycoprotein were resistant to doxourbicin. The difference in frequency of intrinsic doxourbicin resistance between P-glycoprotein-negative and-positive tumors was highly significant (P<.001).Similar trends were observed in each of the individual tumor categories and were statistically significant in myeloma and breast cancer. Four of he biopsy specimens that stained positively for P-glycoprotein and exhibited doxorubicin resistance were from patients who had not received prior cytotoxic chemotherapy. Similar conclusions were reached when results of drug sensitivity tests were ranked in relation to the median infective dose rather than by criteria based on correlations with clinical drug resistance. Our findings indicate that positive staining for P-glucoprotein associated with multidrug resistance predicts intrinsic cellular resistance of human cancers to doxourbicin. We anticipate that immunohistochemical staining for P-glucoprotein will prove useful in clinical oncology. [J Natl Cancer Inst 81:696–701, 1989]