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Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas
T A Holzmayer1, S Hilsenbeck, D D Von Hoff
1Department of Genetics, University of Illinois, Chicago 60612.
Background:
Expression of the MDR1 (P-glycoprotein) gene causes resistance to several classes of lipophilic anti-cancer drugs, but MDR1 expression in untreated ovarian and lung carcinomas is rarely detectable by standard assays.
Purpose:
This study was designed to measure the MDR1 messenger RNA (mRNA) content of ovarian and lung carcinomas and to analyze clinical correlations of MDR1 expression in these tumors.
Methods:
A sensitive assay based on the polymerase chain reaction (PCR) was used in a retrospective study to measure MDR1 mRNA in biopsy samples of 100 solid tumors, including 60 ovarian and 32 lung carcinomas. The levels of MDR1 mRNA were correlated with history of chemotherapeutic treatment for all tumors; for ovarian and small-cell lung carcinomas (SCLCs), these levels were also correlated with subsequent tumor response to chemotherapy.
Results:
Among previously untreated patients, MDR1 mRNA was expressed in 68% (50 of 74) of all tumors. Among patients pretreated with chemotherapy regimens that included at least one P-glycoprotein-transported drug (MDR regimens), 95% (20 of 21) of all tumors expressed MDR1 mRNA though the incidence of high-level MDR1 expression was decreased among the treated tumors. MDR1 mRNA was expressed in only one of five tumors treated with regimens that included no P-glycoprotein substrates (non-MDR regimens). Subsequent tumor response to chemotherapy was evaluated in 35 patients with ovarian carcinoma and seven patients with SCLC. The presence of even very low levels of MDR1 mRNA correlated with the lack of response to MDR regimens in these tumor types (P < .035 for ovarian carcinomas, P < .029 for SCLCs, and P < .0005 for both tumor types; Fisher's Exact Test).
Conclusions:
Low-level expression of MDR1 mRNA correlates with clinical resistance to combination chemotherapy in ovarian cancer and SCLC. We hypothesize that MDR1 is expressed in a subpopulation of more malignant tumor cells possessing multiple mechanisms of drug resistance.
Implications:
The presence of MDR1-expressing tumor cells may be useful as a predictive marker for clinical resistance to combination chemotherapy in ovarian cancer and SCLC. Prospective studies are needed to confirm this hypothesis.
Insights
Low-level expression of MDR1 mRNA correlates with chemotherapy resistance in ovarian and lung cancers. This finding suggests MDR1 may serve as a predictive marker for treatment outcomes in these malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The MDR1 (P-glycoprotein) gene confers resistance to lipophilic anti-cancer drugs.
- MDR1 expression is typically undetectable in untreated ovarian and lung carcinomas using standard assays.
Purpose of the Study:
- To quantify MDR1 messenger RNA (mRNA) levels in ovarian and lung carcinomas.
- To investigate the clinical correlation between MDR1 expression and tumor characteristics.
Main Methods:
- A sensitive polymerase chain reaction (PCR) assay was employed to measure MDR1 mRNA in 100 solid tumor biopsy samples, including 60 ovarian and 32 lung carcinomas.
- MDR1 mRNA levels were correlated with prior chemotherapeutic treatment history.
- For ovarian and small-cell lung carcinomas (SCLCs), MDR1 mRNA levels were correlated with subsequent chemotherapy response.
Main Results:
- MDR1 mRNA was detected in 68% of untreated tumors.
- In patients pretreated with MDR regimens, 95% of tumors expressed MDR1 mRNA.
- Low-level MDR1 mRNA expression significantly correlated with a lack of response to chemotherapy in ovarian carcinomas (P < .035) and SCLCs (P < .029).
Conclusions:
- Low-level MDR1 mRNA expression is linked to clinical resistance to combination chemotherapy in ovarian cancer and SCLC.
- MDR1 expression may indicate a subpopulation of highly malignant cells with multiple drug resistance mechanisms.
- MDR1-expressing tumor cells could serve as a predictive marker for chemotherapy resistance, warranting prospective validation.