Holzmayer T A, Hilsenbeck S, Von Hoff D D, Roninson I B
Department of Genetics, University of Illinois, Chicago 60612.
J Natl Cancer Inst. 1992 Oct 7;84(19):1486-91. doi: 10.1093/jnci/84.19.1486.
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.
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.
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.
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).
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.
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.
多药耐药基因1（MDR1，P-糖蛋白）的表达会导致对几类亲脂性抗癌药物产生耐药性，但在未经治疗的卵巢癌和肺癌中，通过标准检测方法很少能检测到MDR1的表达。
本研究旨在测定卵巢癌和肺癌中MDR1信使核糖核酸（mRNA）的含量，并分析这些肿瘤中MDR1表达的临床相关性。
在一项回顾性研究中，采用基于聚合酶链反应（PCR）的灵敏检测方法，测定100例实体瘤活检样本中的MDR1 mRNA，其中包括60例卵巢癌和32例肺癌。所有肿瘤的MDR1 mRNA水平与化疗治疗史相关；对于卵巢癌和小细胞肺癌（SCLC），这些水平还与后续肿瘤对化疗的反应相关。
在未经治疗的患者中，68%（74例中的50例）的所有肿瘤均表达MDR1 mRNA。在接受过至少一种P-糖蛋白转运药物的化疗方案（MDR方案）治疗的患者中，95%（21例中的20例）的所有肿瘤均表达MDR1 mRNA，尽管在接受治疗的肿瘤中高水平MDR1表达的发生率有所降低。在接受不包括P-糖蛋白底物的方案（非MDR方案）治疗的5例肿瘤中，只有1例表达MDR1 mRNA。对35例卵巢癌患者和7例SCLC患者的后续肿瘤对化疗的反应进行了评估。即使是极低水平的MDR1 mRNA的存在也与这些肿瘤类型对MDR方案缺乏反应相关（卵巢癌P < 0.035，SCLC P < 0.029，两种肿瘤类型P < 0.0005；Fisher精确检验）。
MDR1 mRNA的低水平表达与卵巢癌和SCLC对联合化疗的临床耐药性相关。我们推测MDR1在具有多种耐药机制的更恶性肿瘤细胞亚群中表达。
表达MDR1的肿瘤细胞的存在可能作为卵巢癌和SCLC对联合化疗临床耐药性的预测标志物。需要进行前瞻性研究来证实这一假设。
