Response of small-cell lung cancer xenografts to chemotherapy: multidrug resistance and direct clinical correlates.

Abstract

Patients with small-cell lung carcinomas (SCLCs) initially respond to combination chemotherapy. Only a few benefit in terms of long-term survival because most relapse. Such outcome may be attributable to development of multidrug resistance. The response of SCLC to chemotherapy was examined in terms of (a) patient survival, (b) drug sensitivity of tumors in patients and of tumor xenografts in nude mice, and (c) expression of multidrug resistance gene MDR1 and GST-pi gene. Tumor samples obtained from seven untreated patients and from one patient both before and after chemotherapy were transplanted into nude mice. The patients were treated with a combination of cyclophosphamide (C'), cisplatin (C), doxorubicin (A), and etoposide (V) (C'CAV) or C'AV and radiotherapy. Drug sensitivity of SCLCs was tested in nude mice that had received tumor xenografts from these seven patients. The expression of MDR1 and GST-pi genes was assessed in the mRNA extracted from xenografts by Northern blot analysis. P-glycoprotein was quantified by enzyme immunoassay. The patients' responses to C'CAV closely correlated with those of the corresponding xenografts. The tumors of the two patients who showed long-term survival after C'CAV completely regressed when they were transplanted into nude mice and subsequently treated with C'CAV. Despite initial complete response, the remaining five patients died during year 1. A high percentage of mice receiving the tumor grafts from these five patients showed only partial tumor regression after C'CAV treatment. The MDR1 transcript was detected in all five of these xenografts. Four of five xenografts were from untreated patients, and the fifth was from a treated patient. MDR1 mRNA expression was absent in the tumor of this fifth patient before chemotherapy, but both the mice receiving the corresponding xenograft and the patient showed expression of MDR1 after C'CAV treatment. MDR1 mRNA expression was absent in the tumor xenografts obtained from two patients with long-term survival. Expression of P-glycoprotein correlated with MDR1 mRNA expression. All xenografts except one expressed the GST-pi gene. The absence of MDR1 gene expression during chemotherapy for SCLC indicates a favorable prognosis, gene expression is often coincident with ineffective chemotherapy, and tumor xenografts can be appropriately used to predict response to chemotherapy. Failure of chemotherapy to control SCLC seems to be related to an acquired multidrug resistance involving the MDR1-mediated mechanism. Therapeutic benefit could therefore be expected from chemotherapy combined with inhibitors of MDR1.