Chemotherapy plus surgery is feasible and potentially effective in selected patients with small cell lung cancer (SCLC) and provides a unique opportunity to study SCLC early in its biological history. The in vitro characteristics of a SCLC cell line derived from a resected lung primary tumor after treatment with 3 courses of chemotherapy is described. The original SCLC cell line UMC-SCLC-1 exhibited features of classic SCLC with typical morphology and growth characteristics, high levels of dopa decarboxylase, bombesin-like peptides, neuron-specific enolase and calcitonin, and the presence of neurosecretory granules and demonstrated the deletion of the short arm of chromosome 3. After multiple passages, UMC-SCLC-1 gradually changed its culture characteristics to a cell line, UMC-SCLC-1A, with morphological features of large cell anaplastic carcinoma, an altered growth pattern, decrease in calcitonin, and increase in radioresistance but retained the other biochemical markers of classic SCLC (bombesin and dopa decarboxylase production). Serial DNA content analyses showed that increased aneuploidy during continuous culture in vitro was associated with the morphological changes. Both UMC-SCLC-1 and UMC-SCLC-1A demonstrated the deletion of chromosome 3p, amplification and abundant expression of N-myc, and increased expression of c-raf. Chemotherapy sensitivities were stable throughout multiple passages and correlated with in vivo response. UMC-SCLC-1A represents a unique SCLC cell line with heterogeneous properties of both classic and morphological variant SCLC cell lines. In addition, the characteristic deletion of 3p, previously described in cultures derived from metastatic lesions and heavily pretreated patients, is seen in a primary lesion early in the natural history of SCLC.