Because most small-cell lung cancers (SCLC) are initially chemosensitive and express neuroendocrine (NE) cell markers and most non-SCLC tumors (NSCLC) are chemoresistant and do not express NE cell markers, we investigated the association between morphological type and NE cell differentiation with in vitro chemosensitivity. We tested a panel of 55 lung cancer cell lines established from previously untreated patients. These were tested against five cytotoxic drugs commonly used in the therapy of lung cancer, using the MTT assay. For comparative purposes, we also tested cell lines established from previously treated patients with SCLC and from colorectal tumors. The logarithms of the IC50 values of all of the cell lines were normally distributed, permitting the use of Student's t-test for assessment of differences. In general, the in vitro sensitivities of SCLC, NSCLC, and colorectal cell lines mirrored the clinical experience with these tumor types. Cell lines started from previously treated patients with SCLC were more resistant than those from previously untreated patients who responded to initial therapy. For all of the cell lines, the sensitivities to the five drugs tested were highly significantly correlated with each other. Thus, for comparative purposes, each group could be assigned an average standardized mean rank. About 15% of NSCLC tumors express multiple neuroendocrine (NE) cell markers and 4 of 5 lines from these NSCLC-NE tumors were relatively chemosensitive, similar to SCLC lines and significantly different from other NSCLC lines. Other NE cell lines tested included bronchial carcinoids and cell lines from small-cell carcinomas arising in extra-pulmonary locations (ExPuSC).(ABSTRACT TRUNCATED AT 250 WORDS)