The neurotoxin 1-methyl-4-phenylpyridinium: A selective cytostatic agent in small-cell lung cancer cell lines with neuroendocrine properties

Background: Small cell lung cancer (SCLC) is a common maliganancy that is usually fatal, since it metastasizes and recurs even after aggressive chemotherapy. While the cellular origin of this cancer is not well established, the cells of certain tumors exhibit neuroendocrine markers, including L dopa decarboxylase. Purpose: We designed in vitro and in vivo studies to investigate whether the neuroendocrine features in classic SSLC cell lines were sufficinet to make them sensitive to 1-methyl1-4-phenylpridiunium (MPP+), a known neurotioxin that destroys nigrostraioatal dopaminergic neurons. Methods: Both classic SCLS cell line (NCI-H345, NCI-H510, NCI-H187, and NCI-H146, NCI-H482, NCI-H445, and NCI-H524) were exposed to MPP+ (0-512 μM) fro 3 days. Inhabition of (³H)thymidine incopertation assays. In a related experinent MPP+ was removed fromthe classic cell line culture, and the incopertation of (³H)thymidine was determined. In the in vivo astudy, male athymic nude mice received substanneaous injections of 0.5 mL tumor cells with martigel for 10 days to enchance tumor growth, followed by MPP+ at doses of 100-400 μg/d given intraperitoneally for 2 days. Results: All four classic SCLC cell lines showed great sensitivity to MPP+ with detachment from Iaminin substrates and inhabition of DNA synthesis. MPP+ interfered with (³H)thymidine incorportation and thus, with DNA synthesis in classic SCLC cell lines at low doses (median ± SD, 12 ± 4 μ.M), whereas much higher doses (median, >512 μM) were required to inhibit [3H]thymidine incorporation in the variant lines. Treated cells excluded trypan blue dye, showing that inhibition of DNA synthesis was not due to cytotoxicity, and the cells incorporated [3H]thymidine when MPP+ was removed from the culture medium, demonstrating that the inhibition was reversible. MPP+ inhibited the growth of the classic NCI-H187 and variant NCI-H417 cell lines implanted in nude mice. Conclusions: These results suggest that MPP+ differentially interferes with DNA synthesis in SCLC cell lines in vitro; the selective inhibitory effect on classic cell lines suggests that the neuroen docrine properties expressed by classic SCLC cells may be responsible for the differential effect. Implications: MPP+ exerts a cytostatic effect on these cell lines, and the differential sensitivity observed in vitro is maintained in vivo, suggesting that MPP⁺ or other pyridinium compounds may be of therapeutic value in SCLC. [J Natl Cancer Inst 84: 1582-1587, 1992]