Effect of vesnarinone in combination with anti-cancer drugs on lung cancercell lines

Vesnarinone, a quinolinone derivative which is used as an oral inotropic ag ent in the clinic, has recently also been shown to have anti-cancer activit y. We have studied the anticancer effect of vesnarinone in combination with cisplatin, VP-16 (etoposide) and gemcitabine, against human lung cancer ce ll lines (PC-9 and Lu 134A) using the MTT assay and isobologram analysis. S imultaneously, by establishing two cisplatin-resistant sublines, i.e. PC-S/ CDDP and Lu 134A/CDDP, we analyzed the cross-resistance between vesnarinone and cisplatin and the resistance-reversing effect of vesnarinone. Nuclear fragmentation, as the presumed mechanism of tumor cell growth inhibition, w as further studied quantitatively using flow cytometric analysis. Combinati on of vesnarinone with the studied anti-cancer drugs had a synergic or addi tive inhibitory effect on both PC-9 and Lu 134A tumor cell growth. Neither decrease of the sensitivity to vesnarinone nor cross-resistance between ves narinone and anti-cancer drugs was observed. On the contrary, vesnarinone s howed a resistance-reversing effect. Both vesnarinone and the studied anti- cancer drugs could induce tumor cell apoptosis, but a definite correlation between nuclear fragmentation and the growth inhibitory effect was not esta blished. [(C) 1999 Lippincott Williams & Wilkins.]