KF22678, a novel thioester derivative of
leinamycin with the 1-oxo-1,2-dithiolane-3-one moiety, was examined for anti-
tumor activity, toxicity in mice and activation mechanism.
KF22678 showed a broad antitumor spectrum against human
carcinoma xenografts (lung, colon, ovary and prostate). The efficacy of
KF22678 was significantly higher than that of
cisplatin.
KF22678 exhibited low cross-resistance against various
drug-resistant cell lines of MDR1 or MRP overexpressing human
tumors, and, in addition, exhibited more potent antitumor activity in vivo than ADM against A2780/ADM and KB/MRP xenograft. DL-
Buthionine sulfoximine (BSO) pretreatment significantly reduced intracellular
glutathione (GSH) level in human lung
carcinoma A549 cells, leading to decrease in the cytotoxicity of
KF22678, whereas the cytotoxicity of
melphalan was augmented by BSO pretreatment.
DNA single-strand breaks (SSB) were observed in A549 cells treated with
KF22678 and
bleomycin.
DNA SSB induced by
KF22678 was greatly reduced in the presence of BSO in the cells, whereas
DNA SSB induced by
bleomycin was not. In addition, the antitumor activity of
KF22678 against BSO-pretreated human lung
carcinoma PC-9
tumor was significantly decreased. These results suggest that the activation of
KF22678 by intracellular GSH might be important for
DNA SSB and antitumor activity in vitro and in vivo.