FR901463,
FR901464 and
FR901465, novel antitumor substances, were isolated from the fermentation broth of Pseudomonas sp. No. 2663. Their antitumor activities were examined in three mouse
tumor systems and one human
tumor system. The three FR compounds prolonged the life of mice bearing murine ascitic
tumor P388 leukemia (T/C values were 160%, 145% and 127% for
FR901463,
FR901464 and
FR901465, respectively), and inhibited the growth of a human solid
tumor, A549
lung adenocarcinoma, with different effective dose ranges.
FR901464 exhibited most prominent effects on these
tumor systems among the three FR compounds.
FR901464 also inhibited the growth of murine solid
tumors, Colon 38
carcinoma and Meth A
fibrosarcoma. To address the involvement of transcriptional activation ability of the three FR compounds in the antitumor effect, we selected
FR901464 as a candidate compound and investigated cell cycle transition,
chromatin status and endogenous gene expression in FR901464-treated
tumor cells having elevated transcriptional activity.
FR901464 induced characteristic G1 and G2/M phase arrest in the cell cycle and internucleosomal degradation of genomic
DNA with the same kinetics as activation of SV40 promoter-dependent cellular transcription in
M-8 tumor cells. In contrast to the potent activation of the viral promoter,
FR901464 suppressed the transcription of some inducible endogenous genes but not house keeping genes in
M-8 cells. These results suggest that
FR901464 may induce a dynamic change of
chromatin structure, giving rise to strong antitumor activity, and therefore may represent a new type of
drug for
cancer chemotherapy.