NEW ANTITUMOR SUBSTANCES, FR901463, FR901464 AND FR901465 .2. ACTIVITIES AGAINST EXPERIMENTAL-TUMORS IN MICE AND MECHANISM OF ACTION

FR901463, FR901464 and FR901465, novel antitumor substances, were isol ated from the fermentation broth of Pseudomonas sp. No. 2663. Their an titumor 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 inhi bited the growth of a human solid tumor, A549 lung adenocarcinoma, wit h different effective dose ranges. FR901464 exhibited most prominent e ffects on these tumor systems among the three FR compounds. FR901464 a lso inhibited the growth of murine solid tumors, Colon 38 carcinoma an d Meth A fibrosarcoma. To address the involvement of transcriptional a ctivation ability of the three FR compounds in the antitumor effect, w e selected FR901464 as a candidate compound and investigated cell cycl e transition, chromatin status and endogenous gene expression in FR901 464-treated tumor cells having elevated transcriptional activity. FR90 1464 induced characteristic G(1) and G(2)/M phase arrest in the cell c ycle and internucleosomal degradation of genomic DNA with the same kin etics 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 endo genous genes but not house keeping genes in M-8 cells. These results s uggest that FR901464 may induce a dynamic change of chromatin structur e, giving rise to strong antitumor activity, and therefore may represe nt a new type of drug for cancer chemotherapy.