Six GEX1 compounds, GEX1A/herboxidiene and its related 5 novel compounds, were isolated from a culture broth of Streptomyces sp. GEX1 compounds induced both G1 and G2/M arrest in a human normal fibroblast cell line, WI-38. All six compounds up-regulated luciferase reporter gene expression directed by enhancer/promoter of various genes, such as cdc2, IL-2 and SV40 early genes. All GEX1 compounds showed cytotoxic activities in the same order of the up-regulating activities on gene expression, suggesting that these two activities are related. Despite the up-regulating activities on the reporter gene expression, GEX1A/herboxidiene did not enhance the expression of any endogenous genes involved in the cell cycle, proliferation and apoptosis. Although the unique effects of GEX1 compounds on cell cycle and the reporter gene expression were similar to those of trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), GEX1A/herboxidiene did not affect histone acetylation in cells. In addition, GEX1A/herboxidiene treatment gave rise to the shorter sized transcripts of the cdc25A and cdc2 genes as well as the normal sized ones. These results suggest that GEX1 compounds modulate gene expression by an unknown mechanism. New generation of anti-tumor agents exert inhibitory activities on cell proliferation by modulating the cell cycle and gene expression, e.g. histone deacetylase (HDAC) inhibitors1) and all-trans-retinoic acid2). Thus these pathways are attractive targets for anti-cancer drug discovery. We recently isolated six structurally related antitumor antibiotics, GEX1 compounds, from the culture broth of Streptomyces sp.3). A major compound GEX1A was identified as a herbicide, herboxidiene4), and GEX1 Q1-Q5 were novel compounds (Fig. 1). GEX1 compounds had cytotoxic activity, but the mechanism of action was unknown. In this paper, we report the effects of these compounds on the cell cycle and gene expression analyzed by flow cytometry, luciferase reporter assay and RT-PCR methods, and discuss the mode of action of GEX1 compounds. Materials and Methods Drugs GEX1 compounds were isolated from the culture broth of Streptomyces sp. GEX13). Trichostatin A was purchased from Wako Pure Chemical Industry, LTD. Test samples were dissolved in dimethyl sulfoxide (DMSO), diluted

Six structurally related antitumor antibiotics named GEX1 compounds were isolated from a culture broth of Streptomyces sp. GEX1A was identified as a known herbicide, herboxidiene, structurally interested by the tetrahydropyran moiety and the side chain including a conjugated diene. GEX1Q1-Q5 were determined as novel compounds related to herboxidiene. All GEX1 lines in vitro, but were not active against both Gram-positive and-negative bacteria. Though GEX1A/herboxidiene exhibited antitumor activity in murine tumor-planted mouse models, both GEX1Q3 and GEX1Q5 did not. In the course of a screening for new antitumor antibiotics, we isolated six structurally related compounds from a culture broth of Streptomyces sp. Among them, GEX1Q1, GEX1Q2, GEX1Q3, GEX1Q4 and GEX1Q5 are novel compounds. The major product, GEX1A was identified as a known herbicide, herboxidiene1). In this paper, the taxonomy of the producing strain, fermentation, isolation, and antitumor properties of GEX1 compounds are described. The structure determination of GEX1Q1-Q5 will be reported in elsewhere. Materials and Methods Microorganism The producing strain GEX1 compounds was isolated from a soil sample collected in Yamanashi prefecture, Japan. The strain has been deposited at the International

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