Activities lines, human colonic

In 1990, researchers at Bristol-Myers Squibb reported the isolation of Bmy-41950 (322) from S. staurosporeus strain R10069 (ATCC 55006). This isolate showed in vitro activity against human colon cancer cells (HCT-116) (307). Two years later, Isono et al. reported the isolation of the same natural product from a different Streptomyces sp., S. platensis subsp. malvinus RK-1409 and named it RK-1409 (7-oxostaurosporine) (322) (308,309). In nature, this isolate was obtained in its optically active form [ Id + 38.3 (c 0.06, CHCI3) (309). The PKC inhibitor RK-1409 (7-oxostaurosporine) inhibited the morphological change of a human erythroleukemia cell line, K-562, induced by phorbol 12,13-dibutyrate (PDBu), and also showed a weak antimicrobial activity against Chlorella vulgaris and Pyricularia oryzae (308). 

Tesei, A., Ulivi, P, Eabbri, R, Rosetti, M., Leonetti, C., Scarsella, M., et al. (2005). In vitro and in vivo evaluation of NCX 4040 cytotoxic activity in human colon cancer cell lines. J. Transl. Med. 3, 7. 

Peters, W. H. N., Roelofs, H. M. J., Time-dependent activity and expression of glutathione S-transferases in the human colon adenocarcinoma cell line Caco-1, Biochem. J. 1989, 264, 613-616. 

Cell monolayers grown on permeable culture inserts form confluent mono-layers with barrier properties and can be used for drug absorption experiments. The most well-known cell line for the in vitro determination of intestinal drug permeability is the human colon adenocarcinoma Caco-2 [20, 21], The utility of the Caco-2 cell line is due to its spontaneous differentiation to enterocytes under conventional cell culture conditions upon reaching confluency on a porous membrane to resemble the intestinal epithelium. This cell model displays small intestinal carriers, brush borders, villous cell model, tight junctions, and high resistance [22], Caco-2 cells express active transport systems, brush border enzymes, and phase I and II enzymes [22-24], Permeability models... 

Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, Okuyama Y, Fujita T, Ohtani-Fujita N, Matsukawa Y, Tokino T, Yamagishi H, Oka T, Nomura H, Sakai T. (1997) Butyrate activates the WAFl/Cipl gene promoter through Spl sites in a p53-negative human colon cancer cell line. J Biol Chem 212 22199-22206. 

Recently, the piperazine intermediate 15 for the total synthesis of (—)-lemon-omycin (9) was reported by Fukuyama et al. [14], (—)-Lemonomycin possesses interesting antibiotic activity against methiciUin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, as well as cytotoxicity against the human colon tumor cell line HCT-116 [15]. The reaction of 2-isocyanoethyl phenyl carbonate 11 gave Ugi product 14, which was further transformed to a piperazine intermediate 15 (Scheme 2). 

The rationale for combining 9-AC with irradiation was based on in vitro work with human colon and pancreatic cancer cell lines showing dose dependency for cytotoxicity and radiation sensitization and other reports that it is a potent radiation sensitizer in vivo (21). Unfortunately, this agent is not very well tolerated in man and clinical studies have been abandoned (12). Another agent is 9-nitro-camptothecin that is converted into 9-AC in vivo, which has also been shown to be active in vitro and in vivo (44,45). 

Recently, Barrero et al. [20] have tested the activity of natural podolactones LL-Z1271a (63) and 68, and of synthetic derivatives 94-99, the latter being a mixture of isomers, against four tumoral cell lines P-388, A-549 (human lung carcinome), HT-29 (human colon carcinome) and MEL-28 (human melanome) (Table 2). The two natural compounds, as well as 98 showed a potent activity (ICso[Pg.470]

Human colon microsomal cytochrome P450 enzymes can demethylate 1,2-dimethylhydrazine, yielding formaldehyde, and activities in the descending colon are always higher than in the ascending or transverse colon (Newaz et al., 1983). A-Demethylation was also detected in microsomes from a human colon tumour line, adenocarcinoma LS 174T cells. The activity was inducible by phenobarbital and/or hydrocortisone. 

The tribrominated bisindole alkaloid dragmacidin (30) from the marine sponge Dragmacidon sp. has antitumor activity against P-388 cells (IC5o 15 pg/ml), A-549 (human lung), HCT-8 (human colon), and MDAMB (human mammary) cancer cell lines (IC501-10 pg/ml) [43]. 

The cytotoxicity of makaluvamine F (167), a pyrroloiminoquinone from the Fijian sponge Zyzzya cf. marsailis, against the human colon tumor cell line HCT-116 (IC50 0.17 pM) and Chinese hamster ovary cell line xrs-6 (IC50 0.08 pM) is one to two orders of magnitude higher than the activity of the halogen-free makaluvamines A-E [128]. 

Fujianmycins A and B were isolated from a Streptomyces species (IA-CAS-114) in Fujian, China [167], The structure of fujianmycin A (34a) may be regarded as the 2,3-hydrated form of (33a), and fujianmycin B (34b) as its methyl ether derivative. The structure of antibiotic PD-116740 (35), isolated from an unidentified actinomycete species (WP-4669) and possessing activity against L1210 leukaemia in vitro and HCT-8 human colon adenocarcinoma cell line [168], may be visualized as the 3-hydroxylated 8-methyl-5,6-diol derivative of (33a). All these antibiotics contain the characteristic 2-phenylnaphthalene structural feature. 

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