Human-derived tumor cell growth inhibitors

Details Human-derived tumor cell growth inhibitors Human-derived tumor cell growth inhibitors

1996-02-05

1998-07-21

Walsh, Stephen

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

435 695, 43525231, 4353201, 530324, 536 235, 536 241, C12N 1512, C12N 1574, C12N 1575

Patent

active

057834172

DESCRIPTION:

BRIEF SUMMARY
This application is a PCT/JP94/100895 filed Jun. 2, 1994.


BACKGROUND OF THE INVENTION

1. Technical Field
The present invention relates to a novel human-derived tumor cell growth inhibitor, a DNA fragment encoding the inhibitor, an expression plasmid of said human-derived tumor cell growth inhibitor bearing the DNA fragment, Bacillus brevis transformed by the expression plasmid, and a method for producing the human-derived tumor cell growth inhibitor using Bacillus brevis by a genetic engineering technique.
2. Background Art
Synthetic drugs such as chemotherapeutic agents or immunotherapeutic agents have been heretofore widely used as anti-tumor agents. However, these drugs generally encounter problems that their specificity is low and side-effects are serious. On the other hand, many tumor cell growth inhibitors have been found in tissue culture cells. These inhibitors could be such anti-tumor agents that would be highly specific and would have minimized side-effects. Representative examples of such inhibitors are interferon, lymphotoxin and tumor necrosis factor (TNF).
Recently, a tumor cell cytotoxic factor obtained from human fibroblast and a tumor cell growth inhibitor obtained from human lung cancer cells are reported in Japanese Patent KOKAI Nos. 1-148197 and 1-187094, respectively.
On the other hand, some cell growth inhibitors are isolated from the fibroblastic 3T3 cell line established from the cells obtained from Swiss fetal mice. For example, Natraj et al. has reported that a growth inhibitor was obtained from the cell membrane of 3T3 cells in the stationary phase, cf., Proc. Natl. Acad. Sci. U.S.A., 75, 6115-6119 (1978). Harel et al. has reported that a growth inhibitor having a molecular weight of 40 kDa was obtained from the culture supernatant of 3T3 cells, see J. Cell. Physiol., 119, 101-106 (1984), ibid., 123, 139-143 (1985). However, it is known that these growth inhibitors all fail to show any significant inhibitory action on tumor cells.
A mouse-derived tumor cell growth inhibitor isolated and purified from the culture supernatant of the established cell line NIH3T3-sf, which is obtained by focus cloning from NIH3T3 cells (J. Virol., 4, 549 (1969)), one of fibroblastic 3T3 cell lines established from Swiss fetal mice, is reported in Japanese Patent Application No. 3-11950 as the inhibitor having a significantly inhibitory activity on tumor cells. This mouse-derived tumor cell growth inhibitor exhibits a potent growth inhibition activity on tumor cells such as human promyelogenous leukemia cells or human cervical carcionoma cells and is expected to be effective as a new drug for the treatment of cancer. However, the inhibitor is a mouse-derived one so that there might be an antigenicity problem when applied to human.


DISCLOSURE OF THE INVENTION

The present inventors previously succeeded in cloning of,cDNA encoding the mouse-derived tumor cell growth inhibitor which was isolated from the culture supernatant of NIH3T3-sf cells described above and already filed PCT/JP92/01580 directed to its nucleotide sequence.
In order to obtain a novel human-derived tumor cell growth inhibitor, the present inventors have made studies on cloning of cDNA encoding a human-derived tumor cell growth inhibitor from human placenta chromosomal DNA-derived DNA library and from human colon tumor cell-derived cDNA library and found a novel human-derived tumor cell growth inhibitor and a DNA fragment encoding the inhibitor.
The present inventors have made further studies to provide an industrially advantageous method for producing the inhibitor by recombinant DNA technique, using the DNA fragment encoding the human-derived tumor cell growth inhibitor. As a result, it has been discovered that by expressing the inhibitor using a promoter and a DNA fragment encoding a signal perptide as a regulator gene, derived from Bacillus brevis and using Bacillus brevis as a host, the inhibitor can be secreted out of the cell to produce the inhibitor in a large quantity. The present invention has thus been accomplished.
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REFERENCES:
patent: 4524145 (1985-06-01), Matson
patent: 5384394 (1995-01-01), Kamurasaki et al.
patent: 5523391 (1996-06-01), Komurasaki

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