Antitumor preparations

Details Antitumor preparations Antitumor preparations

1997-06-23

2000-09-05

Caputa, Anthony C.

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

435247, 435248, 4352521, 4352534, 435260, 435885, C12N 100, C12N 104, C12N 112, C12N 120

Patent

active

061141615

DESCRIPTION:

BRIEF SUMMARY
RELATED APPLICATIONS

Applicant claims priority based on European patent application no. 95101208.7, filed Jan. 30, 1995, for the United Kingdom, and international application no. PCT/EP96/00309, filed Jan. 24, 1996.


FIELD OF THE INVENTION

The invention concerns a new lipoteichoic acid (in the following LTA-T), a pharmaceutical composition comprising it, optionally together with a monokine and/or hyaluronidase, a method of treating cancer comprising administration of an antitumor effective amount thereof, a method of producing the new compound and the new pharmaceutical composition, two degradation products of the new LTA-T and their use, and the new Streptococcus strain from which the new compound can be isolated.


BACKGROUND OF THE INVENTION

Lipoteichoic acids (LTAs) are a group of amphipathic substances found in the cell wall of gram-positive bacteria extending from the outer cell membrane through the cell wall to the surface. The main group of LTAs consists of a hydrophilic poly(glycerophosphate) backbone and a hydrophobic glycolipid moiety. The hydrophilic backbone may be substituted with alanine, hexoses and hexosamines. The glycolipids de-scribed so far were mainly dihexosylglycerols and some trihexosylglycerols. Lipoteichoic acids show genus and species variation in the degree of polymerization of the hydrophilic chain, in the nature and degree of glycosidic substitution, in the extent of D-alanyl ester substitution, and in the structure of the lipid moiety (A. J. Wicken et al., Science, 187, 1161-1167, (1975), and Microbiology, 360-365, (1977); Fischer W., Physiology of lipoteichoic acids in bacteria. Adv. Microb. Physiol., 29(233): 233-302 (1988), Fischer W., Mannsfeld T., Hagen G., On the basic structure of poly-(glycerophosphate) lipoteichoic acids, Biochem. Cell Biol., 68(1): 33-43, (1990).
LTAs have been reported as having antitumor activity (EP 135 820; U.S. Pat. No. 4,678,773; A. Yamamoto et. al. 1985, Br. J. Cancer, 51, 739-742; and H. Usami et. al., Br. J. Cancer, 1988, 57, 70-73).
LTAs were isolated from e. g. Lactobacillus helveticus (NCIB 8025), Lactobacillus fermenti (NCTC 6991), Streptococcus faecalis, 39, Streptococcus lactis (ATCC 9936), Streptococcus mutans, AHT (A. J. Wicken et al, 1975), and Streptococcus pyogenes SV strain (ATCC 21059) (EP 135 820, U.S. Pat. No. 4,678,773, H. Usami et. al. 1985).
A glycerophosphogalactofuranosylglycerol has been described by J. H. Veerkamp and F. W. van Schalk, (1974), Biochim et Biophys. Acta, 348, pages 370-387. The isolation from Bifidobacterium bifidum var. pennsylvanicus, however did not result in pure compounds. An amount of 10 to 20% of the corresponding galactopyranosyl compounds was still present. The structure of the major compounds from this bacterium was later proposed by Werner Fischer, Eur. J. Biochem, 165, 639-646 (1987). It is unrelated to the LTAs of the present invention.
K. K:Brown disclose in WO 94/20115 the use of hyaluronic acid for the treatment of cancer whereby also lipoteichoic acids may be used in combination therewith.
A streptococcal acid glycoprotein (SAGP) with antitumor activity was isolated by M. Kanaoka et. al., Jp. J. Cancer Res. (Gann), 78, 1409-1414, (1987) from the low virulent strain Streptococcus pyogenes Su ATCC 21060. OK-432, a cell preparation from said strain, has found clinically use as an antitumor agent. However, in the meantime it was withdrawn from the market.
The LTAs described up to now carried more than one monosaccharide in the glycceroglycolipid anchor. Different glycolipid structures have been described by Fischer et al. 1988 and 1990.
An LTA with a monohexosyldiacylglyceroglycolipid as lipid anchor has not been described so far.


OBJECT OF THE INVENTION

It is an object of the invention to provide a purified new LTA with a strong antitumor activity.
It is a further object to provide pharmaceutical preparations comprising this new LTA, optionally in combination with a monokine and/or hyaluronidase.
It is a further object to provide a method of treating cancer comprising administration

REFERENCES:
patent: 5610011 (1997-03-01), Smith et al.

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