Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing
Reexamination Certificate
1999-12-13
2001-06-12
Riley, Jezia (Department: 1656)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C514S183000, C514S247000, C514S359000, C514S228800
Reexamination Certificate
active
06245734
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel physiologically active substances, polyoxypeptin and deoxypolyoxypeptin, which have each an anti-cancer activity and an antibacterial activity against gram-positive bacteria. Polyoxypeptin and deoxypolyoxypeptin according to this invention are physiologically active substances which have an activity of inducing apoptosis not only on such human pancreatic adenocarcinoma cells of a type susceptible to apoptosis and capable of causing apoptosis by treatment with an anti-cancer drug, but also have an activity of inducing apoptosis on such human pancreatic adenocarcinoma cells of a type resistant to apoptosis even upon the treatment with the anti-cancer drug, for example, on AsPC-1 cell, whereby polyoxypeptin and deoxypolyoxypeptin possess anti-cancer or anti-tumor activities. This invention also relates to a process for the production of polyoxypeptin and/or deoxypolyoxypeptin. This invention further relates to an anti-tumor or anti-cancer composition containing polyoxypeptin or deoxypolyoxypeptin as active ingredient. Further, this invention embraces, as a novel microorganism, Streptomyces sp. MK498-98F14 strain which has a characteristic nature capable of producing the physiologically active substances above-mentioned.
BACKGROUND ART
Apoptosis is such a schemed death of cells, of which a particular feature is an immediate death of cells. In 1970's, apoptosis was reported as a new conception for the death of cells [see “Int. Rev. Cytol.”, 68, 251(1980)]. As compared with a necrosis which was an old conception for the death of cells already known in the art, apoptosis is characterized in that the period of time lapsed between the time of impartment of a stimulus of causing the death of cells by apoptosis and the time of occurrence of the death of cells by apoptosis is shorter than that for the necrosis, and also that apoptosis does involve no inflammation in the peripheral tissues of the cancer region, and so on. Afterwards, there have been reported that many anti-cancer drugs such as adriamycin and cisplatin have the activities of inducing the apoptosis on some of incubated cancer cells [“Cancer Res.”, 53, 1845 (1993) and “Exp. Cell Res.”, 211, 231 (1994)].
However, it has become clear now that adriamycin or cisplatin as the anti-cancer drug can have an activity of inducing the apoptosis of cells on the leukemia cells and on the experimental cancer cells which were artificially generated by carcinogen virus and the like, but that adriamycin or cisplatin does not induce apoptosis on many of the spontaneously generated human solid cancer cells [see “Rinsho Igaku”, 21, No.9, 42-45 (1995)]. That is to say, there exist such human solid cancer cells which possess such property of not inducing the apoptosis by the anti-cancer drugs known and utilized in the art, and which are of the apoptosis-resistant type.
An human pancreatic adenocarcinoma cell, AsPC-1 cell, is a cancer cell described in “In Vitro”, 18, 24 (1982)”, and AsPC-1 cell exhibits a very strong apoptosis-resistance against such anti-cancer drugs as adriamycin, etc. While, another human pancreatic adenocarcinoma cell, BxPC-3 cell [described in “Cancer Investigation”, 4, 15 (1986)], is susceptible to apoptosis. For example, it is already known that adriamycin can induce apoptosis on BxPC-3 cell within 24 hours from the start of treatment with adriamycin at the concentration of 3 &mgr;g/ml, but adriamycin does not induce apoptosis on AsPC-1 cell even at the concentration of 30 &mgr;g /ml of adriamycin.
In the past, nothing was known about such investigations which seek for the drugs capable of inducing the apoptosis on the apoptosis-resistant cancer cells such as the human pancreatic adenocarcinoma cell, AsPC-1 cell. In the clinical applications of conventional anti-cancer drugs of the type which can exhibit a cytotoxicity against cancer cells, it is considered that the “in vivo” contact time between the conventional anti-cancer drug and the cancer cells is a limited one. Thus, it is deducible that a more effective agent would be such an anti-cancer drug which is capable of inducing the apoptosis of cancer cells and thereby capable of making the cell death to be caused on the cancer cells in a shorter time than the conventional anti-cancer drug. It is further demanded to explore such a novel anti-cancer drug which is capable of inducing apoptosis and which is effective to cause apoptosis to effect even on such type of cancer cells insusceptible to induction of immediate death of cells by apoptosis, as long as they are treated by the known anti-cancer drug. It is therefore demanded now to provide such novel compounds which have an activity of inducing apoptosis effectively even on cancer cells of such type insusceptible to induction of apoptosis (immediate death of cells) when treated with the known anti-cancer drugs.
DISCLOSURE OF THE INVENTION
We, the present inventors, have now made our investigations with the intention of providing some novel compounds which have activities to induce apoptosis strongly on cancer cells and which are thus useful to treat therapeutically the cancer. In this connection, we have an expectation that such physiologically active substance capable of inducing the apoptosis even on the human pancreatic adenocarcinoma cell, AsPC-1 cell, can exhibit a usefully effective anti-cancer activity, seeing that the AsPC-1 cell cannot induce apoptosis by the treatment with the conventional anti-cancer drug. Thus, we have made investigations to detect novel compound(s) having an activity of inducing the apoptosis on the AsPC-1 cell out of the metabolic products of microorganisms. As a result, we have now found that when such a strain of microorganism belonging to genus Streptomyces which we have newly isolated from a soil sample and we have allotted a strain No. MK498-98F14 is incubated, said strain has produced in the resulting culture broth such a substance which is capable of inducing apoptosis on the AsPC-1 cells. Then, we have successfully isolated this substance having the apoptosis-inducing activity and have studied on the physico-chemical properties and physiological activities of said substance, to find out that this substance be a novel compound. Thus, we have designated this compound as “polyoxypeptin”.
We have further found that a second substance capable of inducing apoptosis on the AsPC-1 cells was also produced and present in the culture broth of the MK498-98F14 strain above-mentioned. We have successfully isolated the second compound, too. Then, we have studied on the physico-chemical properties and physiological activities of the second substance to find out that the second substance be a novel compound. Further, we have succeeded in deciding the chemical structures of polyoxypeptin firstly obtained, as well as the second substance subsequently obtained. We have then designated the second substance as “deoxypolyoxypeptin”. We further have confirmed that deoxypolyoxypeptin has an apoptosis-inducing activity. Further, we have recognized that polyoxypeptin and deoxypolyoxypeptin can be represented collectively by a general formula (I) as shown below. It has further been found that polyoxypeptin and deoxypolyoxypeptin can be reacted at the site of acidic group thereof with an inorganic base or an organic base to form a salt, for example, sodium salt, potassium salt and an alkylamine salt.
According to a first aspect of this invention, therefore, there is provided, as the novel physiologically active substance, polyoxypeptin or deoxypolyoxypeptin, which is a compound represented by the following general formula (I)
wherein R denotes a hydroxyl group for polyoxypeptin or R denotes a hydrogen atom for deoxypolyoxypeptin, or a pharmaceutically acceptable salt thereof.
Polyoxypeptin according to the first aspect of this invention is the compound represented by the following formula (Ia)
Deoxypolyoxypeptin according to the first aspect of this invention is the compound represented by the following formula (Ib)
Hamada Masa
Ikeda Yoko
Kondo Shin-ichi
Naganawa Hiroshi
Takeuchi Tomio
Larson & Taylor PLC
Riley Jezia
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
LandOfFree
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