WO1986000225A1 - Inhibition of tumor development - Google Patents
Inhibition of tumor development Download PDFInfo
- Publication number
- WO1986000225A1 WO1986000225A1 PCT/US1985/001168 US8501168W WO8600225A1 WO 1986000225 A1 WO1986000225 A1 WO 1986000225A1 US 8501168 W US8501168 W US 8501168W WO 8600225 A1 WO8600225 A1 WO 8600225A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound derivative
- acid
- peroxydiphosphoric
- pharmaceutically acceptable
- ester
- Prior art date
Links
- 230000005748 tumor development Effects 0.000 title abstract description 18
- 230000005764 inhibitory process Effects 0.000 title description 4
- 241001465754 Metazoa Species 0.000 claims abstract description 32
- -1 compound derivative of peroxydiphosphoric acid Chemical class 0.000 claims abstract description 20
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 19
- 231100000252 nontoxic Toxicity 0.000 claims description 19
- 230000003000 nontoxic effect Effects 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000001417 5'-guanylyl group Chemical group C=12N=C(N([H])[H])N([H])C(=O)C=1N=C([H])N2[C@@]1([H])[C@@](O[H])([H])[C@@](O[H])([H])[C@](C(OP(=O)(O[H])[*])([H])[H])([H])O1 0.000 claims description 10
- 230000037396 body weight Effects 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 10
- 125000001572 5'-adenylyl group Chemical group C=12N=C([H])N=C(N([H])[H])C=1N=C([H])N2[C@@]1([H])[C@@](O[H])([H])[C@@](O[H])([H])[C@](C(OP(=O)(O[H])[*])([H])[H])([H])O1 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
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- 230000000968 intestinal effect Effects 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- YVDPOVXIRVBNAL-UHFFFAOYSA-J tetrapotassium;phosphonatooxy phosphate Chemical group [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OOP([O-])([O-])=O YVDPOVXIRVBNAL-UHFFFAOYSA-J 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 210000004211 gastric acid Anatomy 0.000 claims description 6
- NUGJFLYPGQISPX-UHFFFAOYSA-N peroxydiphosphoric acid Chemical compound OP(O)(=O)OOP(O)(O)=O NUGJFLYPGQISPX-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
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- 229910052725 zinc Inorganic materials 0.000 claims description 6
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
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- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
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- PEKPGBKEIWFPAS-UHFFFAOYSA-J tetrapotassium;[oxido(oxidooxy)phosphoryl] phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]OP([O-])(=O)OP([O-])([O-])=O PEKPGBKEIWFPAS-UHFFFAOYSA-J 0.000 description 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates to the inhibition of tumor development with respect to tumor cells _in. vitro and actual tumor development in vivo in warm blooded animals.
- the disease of cancer results from development of malignant tumors.
- a vast amount of medical research has been committed to reducing and overcoming the scourge of cancer.
- a cure for cancer has not been found.
- the present invention builds on this knowledge to provide a material which inhibits tumor development and a method for inhibiting such development.
- lymphocytes Among the cells contained in mammalian body fluids are lymphocytes, monocytes, macrophages and polymorphonuclar cells. These cells act as a natural surveillance system against tumor development in lower mammals, such as rodents up to humans. In recent years it has been observed that a particular subpopulation of lymphocytes or lymphoid cells, termed “Natural Killer” or “NK” cells, destroy tumor cells and thus prevent development of cancer. The weight of evidence suggests that NK cells possess cytolytic activity related to generation of an active oxygen species such as hydrogen peroxide (H Gan0 flick) or oxygen-containing radicals, e.g. hydroxyl anion (OH) and superoxide anion (0 ").
- H hydrogen peroxide
- OH hydroxyl anion
- superoxide anion e.g. hydroxyl anion (OH) and superoxide anion (0 ").
- NK cells and active oxygen phenomena are described by Herberman et al, Science, Vol. 214, 2 October 1981, pages 24-30; Roder et al, Nature, Vol. 298, 5 August 1982, pages 569-572; Nathan et al, Journal of Immunology, Vol. 129, No. 5, November, 1982, pages 2164-2171; and Mavier et al, Journal of Immunology, Vol. 132, No. 4, April, 1984, pages 1980-1986.
- Peroxydiphosphate compound differs from most oxygen providing compounds in that it does not provide an initial burst of hydrogen peroxide. Rather, it releases hydrogen peroxide slowly such that when equivalent concentrations are compared to hydrogen peroxide, the amount of oxygen released by the peroxydiphosphate is one-tenth the amount of available oxygen released by hydrogen peroxide. Moreover, only about 50% of the active oxygen is released in 20 hours at 25°C in the presence of alkaline phosphatase or acid phosphatase each of which is present in the bodies of warm blooded animals, including mice, rats, humans, etc.
- tumor development is inhibited on tumor cells in vitro and in actual malignant tumor development in vivo in warm blooded animals, such as rodents ranging up to humans.
- this invention relates to a composition comprising a dosage amount of about 0.1-10% of a non-toxic water-soluble pharmaceutically acceptable compound derivative of peroxydiphosphoric acid dissolved or dispersed in a pharmaceutical carrier.
- this invention relates to a method of inhibiting tumor formation having malignant tumor cells in which a composition comprising a non-toxic dosage amount of about 0-1.6 gm per kg of body weight of a warm blooded animal of a non-toxic water-soluble pharmaceutically acceptable compound derivative of peroxydiphosphoric acid dissolved or dispersed within a pharmaceutical carrier is administered to a warm blooded animal host by oral ingestion in a regimen which provides about 0-1.6 gm per kg body weight of said warm blooded animal per day.
- this invention relates to a method of inhibiting tumor formation in which a composition comprising a non-toxic dosage amount of about 0-1.2 gm per kg of body weight of a warm blooded animal having malignant tumor cells of a non-toxic water-soluble pharmaceutically acceptable compound derivative of peroxydiphosphoric acid dissoved or dispersed in a pharmaceutical carrier is administered systemically to a warm blooded animal host in a regimen which provides about 0.1-2 gm per kg body weight of same warm blooded animal.
- the peroxydiphosphate compound is in the form of a non-toxic pharmaceutically acceptable compound, which goes beyond salt indicated in earlier mentioned U.S. Patent 4,041,149.
- Compounds include alkali metal (e.g. lithium, sodium and potassium) alkaline earth metal (e.g. magnesium, calcium and strontium), zinc and tin salts as well as organic peroxydiphosphate C, , accent alkyl, adenylyl, guanylyl, cytosylyl and thymylyl esters and also quaternary ammonium and the like salts.
- Alkali metal, particularly potassium salt is preferred from among the inorganic cations.
- the tetrapotassium peroxydiphosphate is a stable, odorless, finely divided, free-flowing, white non-hygroscopic crystalline solid having a molecular weight of 346.35 and an active oxygen content of 4.6%.
- Tetrapotassium peroxydiphosphate is 47-51% water-soluble at 0°-61°C, but insoluble in common solvents such as acetonitrile, alcohols, ethers, ketones, dimethyl formamide, dimethyl sulfoxide, and the like.
- a 2% aqueous solution has a pH of about 9.6 and a saturated solution thereof a pH of about 10.9.
- a 10% solution in water at 25°C showed no active oxygen loss after four months; and at 50°C a 10% solution showed an active oxygen loss of 3% in six months.
- the organic salts can be particularly suitable for administration against malignant tumors.
- organic esters those providing hydrophobic properties such as C, , rule alkyl radical and those which facilitate the rapid uptake of peroxydiphosphate moiety by the cells, such as adenylyl, guanylyl, cytosylyl and thymylyl, esters are preferred.
- Pharmaceutical carriers suitable for oral ingestion are coated tablets composed of material which resists breakdown by gastric acids in the stomach pH (about 1-3) since peroxydiphosphate would be inactivated by such gastric acids. Rather, the carriers, with tableted granules of the peroxydiphosphoric acid salt solid material therein, are dissolved by intestinal fluids which have a higher pH (about 5.5-10) and do not inactivate the peroxydiphosphate, leaving it subject to enzymatic action by phosphatase present in humans or other warm blooded animals.
- a desirable tablet coating solution is composed of a fatty acid ester such as N-butyl stearate (typically about 40-50, preferably about 45 parts by weight), wax such as carnuba wax (typically about 15-25, preferably about 20 parts by weight), fatty acid such as stearic acid (typically about 20-30 parts, preferably 25 parts by weight) and cellulose ester, such as cellulose acetate phthalate (typically about 5-15, preferably about 10 parts by weight) and organic solvent (typically about 400-900 parts).
- Other desirable coating materials include shellac and copolymers of maleic anhydride and ethylenic compounds such as polyvinyl methyl ether. Such coatings are distinct from tablets which are broken down in the oral cavity in which the tablet material typically contains about 80-90 parts by weight of mannitol and about 30-40 parts by weight of magnesium stearate.
- Tabletted granules of the peroxydiphosphate salt are formed by blending about 30-50 parts by weight of the peroxydiphosphate salt with about 45-65 parts by weight of a polyhydroxy sugar solid such as mannitol and wetting with about 20-35 parts by weight of a polyhydroxy sugar compound solution such as sorbitol, screening to size, blending with about 20-35 parts by weight of a binding agent such as magnesium stearate and compressing the granules into tablets with a tablet compressing machine.
- the tabletted granules are coated by spraying a foam of a solution of the coating material thereon and drying to remove solvent.
- Such tablets differ from dental tablets which are typically compressed granules without a special protective coating.
- An effective dosage of administration of peroxydiphosphate with a prescribed regimen when administration is by oral ingestion, is about 0.1-6 kg of body weight daily; when administration is systemic, such as by intramuscular, intraperitoneal or intravenous injection, the dosage is about 0.1-2 kg of body weight daily.
- Physiologically acceptable pyrogen-free solvents are suitable carriers for use in the art-recognized manner for systemic administration.
- Saline solution buffered with phosphate to a physiological pH of about 7 to 7.4 is the preferred carrier for systemic administration.
- Such solvents are distinct from water- humectant vehicles typically used in dentifrices.
- Such solution is typically prepared by sterilizing deionized distilled water, checking to insure non-pyrogenicity using the Limulus amebocyte lysate (LAL) test described by Tsuji et al in "Pharmaceutical Manufacturing", October, 1984, pages 35-41, and then adding thereto a phosphate buffer (pH e.g.
- LAL Limulus amebocyte lysate
- PDP Peroxydiphosphate compound release hydrogen peroxide slowly in the presence of phosphatase enzymes in accordance with the following equation: wherein X is a non-toxic pharmaceutically acceptable cation or completes an organic ester moiety. Phosphatase to break down the peroxydiphosphate is present in saliva as well as in plasma, intestinal fluids and white blood cells. The slow oxygen release is particularly effective in supplementing the effectiveness of NK cells against malignant tumor cells which respond to peroxydiphosphate therapy. When warm bloode ⁇ animals are treated with PDP in accordance with the present invention it is desirable to provide a regimen whereby treatment continues at least until tumors are regressed.
- PDP potassium salt
- the cell viability is determined by removing aliquots from the wells over the time specified in Table 1. The viability is assessed by the trypan blue exclusion test. Fresh medium is added in each well, each day to maintain the necessary - 7 - growth conditions. The inhibition was calculated by comparing % of cells alive in phosphate buffer saline (PBS) vs. PDP. The data is summarized in Table 1.
- PBS phosphate buffer saline
- potassium salt of PDP is highly cytotoxic and inhibitative to the murine myeloma (cancer) cells.
- Table 2 describes the effects on normal cells (human gingival fibroblast) .
- mice having an average weight of 20 grams ⁇ 3 grams groups of 25 animals each: (a) control treated with phosphate buffer saline (PBS); (b) treated with potassium peroxydiphosphate (PDP) and PBS, pH 7.0; and (c) potassium pyrophosphate (KPP) and PBS as a phosphate control.
- PBS phosphate buffer saline
- PDP potassium peroxydiphosphate
- KPP potassium pyrophosphate
- Each animal receives 0.2 ml of Pristane intraperitoneally (I.P.) to prime animals for malignant SPsmelling cells (murine myeloma carcinoma tumor cells) implantation. After three weeks, the animals are put on oral ingestion treatment regime as follows: group (a) receiving via I.P.
- I.P. Pristane intraperitoneally
- each animal is inoculated (I.P.) with 2 to 3 10 cells of SP playing (mice tumor cells, murine myeloma). Thereafter, the animals are given their respective materials, once daily for 5 days/week. That is, (a) PBS, (b) PDP or (c) KPP. The animals are scored for tumor development and death each week. The data is analyzed using the Mantel-Haenszel procedure (Statistical Aspects of the Analysis of Data from Retrospective Studies of Disease, J.
- Organic compounds of PDP particularly C, , alkyl, adenylyl, guanylyl, cytosylyl, thymylyl esters and tetramethyl ammonium salts are also effective in countering growth of murine myeloma malignant tumor cells.
- the tablets are coated with an enteric coating solution of the following composition:
- the coating is carried out by a pouring procedure in a conventional coating pan.
- Deionized distilled water is stabilized at atmospheric pressure for 20 minutes in an autoclave. After cooling, it is tested for non-pyrogenicity using the Limulus Amebocyte Lystate (LAL) as described by Tsuji et al in "Pharmaceutical Manufacturing", October, 1984, pages 35-41. 50 parts of potassium peroxydiphosphate, sodium chloride in amount corresponding to 0.9% of solution and 0.1 M phosphate buffer containing KH Constant, and Na ⁇ -HPO, , pH 9.4 are added to the pyrogen-free sterile water. The solution is then sterilized by passing it through a 0.5 micropore filter and is then packed in sterile files.
- LAL Limulus Amebocyte Lystate
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62506784A | 1984-06-27 | 1984-06-27 | |
| US625,067 | 1984-06-27 | ||
| US72654585A | 1985-04-24 | 1985-04-24 | |
| US726,545 | 1985-04-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1986000225A1 true WO1986000225A1 (en) | 1986-01-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1985/001168 WO1986000225A1 (en) | 1984-06-27 | 1985-06-21 | Inhibition of tumor development |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3528379A1 (de) * | 1985-08-07 | 1987-02-12 | Peter Berger | Mittel zur behandlung waessriger systeme sowie zur regenerierung von koerperzellen |
| FR2586350B1 (fr) * | 1985-08-22 | 1992-05-15 | Colgate Palmolive Co | Composition pharmaceutique a base de peroxodiphosphate pour l'inhibition de la secretion d'hormone parathyroidienne |
| DE3627759A1 (de) * | 1985-08-22 | 1987-03-19 | Colgate Palmolive Co | Pharmazeutische zusammensetzung zum inaktivieren bakterieller endotoxine |
| DE4201858A1 (de) * | 1992-01-24 | 1993-07-29 | Renschler Aloys Dr Med | Mittel zur behandlung maligner zellen |
| KR100426450B1 (ko) * | 2002-03-16 | 2004-04-13 | 박래옥 | 구연산, 알부민 및 아연을 함유한 항암 조성물 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4041149A (en) * | 1976-01-12 | 1977-08-09 | Colgate-Palmolive Company | Composition and method of controlling and preventing mouth odor |
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| US4430325A (en) * | 1981-12-23 | 1984-02-07 | Colgate-Palmolive Company | Topical treatment of skin lesions |
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1985
- 1985-06-03 DK DK248085A patent/DK168191B1/da active
- 1985-06-04 NZ NZ212301A patent/NZ212301A/en unknown
- 1985-06-04 ZW ZW95/85A patent/ZW9585A1/xx unknown
- 1985-06-11 SE SE8502876A patent/SE468501B/sv not_active IP Right Cessation
- 1985-06-13 FR FR8508957A patent/FR2566665B1/fr not_active Expired
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- 1985-06-14 IL IL75518A patent/IL75518A0/xx not_active IP Right Cessation
- 1985-06-14 GB GB08515105A patent/GB2161074B/en not_active Expired
- 1985-06-17 IT IT8548226A patent/IT1209961B/it active
- 1985-06-21 WO PCT/US1985/001168 patent/WO1986000225A1/en unknown
- 1985-06-24 BE BE0/215249A patent/BE902732A/fr not_active IP Right Cessation
- 1985-06-25 AT AT0188385A patent/AT392002B/de not_active IP Right Cessation
- 1985-06-25 FI FI852504A patent/FI84697C/fi not_active IP Right Cessation
- 1985-06-25 PT PT80707A patent/PT80707B/pt unknown
- 1985-06-26 KR KR1019850004549A patent/KR880002266B1/ko not_active Expired
- 1985-06-26 LU LU85976A patent/LU85976A1/fr unknown
- 1985-06-26 IE IE159785A patent/IE58434B1/en not_active IP Right Cessation
- 1985-06-26 DE DE19853523263 patent/DE3523263A1/de not_active Ceased
- 1985-06-26 NL NL8501840A patent/NL8501840A/nl not_active Application Discontinuation
- 1985-06-26 JP JP60140118A patent/JPH0623108B2/ja not_active Expired - Lifetime
- 1985-06-26 ES ES544565A patent/ES8801122A1/es not_active Expired
- 1985-06-26 MA MA20694A patent/MA20467A1/fr unknown
- 1985-06-26 AU AU44187/85A patent/AU578104B2/en not_active Ceased
- 1985-06-27 GR GR851575A patent/GR851575B/el unknown
- 1985-06-27 CH CH2758/85A patent/CH668361A5/de not_active IP Right Cessation
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1987
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4041149A (en) * | 1976-01-12 | 1977-08-09 | Colgate-Palmolive Company | Composition and method of controlling and preventing mouth odor |
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol 71; abst. no. 605962 (Kazan, USSR) Baabanov et al: & Zh. Obshch Khim., 1969, 39(S), 1176-7 (Russ) * |
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