EP2331091A1 - Pharmaceutical combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester for oral treating of tumors - Google Patents
Pharmaceutical combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester for oral treating of tumorsInfo
- Publication number
- EP2331091A1 EP2331091A1 EP09783031A EP09783031A EP2331091A1 EP 2331091 A1 EP2331091 A1 EP 2331091A1 EP 09783031 A EP09783031 A EP 09783031A EP 09783031 A EP09783031 A EP 09783031A EP 2331091 A1 EP2331091 A1 EP 2331091A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fluorouracil
- tetrahydrofuryl
- caffeic acid
- phenethyl ester
- acid phenethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- WWVKQTNONPWVEL-UHFFFAOYSA-N caffeic acid phenethyl ester Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCC1=CC=CC=C1 WWVKQTNONPWVEL-UHFFFAOYSA-N 0.000 title claims abstract description 46
- SWUARLUWKZWEBQ-UHFFFAOYSA-N phenylethyl ester of caffeic acid Natural products C1=C(O)C(O)=CC=C1C=CC(=O)OCCC1=CC=CC=C1 SWUARLUWKZWEBQ-UHFFFAOYSA-N 0.000 title claims abstract description 46
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to a novel pharmaceutical combination of 1-(2- tetrahydrofuryl)-5-fluorouracil and phenolic compound for oral treating of tumors; in particular, it relates to the unexpected synergistic antitumor effect of a combination of phenolic compound and the antitumor agent in the treatment of cancer; and to processes for preparing the composition and its use for oral chemotherapy of tumors, especially malignant tumors.
- Background Art
- Cancer is the uncontrolled growth and spread of cells that may affect almost any tissue of the body. Lung, colorectal and stomach cancer are among the five most common cancers in the world for both men and women. Among men, lung and stomach cancer are the most common tumors worldwide. For women, the most common cancers are breast and cervical cancer.
- TEGAFUR i.e. 1-(2-tetrahydrofuryl)-5- fluorouracil
- GB 1 168 391 INHT ORGANOCHESKOGO SINTEZA, published 22.10.1969
- 5-FU 5-Fluorouracil
- TEGAFUR is metabolized to 5-FU in vivo, predominantly in the liver, and has been reported to be less toxic and to have a higher therapeutic index than 5-FU (see “Cancer Research” 1995, vol.1 , p.839-845).
- US 4 328 229 discloses an anti-cancer composition containing TEGAFUR and uracil.
- the composition is used for delivery of 5-FU to a tumor which is sensitive to 5-FU in a warm-blooded animal. It is disclosed therein that the composition can be co-administered in a variety of dosage forms including an oral dosage form.
- Caffeic acid phenethyl ester is a phenolic compound contained in propolis, which is the generic name of a resinous product derived from the bark of conifer trees and carried by honeybees to their hives (see CHIAO, C. "Apoptosis and altered redox state induced by CAPE in transformed rat fibrolast cells", published in “Cancer Research” 1995, vol.55, no.3576, p.3583). The biological activities of propolis and CAPE have been studied, and it has been shown that CAPE also has an antitumor activity.
- US 5008441 discloses a method for producing CAPE and a method which substantially inhibits the growth of transformed cells without substantially inhibiting the growth of normal cells. This process comprises treating a population of cells with an effective inhibiting amount of CAPE so as to substantially inhibit the growth human breast carcinoma cells, human melanoma cells, colon or renal carcinoma cells.
- MASAHIKO W., et al., "CAPE Induces Apoptosis by Inhibition of NF- ⁇ B and Activation of Fas in Human Breast Cancer MCF-7 Cells", published in "Journal of Biological Chemistry” 2004, vol.279, no.7, p.
- CAPE is described as a phenolic compound, which is a biologically active ingredient of honeybee propolis and strongly inhibits NF- ⁇ B activation. Furthermore, it was demonstrated that apoptosis is induced by CAPE in various cancer cell lines - e.g. human breast cancer MCF-7 cells. It was found by TAKEMA, N., et al., in "Selective antiproliferative activity of CAPE analogues on highly liver-metastatic murine colon 26-L5 carcinoma cell line", published in "Bioorganic&Medicinal Chemistry 2002, vol.10, p.3351-3359, that CAPE possesses selective antiproliferative activity toward a highly metastatic murine colon 26-L5 carcinoma cell line.
- WO 03/090681 discloses synergistic effects of nuclear transcription factor NF- ⁇ B inhibitors and antineoplastic agents in the treatment of cancer.
- NF- ⁇ B inhibitors As an NF- ⁇ B inhibitor CAPE and as an anti-neoplastic agent 5-FU is mentioned.
- 5-FU an anti-neoplastic agent.
- the human breast cancer cell lines MDA-MB 435 and MCF-7 were treated with an NF- ⁇ B inhibitor and an antineoplastic agent.
- WO 2005/105 086 discloses a combination of three drugs TEGAFUR, 2,4-dihydroxy-5-chloropyridine and oxonic acid or a pharmaceutically acceptable salt thereof in a mole ratio of 1 :0.4:1 , which is available as capsules (trade name: S-1).
- SUZUKI IKUKATSU et al. Antitumor and Anticytopenic Effects of Aqueous Extracts of Propolis in Combination with Chemotherapeutic Agents. Cancer Biotherapy&Radiopharmaceuticals. 2002, vol.17, no.5, p.553-562.
- CWSP crude water-soluble propolis
- 5-FU 5-FU
- a pharmaceutical combination of TEGAFUR and CAPE By using a pharmaceutical combination of TEGAFUR and CAPE the following advantageous effects are attained: ⁇ a pharmaceutical combination of TEGAFUR and phenolic compound, like CAPE had high antimetastatic activity in contrast to individual components or pharmaceutical combination of 5-Fu and CAPE at equimolar doses; ⁇ pharmaceutical combination of TEGAFUR and CAPE possessed pronounced synergistic antimetastatic efficacy.
- the unit dosage form is selected according to the purpose of treatment. Examples thereof are oral dosage form such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, etc. These dosage forms can be manufactured by conventional pharmaceutical procedures known in this field.
- the carrier for shaping into the form of tablets there can be employed various excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.; binders such as simple syrup, glucose solution, starch solution, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene-sorbitan fatty acid esters, sodium lauryl sulphate, stearic acid monoglyceride, starch, lactose, etc.; antidisintegrators such as sucrose, stearic acid, cacao butter, hydrogenated oil, etc.; absorption promoters such as quaternary ammonium bases, sodium lauryl sulphate, etc.; humectants such as
- the tablets may be in the form of coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layer tablets, etc.
- the carrier for shaping into the form of pills includes, for example, various excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, gum tragacanth powder, gelatin, etc.; and disintegrators such as laminaran, agar, etc.
- the carrier for shaping into the form of suppositories includes, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.
- Capsules are manufactured by mixing the phenolic compound, like CAPE with
- TEGAFUR TEGAFUR, with any of the carriers mentioned above and encapsulating the mixture in hard gelatin capsule, soft capsule or other capsules.
- a diluent such as, for example, white petrolatum, paraffin, glycerol, cellulose derivatives, polyethylene glycols, silicone, bentonite, etc.
- Example 1 The pharmaceutical activity of orally administrated 5-FU, Tegafur, CAPE and combinations thereof were studied using a spontaneous metastasis model produced by intramuscular injection of Lewis lung carcinoma (LLC) in synergeneic
- LLC Lewis lung carcinoma
- the antitumor activities of 5-FU, Tegafur, CAPE or combinations thereof were determined by their administration to female C57BI/6 mice (weight 19-21 g, age 2 to 2.5 months). Dosage of Tegafur and 5-FU was chosen in suboptimal range as known for 5-FU in ISHIKAWA , T., et al. Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. International Journal of
- mice were randomly divided into 6 groups of 11 mice each: 1 st group: Control group treatment with vehicle, composed of 4.8% ethanol, 7.5%
- 3 rd group TEGAFUR 0.06 mmol/kg in vehicle; 4 th group: CAPE 0.18 mmol/kg and TEGAFUR 0.06 mmol/kg in vehicle.
- Treatment includes oral administration (by probe) of test articles (or their combinations) on 5 consecutive days followed by 2 drug-free-days (5-days-a-week schedule) during 3 weeks (14 administrations) beginning in two days after cancer cells inoculation.
- the size of metastatic nodules and their number on the surface of five lung lobules of each mouse were determined by using a binocular with dimension glass.
- Nonparametric Mann-Whitney U test was used for comparative statistical analysis. A two-tailed p value less than 0.05 was considered as statistically significant.
- the anticancer efficacy of test articles in terms of metastases volume inhibition (MVI) coefficient was calculated using the following formula:
- V met control
- V m et that is the value of metastases volume
- TEGAFUR and CAPE possessed high antimetastatic activity; it inhibited the total volume of metastases by more than 70%.
- Antitumor effect of against LLC could be considered a synergetic one since neither TEGAFUR nor CAPE showed significant antimetastatic efficacy.
- the parenteral solution was prepared according to the above formula.
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The present invention provides pharmaceutical combination of phenolic compound, such as caffeic acid phenethyl ester and cancer chemotherapeutic agent, such as 1-(2-tetrahydrofuryl)-5-fluorouracil. In one embodiment of the present invention, pharmaceutical combination of caffeic acid phenethyl ester and 1-(2-tetrahydrofuryl)-5-fluorouracil can be used for inhibition of tumor metastases.
Description
COMPOSITION OF TEGAFUR AND NATURAL FLAVONOID DERIVATIVE (CAPE) FOR
ORAL TREATING OF TUMOURS
Technical Field
The present invention relates to a novel pharmaceutical combination of 1-(2- tetrahydrofuryl)-5-fluorouracil and phenolic compound for oral treating of tumors; in particular, it relates to the unexpected synergistic antitumor effect of a combination of phenolic compound and the antitumor agent in the treatment of cancer; and to processes for preparing the composition and its use for oral chemotherapy of tumors, especially malignant tumors. Background Art
Cancer is the uncontrolled growth and spread of cells that may affect almost any tissue of the body. Lung, colorectal and stomach cancer are among the five most common cancers in the world for both men and women. Among men, lung and stomach cancer are the most common tumors worldwide. For women, the most common cancers are breast and cervical cancer.
More than 11 million people are diagnosed with cancer every year. It is estimated that there will be 16 million new cases every year by 2020. Cancer causes 7 million deaths every year - or 12.5% of deaths worldwide. Therefore, a great number of studies have been carried out to find anticancer agents, which can be used in chemotherapy of malignant tumors. There are known various anticancer agents and results of cancer treatment improve with every year, nevertheless more effective antitumor agents are needed. The elimination of the primary malignant tumors by surgery is not always possible and in any case does not prevent the metastasizing tumors to invade other target organs, which develop further secondary tumors after months or years from the surgical treatment. These secondary tumors are usually the main cause of death of the patient.
One of anticancer agents is TEGAFUR. TEGAFUR, i.e. 1-(2-tetrahydrofuryl)-5- fluorouracil, is disclosed in GB 1 168 391 (INST ORGANOCHESKOGO SINTEZA, published 22.10.1969) as a prodrug of 5-Fluorouracil, i.e. 5-FU, and proved active in the management of metastatic colorectal cancer. TEGAFUR is metabolized to 5-FU in vivo, predominantly in the liver, and has been reported to be less toxic and to have a higher therapeutic index than 5-FU (see "Cancer Research" 1995, vol.1 , p.839-845).
US 4 328 229 (TAIHO PHARMACEUTICAL, published 04.05.1982) discloses an anti-cancer composition containing TEGAFUR and uracil. The composition is used for delivery of 5-FU to a tumor which is sensitive to 5-FU in a warm-blooded animal. It is disclosed therein that the composition can be co-administered in a variety of dosage forms including an oral dosage form.
Caffeic acid phenethyl ester (CAPE) is a phenolic compound contained in propolis, which is the generic name of a resinous product derived from the bark of conifer trees and carried by honeybees to their hives (see CHIAO, C. "Apoptosis and altered redox state induced by CAPE in transformed rat fibrolast cells", published in "Cancer Research" 1995, vol.55, no.3576, p.3583). The biological activities of propolis and CAPE have been studied, and it has been shown that CAPE also has an antitumor activity.
US 5008441 (UNIV COLUMBIA, published 16.04.1991) discloses a method for producing CAPE and a method which substantially inhibits the growth of transformed cells without substantially inhibiting the growth of normal cells. This process comprises treating a population of cells with an effective inhibiting amount of CAPE so as to substantially inhibit the growth human breast carcinoma cells, human melanoma cells, colon or renal carcinoma cells. In MASAHIKO, W., et al., "CAPE Induces Apoptosis by Inhibition of NF-κB and Activation of Fas in Human Breast Cancer MCF-7 Cells", published in "Journal of Biological Chemistry" 2004, vol.279, no.7, p. 6017-6026, CAPE, is described as a phenolic compound, which is a biologically active ingredient of honeybee propolis and strongly inhibits NF-κB activation. Furthermore, it was demonstrated that apoptosis is induced by CAPE in various cancer cell lines - e.g. human breast cancer MCF-7 cells. It was found by TAKEMA, N., et al., in "Selective antiproliferative activity of CAPE analogues on highly liver-metastatic murine colon 26-L5 carcinoma cell line", published in "Bioorganic&Medicinal Chemistry 2002, vol.10, p.3351-3359, that CAPE possesses selective antiproliferative activity toward a highly metastatic murine colon 26-L5 carcinoma cell line. WO 03/090681 (RES DEV FOUNDATION, published 11.06.2003) discloses synergistic effects of nuclear transcription factor NF-κB inhibitors and antineoplastic agents in the treatment of cancer. As an NF-κB inhibitor CAPE and as an anti-neoplastic agent 5-FU is mentioned. The human breast cancer cell lines
MDA-MB 435 and MCF-7 were treated with an NF-κB inhibitor and an antineoplastic agent.
WO 2005/105 086 (TAIHO PHARMACEUTICAL CO LTD, published 11.10.2005) discloses a combination of three drugs TEGAFUR, 2,4-dihydroxy-5-chloropyridine and oxonic acid or a pharmaceutically acceptable salt thereof in a mole ratio of 1 :0.4:1 , which is available as capsules (trade name: S-1). SUZUKI IKUKATSU, et al. Antitumor and Anticytopenic Effects of Aqueous Extracts of Propolis in Combination with Chemotherapeutic Agents. Cancer Biotherapy&Radiopharmaceuticals. 2002, vol.17, no.5, p.553-562. disclosed use of CWSP (crude water-soluble propolis) and 5-FU on tumor growth over the 5- week period. As it is said in the article CWSP was composed of -10% monosaccharides, specifically fructose and glucose, 4.2% the flavonoid quercetin, and 8.4% protein, no particular compound from CWSP is disclosed. It is said that mice received subcutaneous 5-FU either alone or in combination with oral CWSP every other day for 5 weeks, beginning 24h after tumor inoculation.
Different doses of the 2-fluoropyrimidines, such as 5-FU were administrated daily for 7 days by the p.o. route to mice in the spontaneous metastasis model which is disclosed in ISHIKAWA , T., et al. Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. International Journal of Cancer. 1995, vol.31 , p.516-521. It was said what 5-FU was effective in treatment of the primary tumor only at the toxic dose of 0.4 mmol/kg, but could inhibit pulmonary metastasis started from 0.05-0.1 mmol/kg dose. Disclosure of Invention Technical problem The further aim of present invention is developed effective alternative pharmaceutical combination which significantly inhibits tumor metastases. Technical solution
It was surprisingly and unexpectedly that pharmaceutical combination of Tegafur and CAPE significantly better treated tumor, especially malignant tumor, than 5- FU, Tegafur, CAPE or pharmaceutical combination of 5-FU and CAPE.
While attempting to develop a pharmaceutical combination for malignant tumor treatment having low toxicity, we unexpectedly found that doses adequate to the therapeutic ones of pharmaceutical compositions containing TEGAFUR and CAPE lead to advantageous effects.
Unexpected and surprising was that combination of TEGAFUR and CAPE significantly inhibited tumor metastases.
By using a pharmaceutical combination of TEGAFUR and CAPE the following advantageous effects are attained: ■ a pharmaceutical combination of TEGAFUR and phenolic compound, like CAPE had high antimetastatic activity in contrast to individual components or pharmaceutical combination of 5-Fu and CAPE at equimolar doses; ■ pharmaceutical combination of TEGAFUR and CAPE possessed pronounced synergistic antimetastatic efficacy.
There is no particular restriction on the dosage form which can be adopted for the antitumor composition of the invention in the treatment of malignant tumors in mammals. The unit dosage form is selected according to the purpose of treatment. Examples thereof are oral dosage form such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, etc. These dosage forms can be manufactured by conventional pharmaceutical procedures known in this field.
As the carrier for shaping into the form of tablets, there can be employed various excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc.; binders such as simple syrup, glucose solution, starch solution, gelatine solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene-sorbitan fatty acid esters, sodium lauryl sulphate, stearic acid monoglyceride, starch, lactose, etc.; antidisintegrators such as sucrose, stearic acid, cacao butter, hydrogenated oil, etc.; absorption promoters such as quaternary ammonium bases, sodium lauryl sulphate, etc.; humectants such as glycerol, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; and lubricants such as purified talc, stearic acid salts, boric acid powder, polyethylene glycol, etc. Where necessary, the tablets may be in the form of coated tablets such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double or multi-layer tablets, etc.
The carrier for shaping into the form of pills includes, for example, various excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, gum tragacanth powder, gelatin, etc.; and disintegrators such as laminaran, agar, etc. The carrier for shaping into the form of suppositories includes, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.
Capsules are manufactured by mixing the phenolic compound, like CAPE with
TEGAFUR, with any of the carriers mentioned above and encapsulating the mixture in hard gelatin capsule, soft capsule or other capsules.
For manufacturing in the form of pastes, creams, and gels, there is employed a diluent such as, for example, white petrolatum, paraffin, glycerol, cellulose derivatives, polyethylene glycols, silicone, bentonite, etc.
Best Mode for Carrying Out the Invention The present invention in the following will be described in more detail with reference to pharmacological tests and examples illustrating the preparation of the antitumor effect-potentiating compositions of the invention comprising CAPE and
TEGAFUR.
Example The pharmaceutical activity of orally administrated 5-FU, Tegafur, CAPE and combinations thereof were studied using a spontaneous metastasis model produced by intramuscular injection of Lewis lung carcinoma (LLC) in synergeneic
C57BL/6 mice.
The cell line - Lewis lung carcinoma (LLC). The LLC cells (1O6 CeIIs in 0.1 ml of Hanks' solution) were inoculated intramuscularly (i.m.).
The antitumor activities of 5-FU, Tegafur, CAPE or combinations thereof were determined by their administration to female C57BI/6 mice (weight 19-21 g, age 2 to 2.5 months). Dosage of Tegafur and 5-FU was chosen in suboptimal range as known for 5-FU in ISHIKAWA , T., et al. Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5'-deoxy-5-fluorouridine. International Journal of
Cancer. 1995, vol.31 , p.516-521.
Mice were randomly divided into 6 groups of 11 mice each:
1st group: Control group treatment with vehicle, composed of 4.8% ethanol, 7.5%
1 M NaOH, 7.5% 1 M HCI and distilled water;
2nd group: CAPE 0.18 mmol/kg in vehicle;
3rd group: TEGAFUR 0.06 mmol/kg in vehicle; 4th group: CAPE 0.18 mmol/kg and TEGAFUR 0.06 mmol/kg in vehicle.
5th group: 5-FU 0.06 mmol/kg in vehicle;
6th group: CAPE 0.18 mmol/kg and 5-FU 0.06 mmol/kg in vehicle.
Therapy includes oral administration (by probe) of test articles (or their combinations) on 5 consecutive days followed by 2 drug-free-days (5-days-a-week schedule) during 3 weeks (14 administrations) beginning in two days after cancer cells inoculation.
At the end of experiments the animals were sacrificed. The size of metastatic nodules and their number on the surface of five lung lobules of each mouse were determined by using a binocular with dimension glass. The total volume of lung metastases (Vm, mm3) was calculated using the formula:
dm (0 = 0.5 * i werein n, is number of metastases with diameter dm(i) (mm). Nonparametric Mann-Whitney U test was used for comparative statistical analysis. A two-tailed p value less than 0.05 was considered as statistically significant. The anticancer efficacy of test articles in terms of metastases volume inhibition (MVI) coefficient was calculated using the following formula:
MVI = 100 * V~> ^eatment) - Vmet (control) (%)>
Vmet (control) wherein Vmet, (that is the value of metastases volume) in control groups (control) and experimental groups (treatment).
Table 1 Influence of 5-FU, Tegafur, CAPE or combinations thereof on total volume of LLC lung metastases
*) p<0.01 compared with the control group; p<0.05 compared with CAPE, 5-FU, Tegafur, 5-FU+CAPE group.
Pharmaceutical combination of TEGAFUR and CAPE possessed high antimetastatic activity; it inhibited the total volume of metastases by more than 70%. Antitumor effect of against LLC could be considered a synergetic one since neither TEGAFUR nor CAPE showed significant antimetastatic efficacy.
Formulation Example 1 : Granule
Table 2
Using the conventional procedure, the granules were prepared according to the above formula
Formulation Example 2: Tablet
Table 3
Using the convential procedure, the tablets each weighing 200 mg was prepared according to the above formula. Formulation Example 3: Suppository
Table 4
Using the convential procedure, the suppositories each weighing 250 mg was prepared according to the above formula. Formulation Example 4: Parenteral solution
Table 5
Using the convential procedure, the parenteral solution was prepared according to the above formula.
Claims
I . A combination medicinal product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil or a pharmaceutically acceptable salt thereof and caffeic acid phenethyl ester or a pharmaceutically acceptable salt thereof.
2. The combination medicinal product of claim 1 , wherein the preferable ratio of the active ingredients 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester is from 1 : 100 to 100: 1.
3. The combination medicinal product of claim 1 , wherein the preferable ratio of the active ingredients 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester is from 1 :20 to 20: 1.
4. The combination medicinal product of claim 1 , wherein the preferable ratio of the active ingredients 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester is from 1 :4 to 4: 1.
5. Combination medicinal product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for use in the treatment of tumour.
6. Combination medicinal product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for use according to claim 5, wherein tumour is malignant tumour.
7. Use of combination medical product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for the manufacture of medicaments for treatment tumour.
8. Use of combination medical product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for the manufacture of medicaments for treatment malignant tumour.
9. Combination medicinal product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for use in the prophylaxis and/or inhibiting tumour metastases.
10. Use of combination medical product, which comprises 1-(2-tetrahydrofuryl)-5- fluorouracil and caffeic acid phenethyl ester for the manufacture of medicaments for use in a prophylaxis and/or inhibiting tumour metastases.
I I . A pharmaceutical composition, comprising a combination medicinal product of claim 1 together with a pharmaceutically acceptable diluent or carrier.
12. Use of a combination medicinal product of claim 1 or a pharmaceutical composition of claim 11 for the manufacture of a medicament for administration simultaneously, sequentially or separately for use in treatment tumour.
13. Use of a combination medicinal product of claim 1 or a pharmaceutical composition of claim 11 for the manufacture of a medicament for administration simultaneously, sequentially or separately for use in treatment malignant tumour.
14. Use of a combination medicinal product of claim 1 or a pharmaceutical composition of claim 11 for the manufacture of a medicament for administration simultaneously, sequentially or separately for use in prophylaxis and/or inhibiting tumour metastases.
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|---|---|---|---|
| EP09783031A EP2331091A1 (en) | 2008-09-18 | 2009-09-15 | Pharmaceutical combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester for oral treating of tumors |
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| EP08164589 | 2008-09-18 | ||
| EP09151211 | 2009-01-23 | ||
| PCT/EP2009/061948 WO2010031766A1 (en) | 2008-09-18 | 2009-09-15 | Pharmaceutical combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester for oral treating of tumors |
| EP09783031A EP2331091A1 (en) | 2008-09-18 | 2009-09-15 | Pharmaceutical combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and caffeic acid phenethyl ester for oral treating of tumors |
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-
2009
- 2009-09-15 UA UAA201103225A patent/UA100294C2/en unknown
- 2009-09-15 EA EA201100493A patent/EA019408B1/en not_active IP Right Cessation
- 2009-09-15 WO PCT/EP2009/061948 patent/WO2010031766A1/en active Application Filing
- 2009-09-15 EP EP09783031A patent/EP2331091A1/en not_active Withdrawn
- 2009-09-15 GE GEAP200912190A patent/GEP20135872B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2010031766A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EA019408B1 (en) | 2014-03-31 |
| UA100294C2 (en) | 2012-12-10 |
| GEP20135872B (en) | 2013-07-10 |
| EA201100493A1 (en) | 2011-12-30 |
| WO2010031766A1 (en) | 2010-03-25 |
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