CA2244132A1 - Composition for treating cancer containing a ribose compound, beta-alanine, ascorbic acid and nicotinic acid - Google Patents
Composition for treating cancer containing a ribose compound, beta-alanine, ascorbic acid and nicotinic acid Download PDFInfo
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Abstract
A composition containing beta-alanine, a ribose compound, ascorbic acid and nicotinic acid.
Description
W O 97126893 PCT~B97100136 COMPOSITION FOR TREATING CANCER CONTAINING A RIBOSE CO~POUND, BETA-ALANINE, ASCORBIC ACID AND NICOTINIC ACID
FIELD OF THE lNv~N~ oN
The present invention is directed to a composition useful for treating cancer, particularly melanoma.
BACKG~OUND OF THE ll~VhNllON
Cancer afflicts many individuals each year. Melanoma tum-ors, for instance, originate from melanocytes, pigment cells that are normally present in the epidermis and sometimes in the der-mis. Melanoma affects about 28,000 individuals yearly in the Uni-ted States, and kills about 5,800 of these individuals. Melanoma incidence has increased dramatically (700~ in the last 40 years).
lf the incidence continues to increase at the present rate, risk of melanoma will approximate about 1 percent within a decade lifetime.
Immunomodulating compositions have been designed to treat various ;mmllnodeficiencies and auto;mmllnological disorders.
Ongoing research continues to evaluate whether these compositions may be useful in treating one or more malignant diseases.
Greek Patent ~pecification No. 72,440 discloses an immuno-modulating composition containing a mixture of D-ribose, DL-alpha alanine, nicotinic acid and ascorbic acid. The composition is asserted to have a pronounced immunomodulating activity and to be able to rebuild the metabolic equilibrium and strengthen the immunity of an affected m~mm~.
PCT application CZ94/00015, filed July 12, 1994, discloses an improvement UpO]l the composition of the Greek patent and incorporates 2-deoxy-D-ribose, thiamin, and glutamic acid amide therein. The res~lting improved composition has been found useful in ;mmllnomodulating and adjuvant therapy in combination with a metabolic stressor.
lt has now been unexpectedly discovered that similar compo-W O 97/26893 PCT~B97/00136 sitions in which the DL-alpha alanine is replaced with ~-beta-alanine significantly enhance a m~m~-l ' S resistance to cancer, particularly to melanoma.
It is an object of this invention to produce a composition capable o:E enhancing a m~mm~ '8 resistance to cancer and pro-longing the m~mm~l's life.
It is a further object of this invention to treat a m~mm~l inflicted with cancer by causing the composition to enter the blood stream of the m~m~-l SUMM~RY OF THB lNv~llON
The present invention is directed to compositions containing beta-alanine which are useful for treating cancer. The composi-tion preferably comprises a ribose compound, L-beta-alanine, as-corbic acid, and nicotinic acid. More preferably the composition is ~m;n;stered in a sodium chloride ~saline) solution. The present invention is also directed to a method for treating cancer tumors in ~-mm~ls by introducing the ingredients of the composition into the ~lood stream of the m~mm~1 The present invention is particularly directed to a composition useful for treating melanoma, and a method for treating melanoma with the composition.
DES~RIPTION OF THB DRAWINGS
Fig. 1 is a graph showing the mice survival rate of melanoma-inflicted mice treated with this invention, and untreated melanoma-inflicted mice.
Fig. 2 is a three-~;m~n~ional graph showing the mice survival rate of melanoma-inflicted mice treated with this invention, and untreated melanoma-inflicted mice.
Fig. 3 is a three-~;m~n~ional graph showing the average mice survival rate at 50 days after tumor inducement of melanoma-inflicted mice treated with a composition of this invention at WO 97/26893 PCT~B97/00136 3, 5, 7 and 10 days a~ter tumor inducement (and untreated melanoma-inflicted mice).
Fig. 4 is a three-~;m~n~ional graph ~howing the average mice survival rate at 100 days after tumor inducement of melanoma-inflicted mice treated with a composition of this invention at 3, 5, 7 and 10 days after tumor inducement (and untreated melanoma-inflicted mice).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to compositions containing beta-alanine and the use thereof in the treatment of cancer.
Preferably t~e compositions comprise a ribose compound, L-beta-alanine, ascorbic acid, and nicotinic acid. The present invention is also directed to a method for treating cancer tumors in m~mm~l S with the composition. The present invention is preferably directed to a composition for treating melanoma, and a method for treating melanoma with the composition. A prefera-ble delivery means for intravenous administration of the composition is a sodium chloride (saline) solution. Animal studies indicate that the composition generally prolongs the life of a m~mm~l afflicted with a melanoma by at least about 25% and preferably by as much as 100%, as compared to a m~mm~l with the same melanoma that does not receive any treatment.
Suitable ribose compounds for use herein include, but are not limited to, ribose, deoxyribose (2-deoxy-D-ribose), other ribose derivatives, and mixtures thereof. The ribose compounds and all other ingredients of the composition are known materials and can be obtained from manufacturers such as Sigma Aldrich and Merck.
The ribose compound is generally present in the composition in an amount that is at least about 30 wt %, preferably between about 30 to about 50 wt ~, more preferably between about 35 to about 45 wt %, and even more preferably between about 38 to about 42 wt %, based upon the total weight of the composition. A
W 097/26893 PCT~B97/00136 suitable amount of the beta-alanine is generally at least about 1 wt ~, preferably less than about l to about 45 wt %, more preferably between about 5 to 25 wt %, and more preferably between 8 to about 15 wt ~, based upon the total weight of the composition. Ascorbic acid is generally present in an amount of at least lo wt %, preferably between about 10 to 30 wt %, and more preferably between about 15 to about 25 wt %, based upon the total weight of the composition. Nicotinic acid is generally present in an amount of at least 1 wt ~, preferably at least about 1 to about 20 wt ~, and more preferably from about 5 to about 12 wt ~, based upon the total weight of the composition.
Other ranges within the ranges expressly mentioned above may be suitable.
The composition of this invention may be prepared by mixing the ribose compound, beta-~lAn;ne, ascorbic acid, and nicotinic acid in a sodium chloride (saline) solution. The ingredients may be mixed conventionally, i.e. by stirring, until a substantially homogenous mixture is obtained. The m;~;n~ time required to form the homogenous mixture depends on factors such as the tempera-ture, the degree of m;~;ng, and the like. The mixing temperature is pre~erably about room temperature, but is not critical provided that none of the ingredients are harmed by exposure to heat.
A blended composition containing all of the ingredients of the present composition has been found to have a storage stability of up to about 6 months. To provide enh~nced stabil-ity, it is preferable that the composition be in the form of two premixtures. Thus, the composition is preferably prepared by (i~
forming a first pre-mixture of ascorbic acid, ribose compound, water, and sodium chloride; (ii) forming a second pre-mixture of beta-alanine, nicotinic acid, water, and sodium chloride; and (iii) co~m~bining the two pre-mixtures prior to delivery to the m~m~-l, Generally, the pre-mixtures will be kept separate until shortly prior to A~min;strationl i.e. within a few months.
Although not currently recomm~n~ed~ it may be possible to W O 971Z6893 PCT~B97/00136 administer the two premixtures sequentially.
The cancer-treating compositions may also contain other com-pounds advantageous to the metabolic activity of cells. For example, adenosine triphosphate-forming compounds may be added, e.g. nicotinic acid derivatives or precursors. Suitable such nicotinic acid derivatives include nicotinamide A~en-n~ dinuc-leotide ~NAD), hydronicotinamide adenine dinucleotide (NADH), and nicotinamide a~en; n~ dinucleotide phosphate (NADP). Adenosine monophosphate may be used as a precursor to NAD. Other adenosine compounds may be used. Such compounds may be present in the composition in an amount of at least 5 wt ~, and pre~erably between about 5 to about 50 wt %, based upon the total weight of the composition. Other ranges within the ranges expressly men-tioned above may be suitable.
Further, the composition may contain stabilizers, e.g.
NaHC03, to increase the pH of the composition.
The composition is preferably administered to a m~mm~l in-travenously, but may also be administered in the ~orm of cap-sules, tablets, powders, drinking liquids, suppositories, and the like. The composition may also be a~m; n; fitered intratumorally, intraperitonially, and topically.
The mechanism by which the composition of the present inven-tion prolongs the lives of cancer-inflicted mAmmAls has not been determined, and Applicant does not wish to be bound by any theory. However, evidence suggests that the composition stimulates (i) endogenous immune reactions including the ~AmmAl~s ability to synthesize cytokines, and (ii) primary and secondary immune responses. The compositions may also directly inhibit tumor growth. Evidence also suggests that the beta-alanine forms stronger bonds with other components of the composition, i.e.
nicotinic and ascorbic acids, as compared to the alpha-alanine of the prior art.
W O 97/26893 PCT~B97/00136 The invention is illustrated in the following nonlimiting examples. All parts and per cents are by weight unless otherwise specified.
A composition of this invention (currently referred to as Deranin B by Applicant) was prepared as follows.
A first pre-mixture was formed using a mixer equipped with a stirrer and a source of nitrogen. The mixer was filled with 5 ml water and sterile nitroaen was bubbled thxouah the w~t~r for tumor cells of melanoma B16 to induce melanoma tumors in the mlce .
About 0.05 ml/20 g body weight of the treatment composition as prepared in Example 1 was ~m; n; stered intravenously to each mouse in the experimental group about 24 hours after a~m;n;stra-tion of the melanoma B16. Thereafter, additional doses of the composition were prepared and administered intravenously, at the same dosage rate, ~or each of the next 5 days, i.e. during the first week. During the second to fi~th weeks, additional amounts o~ the composition were administered to the experimental An;m~ls twice a week, i.e. for a total of 14 treatments.
Table 1 identifies the number of days before the last of the mice in the experimental group and the control group died.
Treatment with the beta-alanine containing composition prolonged the mice group survival by 11 days as compared to the untreated control group. Figs. 1 and 2 provide a breakdown of the mice ~urvival of the melanoma-in~licted mice in both the experimental and control groups. As can be seen in the Figures, at the 3Oth day when all of the mice in the control group had died, 11 (55%) of the treated mice remained alive. 50 ~ of the mice in the control group died by the 22nd day. 50~ of the mice in the experimental group lived until the 32nd day.
TA~3~E 1 GROUP MICE ~:iuKvlv~L
Experimental 41 days (beta-alanine) Control 30 days (untreated) COMPARATIVE EXAMP~E A
For comparison purposes, the procedure of Example 2 was re-peated with the exception that a prior art composition (in which the h-beta-alanine was replaced with the DL-alpha-alanine~ was used. The data presented in Table 2 shows that mice treated with WO 97/26893 PCT~B97/00136 the alpha-alanine prior art composition lived only a few days longer than the mice in the untreated control group. Specifi-cally Table 2 indicates that the mice treated with the prior art alpha alanine-cont~;n;ng composition survived only 3 days more than the mice in the control group.
GROUP MIC~E ~UK~/lv~I
Experimental 41 days ~beta-alanine) Comparative Example 33 days (alpha alanine) Control 30 days (no treatment) The treatment composition of this invention significantly prolongs the life of mice afflicted with melanoma as compared to mice treated with an identical composition in which the beta-alanine is replaced by alpha-alanine.
In this Example, a treatment composition was prepared ac-cording to the procedure of Example 1 except that 80 mg of adenosine-5/-monophosphate disodium salt was added to the composition of the second pre-mixture.
To evaluate the effectiveness of this composition in pro-longing the life of m~mm~l S afflicted with melanoma, 50 inbred female mice weighing about 18-20 grams each were divided into one experimental group of 40 mice and a control group of 10 mice. The group of 40 m~m~l S was divided into four subgroups with 10 mice in each subgroup. To induce melanoma tumors in the mice, all 50 mice were subcutaneously ~m; nl stered with about two million tumor cells of melanoma B16.
Thereafter, about 0.05 ml of the treatment composition was W O 97/26893 PCT~B97/00136 a~m;n;,stered twice (once intravenously in the morning and once intraperitonially in the afternoon). In subgroup A, the treatment composition was administered 3 days after tumor inducement. In subgroup B, the treatment composition was ~Am;n~ stered 5 days after tumor inducement. In subgroup C, the treatment composition was administered 7 days after tumor inducement. In subgroup D, the treatment composition was administered 10 days after tumor inducement.
In all subgroups the primary melanoma tumors which formed were surgically removed lo days after tumor inducement ~leaving only metatastic tumors). For subgroup D, the primary melanoma tumor was removed prior to first administration of the treatment composition.
The mice in the control group were ~m;n; stered a physiolo-gical solution daily from the 10th day after tumor inducement until the last mouse died on the 32 day after tumor inducement.
Table 3 identi~ies the num~er of days before the last of the mice in each subgroup and control group died.
SUBGROUP MICE SURVIVAL
A more than 100 days B more than 100 days C more than 100 days D 83 days Control Group 32 days As Table 3 indicates, the treatment composition whether admin-istered at 3, 5, 7, or 10 days a~ter melanoma tumor inducement substantially prolonged the life of the m~m~l S. Specifically, the treatment composition administered 3, 5, or 7 days after tumor inducement resulted in mice living more than 300 % longer than the longest-living mouse in the control group. The mice WO 97/26893 PCT~B97/00136 receiving treatment composition ~m; n~ stered 10 days after tumor inducement lived more than 250 ~ longer than the longest-living control group mouse.
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. The results are shown in Table 4.
TA~3LE 4 A B C D
50 days42.7 42.7 38.6 34.1 100 days57.4 58.8 56 46.3 Control24.5 24.5 24.5 24.5 As Table 4 indicates, the average survival period of mice treated at 3 days was 74 and 134% longer than the average survival period of the control group mice, when calculated at 50 and 100 days after tumor inducement. Similarly, the average survival period of mice treated at 5 days was 74 and 140% longer than the average survival period of the mice in the control group. The average survival period after 50 and 100 days for mice treated at 7 days after tumor induction was 58 and 129 ~
longer than the average survival period of mice in the control group. The average survival period for mice treated at 10 days after tumor induction was 39 and 89% percent longer than the average survival period of the control group mice.
The results suggest that the composition is highly effective in treating cancer in mice and may also be effective in treating cancer in other mAm~Als including ~nmAn~.
EXAMP~E 4 The procedure of Example 3 was repeated except that the com-position did not contain any adenosine-51-monophosphate disodium salt. Table 5 identifies the number of days before the last of W 097/26893 PCT~B97/00136 the mice in the subgroups and the control group died.
SUBGROUP MICE ~u~lvAL
A more than 100 days B more than 100 days C more than 100 days D 51 days Control Group 32 days Table 5 indicates that the treatment composition, whether administered at 3, 5, 7 or 10 days a~ter melanoma tumor induce-ment, substantially prolonged the life o~ the m~mm~l S .
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. Table 6 shows the average survival period of the mice in ~ubgroups A, B, C and D.
A B C D
50 days 37.5 37.3 33.7 33.5 100 days 42.5 47.5 43.7 33.6 Control 24.5 24.5 24.5 24.5 These results suggest that the composition is highly effective in treating cancer in mice and may also be effective in treating cancer in other m~mm~l S including hllm~n~
COMPARATIVE EXAMPLE B
In this Comparative Example, the procedure of Example 4 was repeated with the exception that the m~mm~l S were treated with a composition made from 80 mg D,L-alpha alanine, 150 mg D-ribose, W 097/26893 PCT~B97/00136 150 mg 2-deoxy-D-ribose, lS0 mg ascorbic acid, 50 mg nicotinic acid, 10 ml water and 90 mg sodium chloride, i.e. a composition disclosed in PCT application CZ94/00015 and allowed U.S. Patent Application U.S.S.N. 08/564,328, the U.S. e~uivalent to PCT
application CZ94/00 015.
Table 7 identifies the number of days before the last of the m~mm~l S in the experimental subgroup and the control group dies.
T~3LE 7 SUBCONTROL (~ROUP MICE ~:iu~vlvAI
A 51 days B 50 days C 41 days D 35 days Control 32 days Table 7 indicates that the treatment composition administered at 3, 5, 7, or 10 days a~ter melanoma tumor inducement did not prolong the life of the m~mmAls to the extent that the m~mm~l S
with the compositions of the present invention in Examples 3 and 4 above.
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. Table 8 shows the average survival period (in days) of the mice in subgroups A, B, C and D.
A B C D
50 days 30.9 29.9 28.8 27.8 100 days30.9 29.9 28.8 27.8 Control 24.5 24.5 24.5 24.5 Figs. 3 and 4 are three-~;men.~ional graphs that summarize W O 97126893 PCT~B97/00136 the average survival period ~rom Examples 3, 4, and Comparative Example B.
The data o~ this Comparative Example and Examples 3 and 4 indicate that the treatment composition of the present invention prolonged the life of mice afflicted with melanoma as compared to mice treated with the alpha-alanine-containing compositions of PCT application CZ94/00015.
FIELD OF THE lNv~N~ oN
The present invention is directed to a composition useful for treating cancer, particularly melanoma.
BACKG~OUND OF THE ll~VhNllON
Cancer afflicts many individuals each year. Melanoma tum-ors, for instance, originate from melanocytes, pigment cells that are normally present in the epidermis and sometimes in the der-mis. Melanoma affects about 28,000 individuals yearly in the Uni-ted States, and kills about 5,800 of these individuals. Melanoma incidence has increased dramatically (700~ in the last 40 years).
lf the incidence continues to increase at the present rate, risk of melanoma will approximate about 1 percent within a decade lifetime.
Immunomodulating compositions have been designed to treat various ;mmllnodeficiencies and auto;mmllnological disorders.
Ongoing research continues to evaluate whether these compositions may be useful in treating one or more malignant diseases.
Greek Patent ~pecification No. 72,440 discloses an immuno-modulating composition containing a mixture of D-ribose, DL-alpha alanine, nicotinic acid and ascorbic acid. The composition is asserted to have a pronounced immunomodulating activity and to be able to rebuild the metabolic equilibrium and strengthen the immunity of an affected m~mm~.
PCT application CZ94/00015, filed July 12, 1994, discloses an improvement UpO]l the composition of the Greek patent and incorporates 2-deoxy-D-ribose, thiamin, and glutamic acid amide therein. The res~lting improved composition has been found useful in ;mmllnomodulating and adjuvant therapy in combination with a metabolic stressor.
lt has now been unexpectedly discovered that similar compo-W O 97/26893 PCT~B97/00136 sitions in which the DL-alpha alanine is replaced with ~-beta-alanine significantly enhance a m~m~-l ' S resistance to cancer, particularly to melanoma.
It is an object of this invention to produce a composition capable o:E enhancing a m~mm~ '8 resistance to cancer and pro-longing the m~mm~l's life.
It is a further object of this invention to treat a m~mm~l inflicted with cancer by causing the composition to enter the blood stream of the m~m~-l SUMM~RY OF THB lNv~llON
The present invention is directed to compositions containing beta-alanine which are useful for treating cancer. The composi-tion preferably comprises a ribose compound, L-beta-alanine, as-corbic acid, and nicotinic acid. More preferably the composition is ~m;n;stered in a sodium chloride ~saline) solution. The present invention is also directed to a method for treating cancer tumors in ~-mm~ls by introducing the ingredients of the composition into the ~lood stream of the m~mm~1 The present invention is particularly directed to a composition useful for treating melanoma, and a method for treating melanoma with the composition.
DES~RIPTION OF THB DRAWINGS
Fig. 1 is a graph showing the mice survival rate of melanoma-inflicted mice treated with this invention, and untreated melanoma-inflicted mice.
Fig. 2 is a three-~;m~n~ional graph showing the mice survival rate of melanoma-inflicted mice treated with this invention, and untreated melanoma-inflicted mice.
Fig. 3 is a three-~;m~n~ional graph showing the average mice survival rate at 50 days after tumor inducement of melanoma-inflicted mice treated with a composition of this invention at WO 97/26893 PCT~B97/00136 3, 5, 7 and 10 days a~ter tumor inducement (and untreated melanoma-inflicted mice).
Fig. 4 is a three-~;m~n~ional graph ~howing the average mice survival rate at 100 days after tumor inducement of melanoma-inflicted mice treated with a composition of this invention at 3, 5, 7 and 10 days after tumor inducement (and untreated melanoma-inflicted mice).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is directed to compositions containing beta-alanine and the use thereof in the treatment of cancer.
Preferably t~e compositions comprise a ribose compound, L-beta-alanine, ascorbic acid, and nicotinic acid. The present invention is also directed to a method for treating cancer tumors in m~mm~l S with the composition. The present invention is preferably directed to a composition for treating melanoma, and a method for treating melanoma with the composition. A prefera-ble delivery means for intravenous administration of the composition is a sodium chloride (saline) solution. Animal studies indicate that the composition generally prolongs the life of a m~mm~l afflicted with a melanoma by at least about 25% and preferably by as much as 100%, as compared to a m~mm~l with the same melanoma that does not receive any treatment.
Suitable ribose compounds for use herein include, but are not limited to, ribose, deoxyribose (2-deoxy-D-ribose), other ribose derivatives, and mixtures thereof. The ribose compounds and all other ingredients of the composition are known materials and can be obtained from manufacturers such as Sigma Aldrich and Merck.
The ribose compound is generally present in the composition in an amount that is at least about 30 wt %, preferably between about 30 to about 50 wt ~, more preferably between about 35 to about 45 wt %, and even more preferably between about 38 to about 42 wt %, based upon the total weight of the composition. A
W 097/26893 PCT~B97/00136 suitable amount of the beta-alanine is generally at least about 1 wt ~, preferably less than about l to about 45 wt %, more preferably between about 5 to 25 wt %, and more preferably between 8 to about 15 wt ~, based upon the total weight of the composition. Ascorbic acid is generally present in an amount of at least lo wt %, preferably between about 10 to 30 wt %, and more preferably between about 15 to about 25 wt %, based upon the total weight of the composition. Nicotinic acid is generally present in an amount of at least 1 wt ~, preferably at least about 1 to about 20 wt ~, and more preferably from about 5 to about 12 wt ~, based upon the total weight of the composition.
Other ranges within the ranges expressly mentioned above may be suitable.
The composition of this invention may be prepared by mixing the ribose compound, beta-~lAn;ne, ascorbic acid, and nicotinic acid in a sodium chloride (saline) solution. The ingredients may be mixed conventionally, i.e. by stirring, until a substantially homogenous mixture is obtained. The m;~;n~ time required to form the homogenous mixture depends on factors such as the tempera-ture, the degree of m;~;ng, and the like. The mixing temperature is pre~erably about room temperature, but is not critical provided that none of the ingredients are harmed by exposure to heat.
A blended composition containing all of the ingredients of the present composition has been found to have a storage stability of up to about 6 months. To provide enh~nced stabil-ity, it is preferable that the composition be in the form of two premixtures. Thus, the composition is preferably prepared by (i~
forming a first pre-mixture of ascorbic acid, ribose compound, water, and sodium chloride; (ii) forming a second pre-mixture of beta-alanine, nicotinic acid, water, and sodium chloride; and (iii) co~m~bining the two pre-mixtures prior to delivery to the m~m~-l, Generally, the pre-mixtures will be kept separate until shortly prior to A~min;strationl i.e. within a few months.
Although not currently recomm~n~ed~ it may be possible to W O 971Z6893 PCT~B97/00136 administer the two premixtures sequentially.
The cancer-treating compositions may also contain other com-pounds advantageous to the metabolic activity of cells. For example, adenosine triphosphate-forming compounds may be added, e.g. nicotinic acid derivatives or precursors. Suitable such nicotinic acid derivatives include nicotinamide A~en-n~ dinuc-leotide ~NAD), hydronicotinamide adenine dinucleotide (NADH), and nicotinamide a~en; n~ dinucleotide phosphate (NADP). Adenosine monophosphate may be used as a precursor to NAD. Other adenosine compounds may be used. Such compounds may be present in the composition in an amount of at least 5 wt ~, and pre~erably between about 5 to about 50 wt %, based upon the total weight of the composition. Other ranges within the ranges expressly men-tioned above may be suitable.
Further, the composition may contain stabilizers, e.g.
NaHC03, to increase the pH of the composition.
The composition is preferably administered to a m~mm~l in-travenously, but may also be administered in the ~orm of cap-sules, tablets, powders, drinking liquids, suppositories, and the like. The composition may also be a~m; n; fitered intratumorally, intraperitonially, and topically.
The mechanism by which the composition of the present inven-tion prolongs the lives of cancer-inflicted mAmmAls has not been determined, and Applicant does not wish to be bound by any theory. However, evidence suggests that the composition stimulates (i) endogenous immune reactions including the ~AmmAl~s ability to synthesize cytokines, and (ii) primary and secondary immune responses. The compositions may also directly inhibit tumor growth. Evidence also suggests that the beta-alanine forms stronger bonds with other components of the composition, i.e.
nicotinic and ascorbic acids, as compared to the alpha-alanine of the prior art.
W O 97/26893 PCT~B97/00136 The invention is illustrated in the following nonlimiting examples. All parts and per cents are by weight unless otherwise specified.
A composition of this invention (currently referred to as Deranin B by Applicant) was prepared as follows.
A first pre-mixture was formed using a mixer equipped with a stirrer and a source of nitrogen. The mixer was filled with 5 ml water and sterile nitroaen was bubbled thxouah the w~t~r for tumor cells of melanoma B16 to induce melanoma tumors in the mlce .
About 0.05 ml/20 g body weight of the treatment composition as prepared in Example 1 was ~m; n; stered intravenously to each mouse in the experimental group about 24 hours after a~m;n;stra-tion of the melanoma B16. Thereafter, additional doses of the composition were prepared and administered intravenously, at the same dosage rate, ~or each of the next 5 days, i.e. during the first week. During the second to fi~th weeks, additional amounts o~ the composition were administered to the experimental An;m~ls twice a week, i.e. for a total of 14 treatments.
Table 1 identifies the number of days before the last of the mice in the experimental group and the control group died.
Treatment with the beta-alanine containing composition prolonged the mice group survival by 11 days as compared to the untreated control group. Figs. 1 and 2 provide a breakdown of the mice ~urvival of the melanoma-in~licted mice in both the experimental and control groups. As can be seen in the Figures, at the 3Oth day when all of the mice in the control group had died, 11 (55%) of the treated mice remained alive. 50 ~ of the mice in the control group died by the 22nd day. 50~ of the mice in the experimental group lived until the 32nd day.
TA~3~E 1 GROUP MICE ~:iuKvlv~L
Experimental 41 days (beta-alanine) Control 30 days (untreated) COMPARATIVE EXAMP~E A
For comparison purposes, the procedure of Example 2 was re-peated with the exception that a prior art composition (in which the h-beta-alanine was replaced with the DL-alpha-alanine~ was used. The data presented in Table 2 shows that mice treated with WO 97/26893 PCT~B97/00136 the alpha-alanine prior art composition lived only a few days longer than the mice in the untreated control group. Specifi-cally Table 2 indicates that the mice treated with the prior art alpha alanine-cont~;n;ng composition survived only 3 days more than the mice in the control group.
GROUP MIC~E ~UK~/lv~I
Experimental 41 days ~beta-alanine) Comparative Example 33 days (alpha alanine) Control 30 days (no treatment) The treatment composition of this invention significantly prolongs the life of mice afflicted with melanoma as compared to mice treated with an identical composition in which the beta-alanine is replaced by alpha-alanine.
In this Example, a treatment composition was prepared ac-cording to the procedure of Example 1 except that 80 mg of adenosine-5/-monophosphate disodium salt was added to the composition of the second pre-mixture.
To evaluate the effectiveness of this composition in pro-longing the life of m~mm~l S afflicted with melanoma, 50 inbred female mice weighing about 18-20 grams each were divided into one experimental group of 40 mice and a control group of 10 mice. The group of 40 m~m~l S was divided into four subgroups with 10 mice in each subgroup. To induce melanoma tumors in the mice, all 50 mice were subcutaneously ~m; nl stered with about two million tumor cells of melanoma B16.
Thereafter, about 0.05 ml of the treatment composition was W O 97/26893 PCT~B97/00136 a~m;n;,stered twice (once intravenously in the morning and once intraperitonially in the afternoon). In subgroup A, the treatment composition was administered 3 days after tumor inducement. In subgroup B, the treatment composition was ~Am;n~ stered 5 days after tumor inducement. In subgroup C, the treatment composition was administered 7 days after tumor inducement. In subgroup D, the treatment composition was administered 10 days after tumor inducement.
In all subgroups the primary melanoma tumors which formed were surgically removed lo days after tumor inducement ~leaving only metatastic tumors). For subgroup D, the primary melanoma tumor was removed prior to first administration of the treatment composition.
The mice in the control group were ~m;n; stered a physiolo-gical solution daily from the 10th day after tumor inducement until the last mouse died on the 32 day after tumor inducement.
Table 3 identi~ies the num~er of days before the last of the mice in each subgroup and control group died.
SUBGROUP MICE SURVIVAL
A more than 100 days B more than 100 days C more than 100 days D 83 days Control Group 32 days As Table 3 indicates, the treatment composition whether admin-istered at 3, 5, 7, or 10 days a~ter melanoma tumor inducement substantially prolonged the life of the m~m~l S. Specifically, the treatment composition administered 3, 5, or 7 days after tumor inducement resulted in mice living more than 300 % longer than the longest-living mouse in the control group. The mice WO 97/26893 PCT~B97/00136 receiving treatment composition ~m; n~ stered 10 days after tumor inducement lived more than 250 ~ longer than the longest-living control group mouse.
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. The results are shown in Table 4.
TA~3LE 4 A B C D
50 days42.7 42.7 38.6 34.1 100 days57.4 58.8 56 46.3 Control24.5 24.5 24.5 24.5 As Table 4 indicates, the average survival period of mice treated at 3 days was 74 and 134% longer than the average survival period of the control group mice, when calculated at 50 and 100 days after tumor inducement. Similarly, the average survival period of mice treated at 5 days was 74 and 140% longer than the average survival period of the mice in the control group. The average survival period after 50 and 100 days for mice treated at 7 days after tumor induction was 58 and 129 ~
longer than the average survival period of mice in the control group. The average survival period for mice treated at 10 days after tumor induction was 39 and 89% percent longer than the average survival period of the control group mice.
The results suggest that the composition is highly effective in treating cancer in mice and may also be effective in treating cancer in other mAm~Als including ~nmAn~.
EXAMP~E 4 The procedure of Example 3 was repeated except that the com-position did not contain any adenosine-51-monophosphate disodium salt. Table 5 identifies the number of days before the last of W 097/26893 PCT~B97/00136 the mice in the subgroups and the control group died.
SUBGROUP MICE ~u~lvAL
A more than 100 days B more than 100 days C more than 100 days D 51 days Control Group 32 days Table 5 indicates that the treatment composition, whether administered at 3, 5, 7 or 10 days a~ter melanoma tumor induce-ment, substantially prolonged the life o~ the m~mm~l S .
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. Table 6 shows the average survival period of the mice in ~ubgroups A, B, C and D.
A B C D
50 days 37.5 37.3 33.7 33.5 100 days 42.5 47.5 43.7 33.6 Control 24.5 24.5 24.5 24.5 These results suggest that the composition is highly effective in treating cancer in mice and may also be effective in treating cancer in other m~mm~l S including hllm~n~
COMPARATIVE EXAMPLE B
In this Comparative Example, the procedure of Example 4 was repeated with the exception that the m~mm~l S were treated with a composition made from 80 mg D,L-alpha alanine, 150 mg D-ribose, W 097/26893 PCT~B97/00136 150 mg 2-deoxy-D-ribose, lS0 mg ascorbic acid, 50 mg nicotinic acid, 10 ml water and 90 mg sodium chloride, i.e. a composition disclosed in PCT application CZ94/00015 and allowed U.S. Patent Application U.S.S.N. 08/564,328, the U.S. e~uivalent to PCT
application CZ94/00 015.
Table 7 identifies the number of days before the last of the m~mm~l S in the experimental subgroup and the control group dies.
T~3LE 7 SUBCONTROL (~ROUP MICE ~:iu~vlvAI
A 51 days B 50 days C 41 days D 35 days Control 32 days Table 7 indicates that the treatment composition administered at 3, 5, 7, or 10 days a~ter melanoma tumor inducement did not prolong the life of the m~mmAls to the extent that the m~mm~l S
with the compositions of the present invention in Examples 3 and 4 above.
The average survival periods of the mice in each subgroup and control group were calculated on the 50th and 100th day after tumor inducement. Table 8 shows the average survival period (in days) of the mice in subgroups A, B, C and D.
A B C D
50 days 30.9 29.9 28.8 27.8 100 days30.9 29.9 28.8 27.8 Control 24.5 24.5 24.5 24.5 Figs. 3 and 4 are three-~;men.~ional graphs that summarize W O 97126893 PCT~B97/00136 the average survival period ~rom Examples 3, 4, and Comparative Example B.
The data o~ this Comparative Example and Examples 3 and 4 indicate that the treatment composition of the present invention prolonged the life of mice afflicted with melanoma as compared to mice treated with the alpha-alanine-containing compositions of PCT application CZ94/00015.
Claims (9)
1. A composition characterized by a ribose compound, beta-alanine, ascorbic acid, nicotinic acid.
2. The composition of Claim 1, characterized by the ribose compound being present in an amount ranging from 30 to 50 wt %, the L-beta-alanine being present in an amount ranging from less than 1 to 45 wt %, the ascorbic acid being present in an amount ranging from 10 to 30 wt%, the nicotinic acid being present in an amount ranging from 1 to 20 wt%, based on the total weight of the composition.
3. The composition of Claim 1, characterized by further containing an additional compound selected from the group including adenosine triphosphate-forming compounds, nicotinic acid derivatives, nicotinic acid- precursors, nicotinamide, adenine dinucleotide, hydronicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, adenosine monophosphate, and adenosine-5'-monophosphate disodium salt.
4. The composition of Claim 3, wherein the additional compound is present in an amount ranging from 5 to 50 wt%, based on the total weight of the composition.
5. A composition characterized by combining a ribose compound, beta-alanine, ascorbic acid, and nicotinic acid.
6. The composition of Claim 5, characterized by the ribose compound being present in an amount ranging from 30 to 50 wt %, the L-beta-alanine being present in an amount ranging from less than 1 to 45 wt %, the ascorbic acid being present in an amount ranging from 10 to 30 wt%, the nicotinic acid being present in an amount ranging from 1 to 20 wt%, based on the total weight of the composition.
7. A method for preparing a composition characterized by (i) forming a first pre-mixture of beta-alanine, ascorbic acid, a ribose compound, water, and sodium chloride;
(ii) forming a second pre-mixture of nicotinic acid, water, and sodium chloride, and (iii) combining the first and second pre-mixtures.
(ii) forming a second pre-mixture of nicotinic acid, water, and sodium chloride, and (iii) combining the first and second pre-mixtures.
8. The method of Claim 7, characterized by the ribose compound being present in an amount ranging from 30 to 50 wt %, the L-beta-alanine being present in an amount ranging from less than 1 to 45 wt %, the ascorbic acid being present in an amount ranging from 10 to 30 wt%, the nicotinic acid being present in an amount ranging from 1 to 20 wt%, based on the total weight of the composition.
9. The method of Claim 8, characterized by the composition further containing an additional compound selected from the group including adenosïne triphosphate-forming compounds, nicotinic acid derivatives, nicotinic acid precursors, nicotinamide, adenine dinucleotide, hydronicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, adenosine monophosphate, and adenosine-5'-monophosphate disodium salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1051796P | 1996-01-24 | 1996-01-24 | |
| US60/010,517 | 1996-01-24 | ||
| PCT/IB1997/000136 WO1997026893A1 (en) | 1996-01-24 | 1997-01-22 | Composition for treating cancer containing a ribose compound, beta-alanine, ascorbic acid and nicotinic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2244132A1 true CA2244132A1 (en) | 1997-07-31 |
Family
ID=29422205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2244132 Abandoned CA2244132A1 (en) | 1996-01-24 | 1997-01-22 | Composition for treating cancer containing a ribose compound, beta-alanine, ascorbic acid and nicotinic acid |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2244132A1 (en) |
-
1997
- 1997-01-22 CA CA 2244132 patent/CA2244132A1/en not_active Abandoned
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