CA1228819A - Method and compositions for combatting tumors - Google Patents
Method and compositions for combatting tumorsInfo
- Publication number
- CA1228819A CA1228819A CA000436310A CA436310A CA1228819A CA 1228819 A CA1228819 A CA 1228819A CA 000436310 A CA000436310 A CA 000436310A CA 436310 A CA436310 A CA 436310A CA 1228819 A CA1228819 A CA 1228819A
- Authority
- CA
- Canada
- Prior art keywords
- carnitine
- composition
- tumor
- fatty acid
- chain fatty
- 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.)
- Expired
Links
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Composition and method for combatting tumorous growths in animals involving administration of a composition comprising L-carnitine in relatively large dosages. The L-carnitine can be used in combination with cysteine and this combination has been shown to repress and reverse tumor growth and formation. Along chain fatty acid can be used in combination with L-carnitine also.
Composition and method for combatting tumorous growths in animals involving administration of a composition comprising L-carnitine in relatively large dosages. The L-carnitine can be used in combination with cysteine and this combination has been shown to repress and reverse tumor growth and formation. Along chain fatty acid can be used in combination with L-carnitine also.
Description
~2~88191 . . .
Description Method and Compositions for Ccn~atting Tutors Technical yield The present invention relates to a method and to compositions for cohabiting timorous growths.
no specifically this invention relates to a method and to cor~ositions which promote a reduction in the size of established timorous growths.
Background Art o'er than 50 years ago Otto ~arburg discovered that malignant tumor cells ferment glucose to lactic acid much more rapidly Han most normal cells, i.e. they depend upon glycolysis for their primary source of energy or growth (the "~1arb~urg effect"). (O. ~arburg, my Prime Cause and Prevention of Cancer, Triltsch, Wurzbur~, Germany, 1967 pp.
6-16, Become. Z. 142, 317 (1923)). As used herein, the word "tumor"
refers to an abnormal mass of tissue arising without obvious cause from cells of preexistent tissue and possessing no physiologic function. As is discussed below, such tumors include benign, well-~ncapsulated mammary tumors such as those characteristic of the female Sprague-Dawley rat and well known to those skilled in the art, human breast cancer, and other metastasizing cancers such as human bowel and colon cancers.
Recently, tacker et at have demonstrated high Autopsy activity (AT ASP Pi) in tumor tissue and have proposed that increased Autopsy was required for the high glycolytic activity of tumor cells since AT hydrolysis to DO -I Pi is known to be a rate-limiting step for glucose utilization (Racker, E. and Spector, M. Science 213, 303 (1931)). Thus, although the Racker et at finding support the '`~arburg effect"
the reason for the high rate of aerobic glycolysis in tumor cells has not been planned 3L~2138~
Disclosure of Invention It has now teen found that the Ruth of tumors can be successfully ccm~atted by the adninist-r~tion to a tu~,or-~earing animal. of relatively Llr(Je amo~mts of L-carni.tine.
It has also been found that the growth of malignant tumors in vitro can also be repressed by the presence of L-canlitine.
In addition, it has been found that if the L-carnitine is administered to the anin~l or used in in vitro situations in combination tooth Sistine the repression and actual reversal of tumor growth and formation is enhanced.
It is well known that L-carnitine is normally synthesized in the human liver and kidney from Lawson and methionine; that it is supplied to the heart, skeletal muscle and other tissues via the blood stream; that its prior y fur~tion is to facilitate mitochondrial fatty acid oxidation (Fritz, I
Fishily. Revs. 41, 52 (1961)). It is also Newton that the fatty acid oxidation stunula-tion by carnitine is accomplished through the joint action of the enzymes carnitine transfers I, the carnitine translocator, and carnitine transfers II
because azalea Coy cannot pass across the inner mitochondrial rn~nb.rane (Brerner, I., Trends in Biochemical Science, 2 207, 1977)).
Although the following theoretical explanation is not to be considered binding, it was postulated that since tumor cells require a high rate of glycolysis for their growth, and that since carnitine starlights fatty acid oxidation, the administration of high levels of carnitine might force tumor cells to utilize fatty acids as an energy source which might prevent glycolysis and have harmful effects on such cells. It appeared that carnitine-stirnula-ted fatty acid metabolism might be deleterious in possibly three ways.
1. If there is lowered ability to oxidize fatty acids to COY and OWE, but normal earnitine trouncers activity is present, increased activation of fatty acids Woody lead to the accumulation of long chain azalea carnit.ine and CQ~ esters of fatty acids (Chicano to occur in ischemia - see shag, Lo et at, Arch.
Become. ifs. 187, 25, 1978). Such products
Description Method and Compositions for Ccn~atting Tutors Technical yield The present invention relates to a method and to compositions for cohabiting timorous growths.
no specifically this invention relates to a method and to cor~ositions which promote a reduction in the size of established timorous growths.
Background Art o'er than 50 years ago Otto ~arburg discovered that malignant tumor cells ferment glucose to lactic acid much more rapidly Han most normal cells, i.e. they depend upon glycolysis for their primary source of energy or growth (the "~1arb~urg effect"). (O. ~arburg, my Prime Cause and Prevention of Cancer, Triltsch, Wurzbur~, Germany, 1967 pp.
6-16, Become. Z. 142, 317 (1923)). As used herein, the word "tumor"
refers to an abnormal mass of tissue arising without obvious cause from cells of preexistent tissue and possessing no physiologic function. As is discussed below, such tumors include benign, well-~ncapsulated mammary tumors such as those characteristic of the female Sprague-Dawley rat and well known to those skilled in the art, human breast cancer, and other metastasizing cancers such as human bowel and colon cancers.
Recently, tacker et at have demonstrated high Autopsy activity (AT ASP Pi) in tumor tissue and have proposed that increased Autopsy was required for the high glycolytic activity of tumor cells since AT hydrolysis to DO -I Pi is known to be a rate-limiting step for glucose utilization (Racker, E. and Spector, M. Science 213, 303 (1931)). Thus, although the Racker et at finding support the '`~arburg effect"
the reason for the high rate of aerobic glycolysis in tumor cells has not been planned 3L~2138~
Disclosure of Invention It has now teen found that the Ruth of tumors can be successfully ccm~atted by the adninist-r~tion to a tu~,or-~earing animal. of relatively Llr(Je amo~mts of L-carni.tine.
It has also been found that the growth of malignant tumors in vitro can also be repressed by the presence of L-canlitine.
In addition, it has been found that if the L-carnitine is administered to the anin~l or used in in vitro situations in combination tooth Sistine the repression and actual reversal of tumor growth and formation is enhanced.
It is well known that L-carnitine is normally synthesized in the human liver and kidney from Lawson and methionine; that it is supplied to the heart, skeletal muscle and other tissues via the blood stream; that its prior y fur~tion is to facilitate mitochondrial fatty acid oxidation (Fritz, I
Fishily. Revs. 41, 52 (1961)). It is also Newton that the fatty acid oxidation stunula-tion by carnitine is accomplished through the joint action of the enzymes carnitine transfers I, the carnitine translocator, and carnitine transfers II
because azalea Coy cannot pass across the inner mitochondrial rn~nb.rane (Brerner, I., Trends in Biochemical Science, 2 207, 1977)).
Although the following theoretical explanation is not to be considered binding, it was postulated that since tumor cells require a high rate of glycolysis for their growth, and that since carnitine starlights fatty acid oxidation, the administration of high levels of carnitine might force tumor cells to utilize fatty acids as an energy source which might prevent glycolysis and have harmful effects on such cells. It appeared that carnitine-stirnula-ted fatty acid metabolism might be deleterious in possibly three ways.
1. If there is lowered ability to oxidize fatty acids to COY and OWE, but normal earnitine trouncers activity is present, increased activation of fatty acids Woody lead to the accumulation of long chain azalea carnit.ine and CQ~ esters of fatty acids (Chicano to occur in ischemia - see shag, Lo et at, Arch.
Become. ifs. 187, 25, 1978). Such products
2~819 !
., .
have been shown to inhibit a number of mitochondrial systems and could lyre mitoehondrial and cell m~branes because of their powerful detergent -action. (Snug, AWL., Texas Reports on Boo. and Med.
39f 409 tl979); Cell G et at, J. Blot. Chum.
256. 12740 (1981)~.
2. Since activation of fatty acids utilizes AT and produces IMP + Pi Swahili Coax earnitine stimulated fatty acid activation in tumor cells, where oxide-lion was sled, old lead to lyrical AT levels, diminished Autopsy formation of ASP + Pi, and less glycolysis.
., .
have been shown to inhibit a number of mitochondrial systems and could lyre mitoehondrial and cell m~branes because of their powerful detergent -action. (Snug, AWL., Texas Reports on Boo. and Med.
39f 409 tl979); Cell G et at, J. Blot. Chum.
256. 12740 (1981)~.
2. Since activation of fatty acids utilizes AT and produces IMP + Pi Swahili Coax earnitine stimulated fatty acid activation in tumor cells, where oxide-lion was sled, old lead to lyrical AT levels, diminished Autopsy formation of ASP + Pi, and less glycolysis.
3. Carnitine-stim~la~ed fatty acid oxidation can benefit normal cells (Snug, AWL. et at, Academic Press, NY, NY, Carnitine Biosynthesis, Metabolism and Functions, pp. 321-340 (1980)) by stimulating their energy producing metabolism and production of more AT, thereby making more energy available for the synthesis of anti-tumor substances, e.g. inter-freon. mix coupled with the known increased blood flaw to timorous tissue and the increased uptake of substrates characteristic of tumor cells, earnitine when ac~ninistered in high dosage would, in effect, tend to Salk out and destroy tumor cells.
Detailed Description of the Invention Example 1 In the follc~ing Examples the I~earnitine was achninistered as tile free base (inner salt). The D-carnitine was also ac~ninistered as the free base.
Female Sprac~le-Dawley rats which spontaneously develop a benign ~el1-encapsulated menu tumor were utilized (the tumors were considered to be classic fibroadenomas composed of whorls and bundles of dense co~lacJen). The Sprague-Dawley mammary tumor is a standard model for human breast cancer. Six animals with tumors of various sizes were selected for each group to be ~22~8~g subjected to treatment. ~11 animals were maintained on a high fat diet.
One group of six animals was injected imp. with 3 gm/kilo of L-c~rnitine twice per day. A second set ox six animals received a like dose of D-carnitine. third set of six animals received 3 gmlkilo of L-carnitine and 1 gm~kilo of Sistine twice per day. The injections in each case were continued for 25 days with the tumor size being evaluated on days 8, 15, 19, 22 and 25. The animals Tory observed for an additional 17 days and the tumors evaluated or size on the Thea and ~3rd days.
Results are presented in the Table below.
Average Tumor Size: (inches) ; L,carnitLne Day Control L,carnitine L,cysteine 1 1.5 1.65 1.0 8 1.42 1.45 0.96 1.42 1.45 0.96 19 1.54 1.3 0.79 22 1.54 1.3 0.79 1.66 1.4 0.75 Average tumor change:
0.16 (0.25) (0.25) Percent of change:
+10.66% -15.15% -25.0%
Treatment discontinued day 25:
36 2.45 1.4 0.75 43 2.5 1.5 0.79 Tutor change day 1-43 1.0 (0.15) (0.21) Percent of change:
+G6.6~, -9.09Q -21.0%
i~;288~9 It is evident from the above data that carnitine when administered alone or in combination with Sistine was effective to reduce Thor size.
It is also to be noted that at an injection rate (imp.) of 3 gms./kil,o of body weight, plasma levels of L-carni-tine of greater than 15~M were observed. Since the half life of carnitine in plasma is only about 30 minutes, it is apparent that concentrations of carnitine of loom, as shown in the following Examples can be of clinical importance anti particularly since in Example 1 two injections of carn;tine at 3 gm~s/kilo of body weigh-t were given daily to the rats over a long period of time with no observable harmful effects.
3L22881g .
sample 2 Female Sprague-Da~ley rats with -the mammary terror as in Example 1 were injected respectively with L,carnitine and D-carnitine. Roy control rat received injections of an isotonic saline solution ~0.15 molar). The It and D-carnitine were injected imp. in the amounts specified in Example 1 the D-carnitine was injected in the skim amount as the L-carnitine). The injections were continued on a daily basis for 28 days. Misorient of the tumors was made just prior to the beginning of the injection regimen and at the end of the 28-day time period with the results shown in Table 2.
Tumor Size Ray Original 28-Day Control 3 x 2.5 in. 8.5 x 6.07 in.
L~carnitine injected 1.5 x 1.0 in. 3.00 in.
2.2 x 2.5 in.
D-carnitine injected 4.0 x 4.0 in. 6.57 in.
Visual inspection of the dissected fibroadenomas from the rats having received I.-carnitine revealed that the tumors were very soft, brownish in color and without the lobular growth pattern always observed in the dissected fibroadenomas from the control rats. In addition the fibroadenomas from the LrcarTIitine-treated rats skewed exceptionally high levels of both free and esterified carnitine. Moreover, pathological examination of the tumors from such treated rats showed that in three out of four rats the tenor tissue was dead.
J~xa~
ale effects of various concentrations of It and D-carni-tine were evaluated in their effects upon the proliferation oEVAC~ 5 human bowel cancer cell line in tissue culture in accordance with standard procedures (Symposium - (Ixok) Progress in Clinical and Biological Research, Vol. 48, "Cloning of Tlurnan Tumor Stern Cells", edited by S. E. Sallnon, Publisher - Arthur R. Loss Inc., Now York, pp. 332-338). The ~8~3~L9 Jo L- and D-carni-tine was added to the growth Madeline to achieve the concentrations indicated in 'fable 3. Results obtained are Schick in Table 3.
Treatment mount of Growth* Effect _ None (control) 95 L-carnitine 5mM 26 73% inhibition lam I 58 O.lr~l 52 45%
loD-carnitine firm 92 No inhibition lr~l 95 No inhibition O.lmM 113 19% stimulation *Growth is measured by the nunnery of colonies which appear.
It has also been found that in in vitro studies with tumor cells, the presence of long chain fatty acids, e.g.
palmitic, rustic oleic, Starkey, in the Greek medium appears to enhance the inhibitory effect of L-carnitine on the proliferation of tumor cells as is Chicano in the following Examples.
Example 4 A single cell suspension of Scholl cells, a colon tumor cell line, was prepared; the varying concentrators of both D-and L-carnitine specified in Table 4 were added to portions of this suspension. Lowe respective portions were then putted inn soft agrees ion welt. trays and inc~lba-tecl to l~mlit clarity of the sightless. 'Ire wells were Isolated for each treat~llent. The results were tallied my continue tulle colonies grown in each well and averayirly the three replicates. The results are Chicano byway lZ~38~9 -Grc~th of Control Ave. Grc~th (I Colonies in Treatment) Treatment (# of Colonies) Colonies in Control) 1. Control 152 -2,10 no ~-carnitine294 183%
3.1 nil D-carnitine231 143~
Detailed Description of the Invention Example 1 In the follc~ing Examples the I~earnitine was achninistered as tile free base (inner salt). The D-carnitine was also ac~ninistered as the free base.
Female Sprac~le-Dawley rats which spontaneously develop a benign ~el1-encapsulated menu tumor were utilized (the tumors were considered to be classic fibroadenomas composed of whorls and bundles of dense co~lacJen). The Sprague-Dawley mammary tumor is a standard model for human breast cancer. Six animals with tumors of various sizes were selected for each group to be ~22~8~g subjected to treatment. ~11 animals were maintained on a high fat diet.
One group of six animals was injected imp. with 3 gm/kilo of L-c~rnitine twice per day. A second set ox six animals received a like dose of D-carnitine. third set of six animals received 3 gmlkilo of L-carnitine and 1 gm~kilo of Sistine twice per day. The injections in each case were continued for 25 days with the tumor size being evaluated on days 8, 15, 19, 22 and 25. The animals Tory observed for an additional 17 days and the tumors evaluated or size on the Thea and ~3rd days.
Results are presented in the Table below.
Average Tumor Size: (inches) ; L,carnitLne Day Control L,carnitine L,cysteine 1 1.5 1.65 1.0 8 1.42 1.45 0.96 1.42 1.45 0.96 19 1.54 1.3 0.79 22 1.54 1.3 0.79 1.66 1.4 0.75 Average tumor change:
0.16 (0.25) (0.25) Percent of change:
+10.66% -15.15% -25.0%
Treatment discontinued day 25:
36 2.45 1.4 0.75 43 2.5 1.5 0.79 Tutor change day 1-43 1.0 (0.15) (0.21) Percent of change:
+G6.6~, -9.09Q -21.0%
i~;288~9 It is evident from the above data that carnitine when administered alone or in combination with Sistine was effective to reduce Thor size.
It is also to be noted that at an injection rate (imp.) of 3 gms./kil,o of body weight, plasma levels of L-carni-tine of greater than 15~M were observed. Since the half life of carnitine in plasma is only about 30 minutes, it is apparent that concentrations of carnitine of loom, as shown in the following Examples can be of clinical importance anti particularly since in Example 1 two injections of carn;tine at 3 gm~s/kilo of body weigh-t were given daily to the rats over a long period of time with no observable harmful effects.
3L22881g .
sample 2 Female Sprague-Da~ley rats with -the mammary terror as in Example 1 were injected respectively with L,carnitine and D-carnitine. Roy control rat received injections of an isotonic saline solution ~0.15 molar). The It and D-carnitine were injected imp. in the amounts specified in Example 1 the D-carnitine was injected in the skim amount as the L-carnitine). The injections were continued on a daily basis for 28 days. Misorient of the tumors was made just prior to the beginning of the injection regimen and at the end of the 28-day time period with the results shown in Table 2.
Tumor Size Ray Original 28-Day Control 3 x 2.5 in. 8.5 x 6.07 in.
L~carnitine injected 1.5 x 1.0 in. 3.00 in.
2.2 x 2.5 in.
D-carnitine injected 4.0 x 4.0 in. 6.57 in.
Visual inspection of the dissected fibroadenomas from the rats having received I.-carnitine revealed that the tumors were very soft, brownish in color and without the lobular growth pattern always observed in the dissected fibroadenomas from the control rats. In addition the fibroadenomas from the LrcarTIitine-treated rats skewed exceptionally high levels of both free and esterified carnitine. Moreover, pathological examination of the tumors from such treated rats showed that in three out of four rats the tenor tissue was dead.
J~xa~
ale effects of various concentrations of It and D-carni-tine were evaluated in their effects upon the proliferation oEVAC~ 5 human bowel cancer cell line in tissue culture in accordance with standard procedures (Symposium - (Ixok) Progress in Clinical and Biological Research, Vol. 48, "Cloning of Tlurnan Tumor Stern Cells", edited by S. E. Sallnon, Publisher - Arthur R. Loss Inc., Now York, pp. 332-338). The ~8~3~L9 Jo L- and D-carni-tine was added to the growth Madeline to achieve the concentrations indicated in 'fable 3. Results obtained are Schick in Table 3.
Treatment mount of Growth* Effect _ None (control) 95 L-carnitine 5mM 26 73% inhibition lam I 58 O.lr~l 52 45%
loD-carnitine firm 92 No inhibition lr~l 95 No inhibition O.lmM 113 19% stimulation *Growth is measured by the nunnery of colonies which appear.
It has also been found that in in vitro studies with tumor cells, the presence of long chain fatty acids, e.g.
palmitic, rustic oleic, Starkey, in the Greek medium appears to enhance the inhibitory effect of L-carnitine on the proliferation of tumor cells as is Chicano in the following Examples.
Example 4 A single cell suspension of Scholl cells, a colon tumor cell line, was prepared; the varying concentrators of both D-and L-carnitine specified in Table 4 were added to portions of this suspension. Lowe respective portions were then putted inn soft agrees ion welt. trays and inc~lba-tecl to l~mlit clarity of the sightless. 'Ire wells were Isolated for each treat~llent. The results were tallied my continue tulle colonies grown in each well and averayirly the three replicates. The results are Chicano byway lZ~38~9 -Grc~th of Control Ave. Grc~th (I Colonies in Treatment) Treatment (# of Colonies) Colonies in Control) 1. Control 152 -2,10 no ~-carnitine294 183%
3.1 nil D-carnitine231 143~
4.O.lmM D-carnitine245 152%
5.10 L-carnitine 97 60%
6.1 my L-carnitine 190 118%
7. 0.1 no L-carnitine 182 113%
8. Control 170 - -Average Growth represents the average of the actual number of colonies counted in the three wells of each treatment. % Growth of control represents how such growth took place in the carnitine treated trials in relation to the control trowels. 'this was calculated by dividing the overage Grcx~th of each treatment by 161 (the average growth of the two controls).
It is apparent -from the foregoing data that D-carnitine appears to stimulate growth at all concentrations shcx~7n while L-carnitine exhibits a concentration dependent decrease in kenning efficiency with increasing amount of L-carnitine.
Example 5 A suspension of SKYE, cellulose was prepared as in Example 4.
The varying concentrations of It and D-carnit;.ne cud pal.mitie acid and combinations of L- old D-carnitine with palmitic acid specified in Table 5 were added to portions of the cell sup-pension card plated in soft agrees in well trays in accord-ante with the procedure in Example 4. The results obtained, expressed as % inhibition of growth over the average of the control values Sheehan in Table 4, are set forth yin -the table ' ' below.
Jo i 88~9 additions to Cell % Inhibition Suspension of Growth 1. L-carnitirle Norm 30 2. L-carnitine lo 25 3. I.-carnitine (O.lr~M) 10 4. L-carnitine (loom) + O.Olr~M Palmitic acid (plates lost 5. L-carnitine lam + 0.01 Mel Palmitic acid 65 6. L-carnitine Old O.Olrn~ Punish acid 45 7. L-carnitine (O.OlmM) + Oilier Palmitic acid 20 8. D-carnit;ne (Lowry) slight stymie-lotion of growth
It is apparent -from the foregoing data that D-carnitine appears to stimulate growth at all concentrations shcx~7n while L-carnitine exhibits a concentration dependent decrease in kenning efficiency with increasing amount of L-carnitine.
Example 5 A suspension of SKYE, cellulose was prepared as in Example 4.
The varying concentrations of It and D-carnit;.ne cud pal.mitie acid and combinations of L- old D-carnitine with palmitic acid specified in Table 5 were added to portions of the cell sup-pension card plated in soft agrees in well trays in accord-ante with the procedure in Example 4. The results obtained, expressed as % inhibition of growth over the average of the control values Sheehan in Table 4, are set forth yin -the table ' ' below.
Jo i 88~9 additions to Cell % Inhibition Suspension of Growth 1. L-carnitirle Norm 30 2. L-carnitine lo 25 3. I.-carnitine (O.lr~M) 10 4. L-carnitine (loom) + O.Olr~M Palmitic acid (plates lost 5. L-carnitine lam + 0.01 Mel Palmitic acid 65 6. L-carnitine Old O.Olrn~ Punish acid 45 7. L-carnitine (O.OlmM) + Oilier Palmitic acid 20 8. D-carnit;ne (Lowry) slight stymie-lotion of growth
9. D-carnitine (lr~l) O
10. D-carnitine (Oilier) O
- 11. D-carnitine (Lomb O.OlmM Palrnitic acid 10
12. D-carnitine in + O.Olm~ Palmitic acid 10
13. Palmi-tic acid (O.OlmM) 15
14. Palmitic acid (0.05m~) 65 It is evident from the foregoing data that L-carnitine exhibits an anti-proliferative effect toward the SEIKO, colon tumor cell line and that such effect is enhanced by combination of the L-carnitine with palrnitic acid.
Utilizing the skim cell line as in Exar~?le 5, nude mice were injected subdermally with the viable tumor cells (it is well known in the art that such injection induces the growth of skin lesions on the nude mice). Immediately altar the subdural injection the control mice were injected with saline solution while the test nice were injected with L-carrlitille in an anoint equal to 3 Scholl of booty White.
It Wakeless observed tl-lLIt on those nice reccivirl~ the saline injection the expected slain lcsiolls row in the neural fashion whereas those injected with l,-carnitine habited no skin lessons.
In general, amounts of carnitine frock 1 to about 5 trams par kilo of a n~nal'x weiclht can be awful used for the Sue purpose of the present invention and where Sistine is used in conjunction, the amount of eysteine can range from about 0.5 to about 1.5 grams per kilo of a mammal's weight. When a fatty acid is used in conjunction with L-carnitine amounts can be used which will provide concentration of from Abbott 0.4~1 to about 1.2 my in the blood of the animal. mounts of fatty acid in excess of that which will provide concentrations in excess of 1.2 my should be avoided because of the potential toxic effects which may be associated with such greater lo concentrations.
Utilizing the skim cell line as in Exar~?le 5, nude mice were injected subdermally with the viable tumor cells (it is well known in the art that such injection induces the growth of skin lesions on the nude mice). Immediately altar the subdural injection the control mice were injected with saline solution while the test nice were injected with L-carrlitille in an anoint equal to 3 Scholl of booty White.
It Wakeless observed tl-lLIt on those nice reccivirl~ the saline injection the expected slain lcsiolls row in the neural fashion whereas those injected with l,-carnitine habited no skin lessons.
In general, amounts of carnitine frock 1 to about 5 trams par kilo of a n~nal'x weiclht can be awful used for the Sue purpose of the present invention and where Sistine is used in conjunction, the amount of eysteine can range from about 0.5 to about 1.5 grams per kilo of a mammal's weight. When a fatty acid is used in conjunction with L-carnitine amounts can be used which will provide concentration of from Abbott 0.4~1 to about 1.2 my in the blood of the animal. mounts of fatty acid in excess of that which will provide concentrations in excess of 1.2 my should be avoided because of the potential toxic effects which may be associated with such greater lo concentrations.
Claims (14)
- THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE
IS CLAIMED ARE DEFINED AS FOLLOWS:
l. A composition for combatting tumors in mammals which comprises L-carnitine in fluid injectable dosage form including a pharmaceutically acceptable inert carrier, said L-carnitine being present in an amount of between about 0.5 gm to about 1.5 gm per kilo animal weight. - 2. A composition as claimed in claim 1 comprising L-carnitine and cysteine in admixture.
- 3. A composition 25 claimed in claim 1 comprising L-carnitine and a long chain fatty acid in admixture.
- 4. A composition as claimed in claim 1 comprising L-carnitine, cysteine and a long chain fatty acid.
- 5. A composition as claimed in claim 3 or 4 wherein the long chain fatty acid is selected from palmitic, myristic, oleic and stearic acids.
- 6. A composition as claimed in claim 3 or 4 wherein the long chain fatty acid is palmitic acid.
- 7. A composition as claimed in claim 2 wherein the cysteine is present such that it can be administered to a mammal in an amount of from about 0.5 gm to about 1.5 gm per kilo of the mammal's weight.
- 8. A composition as claimed in claim 3 in unit dosage form and the long chain fatty acid is present such that it can be administered in an amount of from about 0.4 mM to about 1.2 mM per kilo of the mammal's weight.
- 9. A composition as claimed in claim 1, 2 or 3 wherein the tumor is a breast tumor.
- 10. A composition as claimed in claim 1, 2 or 3 wherein the mammal is human.
- 11. A composition as claimed in claim 1, 2 or 3 wherein the tumor is a colon tumor.
- 12. A composition as claimed in claim 7 or 8 wherein the tumor is a breast tumor.
- 13. A composition as claimed in claim 7 or 8 wherein the mammal is human.
- 14. A composition as claimed in claim 7 or 8 wherein the tumor is a colon tumor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41717982A | 1982-09-13 | 1982-09-13 | |
| US417,179 | 1982-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1228819A true CA1228819A (en) | 1987-11-03 |
Family
ID=23652899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000436310A Expired CA1228819A (en) | 1982-09-13 | 1983-09-08 | Method and compositions for combatting tumors |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS59130213A (en) |
| BE (1) | BE897738A (en) |
| CA (1) | CA1228819A (en) |
| IT (1) | IT1169460B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8388949B2 (en) | 2003-12-24 | 2013-03-05 | N.V. Nutricia | Compositions comprising pantothenic acid and their use for stimulating appetite |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0720860B2 (en) * | 1984-02-24 | 1995-03-08 | 理化学研究所 | Anti-cancer drug |
| US6316652B1 (en) * | 1995-06-06 | 2001-11-13 | Kosta Steliou | Drug mitochondrial targeting agents |
| EP1100589B1 (en) * | 1998-07-30 | 2005-01-19 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Use of propionyl l-carnitine and acetyl l-carnitine in the preparation of medicaments with anticancer activity |
-
1983
- 1983-09-06 IT IT22785/83A patent/IT1169460B/en active
- 1983-09-08 CA CA000436310A patent/CA1228819A/en not_active Expired
- 1983-09-12 BE BE0/211518A patent/BE897738A/en not_active IP Right Cessation
- 1983-09-13 JP JP58169097A patent/JPS59130213A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8388949B2 (en) | 2003-12-24 | 2013-03-05 | N.V. Nutricia | Compositions comprising pantothenic acid and their use for stimulating appetite |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8322785A0 (en) | 1983-09-06 |
| BE897738A (en) | 1984-01-02 |
| IT8322785A1 (en) | 1985-03-06 |
| IT1169460B (en) | 1987-05-27 |
| JPS59130213A (en) | 1984-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Khan et al. | Calcium oxalate urolithiasis in the rat: is it a model for human stone disease? A review of recent literature | |
| Fischer et al. | Growth of animal tissue cells in artificial media. | |
| DK2611439T3 (en) | PARENTERAL APPLICATION OF FISH OIL / DHA + EPA BEFORE OR AT THE BEGINNING OF CHEMOTHERAPY | |
| RU2013110491A (en) | USE OF ACID LYSOSOMIC LIPASE FOR TREATMENT OF ACID LYSOSOMIC LIPASE IN PATIENTS | |
| Dippenaar, N.,* Booyens, J.,* Fabbri, D.,* Engelbrecht, P.* & Katzeff | The reversibility of cancer: evidence that malignancy in human hepatoma cells is gamma-linolenic acid deficiency-dependent | |
| CA1228819A (en) | Method and compositions for combatting tumors | |
| KR100239946B1 (en) | The composition containing snapping turtle and tortoise, the preparation and the use thereof | |
| US4898886A (en) | Urea against adenocarcinoma | |
| US5744498A (en) | Inhibiting growth and spread of malignancy and retarding DNA breaks | |
| JP3319597B2 (en) | Β-aretin useful for cell culture and therapy | |
| Chun et al. | Combination immunotherapy of cancer in a mouse model: synergism between tumor necrosis factor and other defense systems | |
| JP7186253B2 (en) | Use of Morchella active substance | |
| AU2004244755B2 (en) | Combined pharmaceutical preparations for the treatment of cancer, containing glutaminase and antineoplastic anthracyclines or platinum compounds | |
| US6046241A (en) | β-alethine as anti-tumor agent | |
| EP0280593A2 (en) | Composition on the basis of an amino-acid and vitamins for use in cancer therapy | |
| JPS62263127A (en) | Remedy for tumor by self-derived lak cell, interleukin-2 andornithine decarboxylase inhibitor | |
| Ohya | Studies on the effect of the tissue substance" cornin" on transplantable malignant tumors in mice | |
| Jurin et al. | Porcine splenic peptides (Polyerga) decrease the number of experimental lung metastases in mice | |
| Holcenberg | Enhanced Effect of an L-Glutamine Antagonist, L-(aS, 5S)-α-Amino-3-chloro-4, 5-dihydro-5-isoxazoleacetic acid, by Acinetobacter L-Glutaminase-L-Asparaginase ¹ | |
| Umezawa | The Leeuwenhoek Lecture, 1982-Studies of microbial products in rising to the challenge of curing cancer | |
| US20230144882A1 (en) | Use of adenosine deaminase and adenosinedeaminase modifier in preparation of medicamentfor wound repair in patient with diabetes | |
| JPS62123128A (en) | Fresh water chlorella containing iodine and anti-cancer drug comprising same as main component | |
| CN113440601B (en) | Application of combination of NK cells and TFPI in preventing and treating nasopharyngeal carcinoma | |
| Berk, Lionel, Bauer, John L. & Castle | Folic acid: A report of 12 patients treated with synthetic pteroylglutamic acid: With comments on the pertinent literature | |
| US3496267A (en) | Pharmaceutical compositions containing lyophilized cardiac mitochondria |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |