CA1227427A - Therapeutic agent for the use in cancer treatment - Google Patents
Therapeutic agent for the use in cancer treatmentInfo
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- CA1227427A CA1227427A CA000461144A CA461144A CA1227427A CA 1227427 A CA1227427 A CA 1227427A CA 000461144 A CA000461144 A CA 000461144A CA 461144 A CA461144 A CA 461144A CA 1227427 A CA1227427 A CA 1227427A
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- tumor
- group
- cells
- polysulfate
- application
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Abstract
Abstract of the Disclosure Therapeutic Agent For The Use In Cancer Treatment Good results are obtained in the selective destruction of tumor cells when a glycosaminoglycan polysulfate, except heparin, is combined with a cytostatic drug.
The known serious secondary effects of the cytostatic drugs are considerably reduced by the combination.
The known serious secondary effects of the cytostatic drugs are considerably reduced by the combination.
Description
I '7 1 S p e c i f i c a t i o n This invention relates to a therapeutic preparation comprising a glycosaminoglycan polysulfate except heparin and at least one cytostatic drug besides otter common carriers and companion substances.
The conventional methods known in the treatment of malignant tumors are substantially restricted to either surgical and/or radiological treatments as well as to the application of cytostatic drugs the disadvantages of both the surgical and the radiological methods of treatment are known When cytostatic drugs are applied in the treatment of malignant tumors both the malignant and the healthy tissue cells are damaged and thus, the narrow bounds ox a therapy may also jeopardize the success of -the treatment in this case.
It is true that "Journal of Medicinal Chemistry 1974, volt 17, No. 12, page 1~35" teaches to increase the efficacy of the treatment of tumors with cytostatic drugs by simultaneously adding heparin. It has been noticed that patients who did no respond to the treatment with Cytostatic drums without heparin, responded better whey heparin was used as an accompanying agent However heparin is not the substance either, for engendering affection of tumor cells preferably when there is an increased number of such cells which would mean, that preferably tumors in the advanced stage could be treated in a particularly efficacious manner furthermore, one can proceed from the assumption that the problem ox serious; unwanted secondary effects is not solved even if the gl~cosaminogl~can pol~sulfate heparin is added to common cytostatic drugs.
~"7'~7 1 The tax underlit this invention thus resides in providing a therapeutic preparation which has a selective and intensified effect on malignant tumor cells, in particular if there is already a great number of such cells.
one preparation is meant to directly destroy these cells to a sigh degree without seriously affecting any healthy cells or health tissue.
this task is solved by the therapeutic preparation defined herein before. With the aid of the combination according lo to the invention it is possible to selectively "open"
the tumor cells Peg by damaging the membrane) and to concertedly introduce cytotoxically and cytolytically, respectively, effective substances, so that -these substances are effective even if the tumor is already in an advanced stage of growth.
Glycosaminoglycan polysulfates also described as sulfated polyanions or formerly designated mucopolysaccharide polo-sulfuric acid esters are known from the therapy ox various diseases. Substances counted among this family are, for example, heparins the coagulation characteristics of which have long been utilized. Other compounds of this class of substances are applied in the treatment of h~perlipoidaemiae and h~percholesteraemiae Peg heparins and hepari~oids~ or they are used as an anti arthritic Peg extracts of cartilage and chondroitin polysulfate) furthermore, the substances observed have been known to distinctively and specifically inhibit enzyme systems (Schaffrath et at. in: ~oppe-Seylers Z. Fishily. Chum.
I 499 (1976)). Investigations of biocytocultures revealed that - after incubative - malignant cells accumulate and store glycosaminoglycan polysulfates in a more intensive manner than benign cells Tao 1 Intensified accumulation of glycosaminoglycan polysulfate results in an inhibition of enzyme systems and thus, in an inhibition of biosynthetic performances in the cell metabolism of malignant cells. Hence a synergistic effect occurs in addition to the effect of the cytostatic drugs simultaneously applied, thus permitting that the latter can be used in concentrations which do either not or only slightly impair benign cells.
Comparative investigations between heparin and other gl~cosaminoglycan pol~sulfates, in particular chondroitin polysulfate have shown that the mode of action of glyco-saminoglycan polysulfates can indeed be different.
It has turned out that gl~cosaminoglycan polysulfates other than whopper are particularly characterized by an intensified effect occurring whenever the tumors already have a great number of cells. though there is no final scientific explanation for this selective mode Of Bavaria it is assumed that both kind and degree of sulfation are responsible for the phenomenon observed It has been absolutely surprising that glycosaminoglycan polysulfates other than heparin would show -this particularly advantageous mode of action According to the invention the following substances can be applied as cytostatic drugs: alkylating cytostatic drugs such as nitrogen mustard derivatives and ethyleneimine derivatives, a~timetabolites such as methotrexate, antagonists of Purina and pyrimidine bases, cytostatically effective antibiotic agents and alkaloids such as cholchicine or vincristin .
In accordance with the invention preferably chondroitin polysulfate is used as glycosaminogl~can polysulfate~
Furthermore, the task underlying the invention is solved by adding the proteolytic enwomb trypsin to the therapeutic preparation 1 The general biochemical expert knowledge includes that the effect of both substances is canceled to a certain degree by the proteol~tic enzyme try pin because of interaction with glycosa~inoglycan pol~sulfates.
Owing to these experiences the person skilled in the art has not been able to continue his work within the meaning of the present invention. Because of reciprocities between all substances used according to the invention, which have still not entirely been understood it is not an inhibiting effect that occurs but - in an absolutely unexpected miner - a synergistic one, as will be one by the experiments of the present patent application.
literature describes tr~psin as cytolytic substance.
It selectively attacks the malignant cell which has been already affected by additional application of a glycosamino-glycan polysulfate.
Addition of trypsin is important because there are biologically different resistant species also within one tumor cell family. such resistant tumor cells are enz~matically partially digested to permit the cytostatic drugs to become effective Tr~psin therefore increases the selective effect of the preparation according to the invention to malignant cells and thus enables concerted application of tiny doses of cytostatic drugs which would affect all cells if solely these drugs were applied in much larger therapeutic doses 'the tumor cells are selectively "opened" by the glycosamino-glycan polysulfate, if desired, together with trypsin9 with cytotoxically and cytol~tically, respectively effective substances being concertedly introduced.
'the preparation according to the invention can parenterall~
be given.
'the therapeutic individual dose of the therapeutic preparation ranges between 5 and OWE my.
'7 1 the quantity ratio of gl~cosaninoglycan pol~sulfate -to cytostatic drugs ranges between 10:1 and 1:10 with regard to parts by weight ox the active substances.
the quantity ox cytostatic drums depends on the kind of cytostatic drugs used.
the invention is explained by the following experiments.
'the following pharmacological active substances have been applied in these experiments:
a) glycosaminoglycan pol~sul~ates:
lo 1. chondroitin polysulfate polysulfated chondroitin of bovine tracheal cartilage; disaccharide units consisting of D-glucuronic acid and acutely galactosamine;
Content owe hexosamine: 10~ Molly my thereof approximately I ox galactosamine glucuronic acid: 97~3 pmol/100 my
The conventional methods known in the treatment of malignant tumors are substantially restricted to either surgical and/or radiological treatments as well as to the application of cytostatic drugs the disadvantages of both the surgical and the radiological methods of treatment are known When cytostatic drugs are applied in the treatment of malignant tumors both the malignant and the healthy tissue cells are damaged and thus, the narrow bounds ox a therapy may also jeopardize the success of -the treatment in this case.
It is true that "Journal of Medicinal Chemistry 1974, volt 17, No. 12, page 1~35" teaches to increase the efficacy of the treatment of tumors with cytostatic drugs by simultaneously adding heparin. It has been noticed that patients who did no respond to the treatment with Cytostatic drums without heparin, responded better whey heparin was used as an accompanying agent However heparin is not the substance either, for engendering affection of tumor cells preferably when there is an increased number of such cells which would mean, that preferably tumors in the advanced stage could be treated in a particularly efficacious manner furthermore, one can proceed from the assumption that the problem ox serious; unwanted secondary effects is not solved even if the gl~cosaminogl~can pol~sulfate heparin is added to common cytostatic drugs.
~"7'~7 1 The tax underlit this invention thus resides in providing a therapeutic preparation which has a selective and intensified effect on malignant tumor cells, in particular if there is already a great number of such cells.
one preparation is meant to directly destroy these cells to a sigh degree without seriously affecting any healthy cells or health tissue.
this task is solved by the therapeutic preparation defined herein before. With the aid of the combination according lo to the invention it is possible to selectively "open"
the tumor cells Peg by damaging the membrane) and to concertedly introduce cytotoxically and cytolytically, respectively, effective substances, so that -these substances are effective even if the tumor is already in an advanced stage of growth.
Glycosaminoglycan polysulfates also described as sulfated polyanions or formerly designated mucopolysaccharide polo-sulfuric acid esters are known from the therapy ox various diseases. Substances counted among this family are, for example, heparins the coagulation characteristics of which have long been utilized. Other compounds of this class of substances are applied in the treatment of h~perlipoidaemiae and h~percholesteraemiae Peg heparins and hepari~oids~ or they are used as an anti arthritic Peg extracts of cartilage and chondroitin polysulfate) furthermore, the substances observed have been known to distinctively and specifically inhibit enzyme systems (Schaffrath et at. in: ~oppe-Seylers Z. Fishily. Chum.
I 499 (1976)). Investigations of biocytocultures revealed that - after incubative - malignant cells accumulate and store glycosaminoglycan polysulfates in a more intensive manner than benign cells Tao 1 Intensified accumulation of glycosaminoglycan polysulfate results in an inhibition of enzyme systems and thus, in an inhibition of biosynthetic performances in the cell metabolism of malignant cells. Hence a synergistic effect occurs in addition to the effect of the cytostatic drugs simultaneously applied, thus permitting that the latter can be used in concentrations which do either not or only slightly impair benign cells.
Comparative investigations between heparin and other gl~cosaminoglycan pol~sulfates, in particular chondroitin polysulfate have shown that the mode of action of glyco-saminoglycan polysulfates can indeed be different.
It has turned out that gl~cosaminoglycan polysulfates other than whopper are particularly characterized by an intensified effect occurring whenever the tumors already have a great number of cells. though there is no final scientific explanation for this selective mode Of Bavaria it is assumed that both kind and degree of sulfation are responsible for the phenomenon observed It has been absolutely surprising that glycosaminoglycan polysulfates other than heparin would show -this particularly advantageous mode of action According to the invention the following substances can be applied as cytostatic drugs: alkylating cytostatic drugs such as nitrogen mustard derivatives and ethyleneimine derivatives, a~timetabolites such as methotrexate, antagonists of Purina and pyrimidine bases, cytostatically effective antibiotic agents and alkaloids such as cholchicine or vincristin .
In accordance with the invention preferably chondroitin polysulfate is used as glycosaminogl~can polysulfate~
Furthermore, the task underlying the invention is solved by adding the proteolytic enwomb trypsin to the therapeutic preparation 1 The general biochemical expert knowledge includes that the effect of both substances is canceled to a certain degree by the proteol~tic enzyme try pin because of interaction with glycosa~inoglycan pol~sulfates.
Owing to these experiences the person skilled in the art has not been able to continue his work within the meaning of the present invention. Because of reciprocities between all substances used according to the invention, which have still not entirely been understood it is not an inhibiting effect that occurs but - in an absolutely unexpected miner - a synergistic one, as will be one by the experiments of the present patent application.
literature describes tr~psin as cytolytic substance.
It selectively attacks the malignant cell which has been already affected by additional application of a glycosamino-glycan polysulfate.
Addition of trypsin is important because there are biologically different resistant species also within one tumor cell family. such resistant tumor cells are enz~matically partially digested to permit the cytostatic drugs to become effective Tr~psin therefore increases the selective effect of the preparation according to the invention to malignant cells and thus enables concerted application of tiny doses of cytostatic drugs which would affect all cells if solely these drugs were applied in much larger therapeutic doses 'the tumor cells are selectively "opened" by the glycosamino-glycan polysulfate, if desired, together with trypsin9 with cytotoxically and cytol~tically, respectively effective substances being concertedly introduced.
'the preparation according to the invention can parenterall~
be given.
'the therapeutic individual dose of the therapeutic preparation ranges between 5 and OWE my.
'7 1 the quantity ratio of gl~cosaninoglycan pol~sulfate -to cytostatic drugs ranges between 10:1 and 1:10 with regard to parts by weight ox the active substances.
the quantity ox cytostatic drums depends on the kind of cytostatic drugs used.
the invention is explained by the following experiments.
'the following pharmacological active substances have been applied in these experiments:
a) glycosaminoglycan pol~sul~ates:
lo 1. chondroitin polysulfate polysulfated chondroitin of bovine tracheal cartilage; disaccharide units consisting of D-glucuronic acid and acutely galactosamine;
Content owe hexosamine: 10~ Molly my thereof approximately I ox galactosamine glucuronic acid: 97~3 pmol/100 my
2. hepa~in-sodium continuity: OWE%
hexosamine: 152 Molly my ~glucosamin~: 145 ymol/
100 my, galactosamine:
0.02 pmol~100 my) ironic Acadia Molly my b) cytostatic drugs:
cyclophosphamide 2'7 ~erir~ent 1 72 homosexual rats (pry Doyle) were randomized in 6 groups, the individual groups were treated with the following active substances:
Group A: sodium heparin c~clophosphamide Group B: sodium heparin Group C: chondroitin polysulfate -I cyclophospha~ide Group D: chondroitin polysulfate Group I: c~clophosphamide lo Group I: control or tumor transmission each animal was inoculated with 20~000 cells of a Yoshida~ascites-sarcoma~
the rats were given the hollowing doses of the active agents (per kg rat):
cyclophosphamide 25 mg/kg sodium heparin 10 mg/kg cho~droitin polysulfate 10 mg/kg Therapy started 24 hours after the tumor had been communicated temporal sequence ox the experiment 1. Application of the therapeutically active substances 24 hours after Auschwitz inoculation;
2. application of the therapeutically active substances 28 hours after Auschwitz inoculation;
hexosamine: 152 Molly my ~glucosamin~: 145 ymol/
100 my, galactosamine:
0.02 pmol~100 my) ironic Acadia Molly my b) cytostatic drugs:
cyclophosphamide 2'7 ~erir~ent 1 72 homosexual rats (pry Doyle) were randomized in 6 groups, the individual groups were treated with the following active substances:
Group A: sodium heparin c~clophosphamide Group B: sodium heparin Group C: chondroitin polysulfate -I cyclophospha~ide Group D: chondroitin polysulfate Group I: c~clophosphamide lo Group I: control or tumor transmission each animal was inoculated with 20~000 cells of a Yoshida~ascites-sarcoma~
the rats were given the hollowing doses of the active agents (per kg rat):
cyclophosphamide 25 mg/kg sodium heparin 10 mg/kg cho~droitin polysulfate 10 mg/kg Therapy started 24 hours after the tumor had been communicated temporal sequence ox the experiment 1. Application of the therapeutically active substances 24 hours after Auschwitz inoculation;
2. application of the therapeutically active substances 28 hours after Auschwitz inoculation;
3. application of the therapeutically active substances 72 hours after Auschwitz inoculation.
l 3 weeks after the last application the results ox the export were valuated.
A table has been draw up ox the results:
Table 1 group withalive~ree from a dead hazing a 12 animals tumor tumor . ,...... _ Jo 1 1 11 '11 C 11 11 'I
lo D 0 0 12 12 Experiment 2 12 female rats (Sprague Hawley) were randomized in 2 groups or tumor transmission each animal was inoculated with 20,000 cells of a Yoshida-ascites-sarcoma.
the rats were given the following doses ox the active substances (per kg rat):
c~clophosphamide 25 mg/kg sodium heparin 10 mg/kg chondroitin pol~sul~ate 10 mg/kg Start of the therapy: 48 hours after tumor transmission 1 After the first application given 48 hours Atari the tumor had been communicated six further applications followed Group a . of the animals was treated with sodium heparin +
cyclopho sphamide .
Group b. of the animals was treated with chondroitin polyp sulfate cyclophosphamide~ A table 2 has been drawn up of the results.
able 2 10 Group with alive tree prom a dead having a 12 animals tumor tumor -- _ _ . _ a 2 2 10 9 by 8 6 It definitely emerges from the results of both experiments 1 and 2 that chondroitin polysulfate acts on malignant cells in a surprisingly better anywhere if there is already an increased number ox such cells. Equally good effect is achieved by the addition of heparin and chondroitin polyp sulfate in case the substances are applied very early, that is, at least 24 hours after the tumor has been communicated Chondroitin polysulfate obviously causes cytostatic drugs to be incorporated also when the cells are in their resting stage. Cytostatic drugs alone and cytostatic drugs and heparin, respectively, destroy tumor cells almost only in a ~itotic stage that is in a phase when the cells are divided. to static drugs and heparin are only slightly superior to cytostatic drugs alone 2'-7 1 It a first clinical application extending over a period of 18 months the two-substance combination glycosamino-glycan polysulfate, except heparin, and cytostatic drug was tested on 125 persons suffering from various tumors such as, for example, carcinoma of the breast, Castro-intestinal carcinoma bronchial carcinoma, melanoma and cancer of the over. In addition to the particular effectiveness to tumors having a great number ox cells, it has moreover been observed - and this is a very 10 decisive innovation - that the know considerable secondary effects of the cytostatic drugs (mitomycin, endoxan, vincristin~ adriblastin) could be clearly reduce Above all, younger women did either not or only slightly suffer from loss of hair. Generally there was no sickness, no vomiting and no diarrhea. What has to be particularly emphasized is the fact, that the injuries of the medulla of a bone caused by cytostatic drums could be remarkably reduced.
Both subjective and objective negative secondary effects of the sole chemotherapy of cancer are thus either reduced or canceled by adding a glycosaminoglycan polysul~ate, except heparin, to a cytostatic drug, with a decisive improvement of the effect to malignant tumors being simultaneously achieved.
All effects of the described combination of active substances according to the invention which have been mentioned herein before, constitute significant innovations hitherto unknown but extraordinarily important for the treatment of malignant tumors.
-- Jo -1 Experiment 36 female rats Sprague Doyle) were divided into 3 groups.
The animals were assigned to the groups according to the usual randomization.
Kind of tumor: Yoshida-ascites (Homer c) Number of cells of Yos~;da-ascites inoculation: approximately 20,000 Beginning of the therapy: 48 hours (!) after the tumor has been inoculated.
Group A: chond~oitin polysulfate trgpsin lo Group I: chondroitin polysulfate + trypsin cyclophosphamide Group C: control Doses of the pharmacological active substances:
chondroitin polysulfate 12 mg/kg trypsin 6 mg/kg cyclophosphamide 26 mg/kg temporal sequence of the experiment 1. Application of the therapeutically active substances 48 hours after Auschwitz inoculation;
2. application of the therapeutically active substances I 3 days after Auschwitz inoculation;
3, application of the therapeutically active substances
l 3 weeks after the last application the results ox the export were valuated.
A table has been draw up ox the results:
Table 1 group withalive~ree from a dead hazing a 12 animals tumor tumor . ,...... _ Jo 1 1 11 '11 C 11 11 'I
lo D 0 0 12 12 Experiment 2 12 female rats (Sprague Hawley) were randomized in 2 groups or tumor transmission each animal was inoculated with 20,000 cells of a Yoshida-ascites-sarcoma.
the rats were given the following doses ox the active substances (per kg rat):
c~clophosphamide 25 mg/kg sodium heparin 10 mg/kg chondroitin pol~sul~ate 10 mg/kg Start of the therapy: 48 hours after tumor transmission 1 After the first application given 48 hours Atari the tumor had been communicated six further applications followed Group a . of the animals was treated with sodium heparin +
cyclopho sphamide .
Group b. of the animals was treated with chondroitin polyp sulfate cyclophosphamide~ A table 2 has been drawn up of the results.
able 2 10 Group with alive tree prom a dead having a 12 animals tumor tumor -- _ _ . _ a 2 2 10 9 by 8 6 It definitely emerges from the results of both experiments 1 and 2 that chondroitin polysulfate acts on malignant cells in a surprisingly better anywhere if there is already an increased number ox such cells. Equally good effect is achieved by the addition of heparin and chondroitin polyp sulfate in case the substances are applied very early, that is, at least 24 hours after the tumor has been communicated Chondroitin polysulfate obviously causes cytostatic drugs to be incorporated also when the cells are in their resting stage. Cytostatic drugs alone and cytostatic drugs and heparin, respectively, destroy tumor cells almost only in a ~itotic stage that is in a phase when the cells are divided. to static drugs and heparin are only slightly superior to cytostatic drugs alone 2'-7 1 It a first clinical application extending over a period of 18 months the two-substance combination glycosamino-glycan polysulfate, except heparin, and cytostatic drug was tested on 125 persons suffering from various tumors such as, for example, carcinoma of the breast, Castro-intestinal carcinoma bronchial carcinoma, melanoma and cancer of the over. In addition to the particular effectiveness to tumors having a great number ox cells, it has moreover been observed - and this is a very 10 decisive innovation - that the know considerable secondary effects of the cytostatic drugs (mitomycin, endoxan, vincristin~ adriblastin) could be clearly reduce Above all, younger women did either not or only slightly suffer from loss of hair. Generally there was no sickness, no vomiting and no diarrhea. What has to be particularly emphasized is the fact, that the injuries of the medulla of a bone caused by cytostatic drums could be remarkably reduced.
Both subjective and objective negative secondary effects of the sole chemotherapy of cancer are thus either reduced or canceled by adding a glycosaminoglycan polysul~ate, except heparin, to a cytostatic drug, with a decisive improvement of the effect to malignant tumors being simultaneously achieved.
All effects of the described combination of active substances according to the invention which have been mentioned herein before, constitute significant innovations hitherto unknown but extraordinarily important for the treatment of malignant tumors.
-- Jo -1 Experiment 36 female rats Sprague Doyle) were divided into 3 groups.
The animals were assigned to the groups according to the usual randomization.
Kind of tumor: Yoshida-ascites (Homer c) Number of cells of Yos~;da-ascites inoculation: approximately 20,000 Beginning of the therapy: 48 hours (!) after the tumor has been inoculated.
Group A: chond~oitin polysulfate trgpsin lo Group I: chondroitin polysulfate + trypsin cyclophosphamide Group C: control Doses of the pharmacological active substances:
chondroitin polysulfate 12 mg/kg trypsin 6 mg/kg cyclophosphamide 26 mg/kg temporal sequence of the experiment 1. Application of the therapeutically active substances 48 hours after Auschwitz inoculation;
2. application of the therapeutically active substances I 3 days after Auschwitz inoculation;
3, application of the therapeutically active substances
4 days after Auschwitz inoculation.
Jo Y
1 JO application ox the therapelltically active substances 6 days after Auschwitz inoculation;
jesting of the e~ficac~:
I days after the Yoshida-ascites tumor has been inoculated table 3 has been drawn up of the results.
Group with alive free from ahead having a 12 animals tumor tumor _ .. . __ _ lo 8 8 4 4 Experiment 3 was partly repeated.
36 female rats (Sprague Hawley) were divided in-to 3 groups.
the animals were assigned to the groups according to the process of randomization.
find of tumor: Yoshida-ascites (hemorrhagic) umber of cells upon tumor inoculation: 20,000 Beginning ox the therapy: 2 days after tumor inoculation 20 group A : chondroitin polysulfate12 mug trypsin mg/kg cyclophosphamide26 mg/kg Group : control Group C : cyclophosphamide26 mg/kg 1 1. Application of -the -therapeutically active substances 2 days after tutor transmission (20,000 cells of the Yoshida-ascites-sarcoma);
2. application of the therapeutically active substances 3 days after tumor transmission;
3. application of the therapeutically active substances
Jo Y
1 JO application ox the therapelltically active substances 6 days after Auschwitz inoculation;
jesting of the e~ficac~:
I days after the Yoshida-ascites tumor has been inoculated table 3 has been drawn up of the results.
Group with alive free from ahead having a 12 animals tumor tumor _ .. . __ _ lo 8 8 4 4 Experiment 3 was partly repeated.
36 female rats (Sprague Hawley) were divided in-to 3 groups.
the animals were assigned to the groups according to the process of randomization.
find of tumor: Yoshida-ascites (hemorrhagic) umber of cells upon tumor inoculation: 20,000 Beginning ox the therapy: 2 days after tumor inoculation 20 group A : chondroitin polysulfate12 mug trypsin mg/kg cyclophosphamide26 mg/kg Group : control Group C : cyclophosphamide26 mg/kg 1 1. Application of -the -therapeutically active substances 2 days after tutor transmission (20,000 cells of the Yoshida-ascites-sarcoma);
2. application of the therapeutically active substances 3 days after tumor transmission;
3. application of the therapeutically active substances
5 days after tutor transmission;
4. application of the therapeutically active substances 7 days after tumor transmission Examination of the test results after 21 days.
A table 4 has been drawn up of the results.
table 4 . . .
Group with alive free from a dead having a 12 animals tumor tumor _ _ __ Similar to the foregoing experiments 24 female rats (Sprague Doyle) were randomized.
umber of groups: 2 tumor : Yoshida-ascites (hemorrhagic) Mummer of cells upon tumor inoculation: approx, 23~000 Group A : chondroitin polysulfate 12 mg/kg -I trypsin my c~clophosphamide 25 mg~kg Group : control 1 Temporal sequence ox the experiment:
tart ox the therapy (1. application of the therapeutically active substances 2 days after tumor transmission 2. application 3 days after tumor transmission, 3. application 4 days after tumor transmission, 4 application 5 days after tumor transmission, 5. application 6 days after tumor transmission
4. application of the therapeutically active substances 7 days after tumor transmission Examination of the test results after 21 days.
A table 4 has been drawn up of the results.
table 4 . . .
Group with alive free from a dead having a 12 animals tumor tumor _ _ __ Similar to the foregoing experiments 24 female rats (Sprague Doyle) were randomized.
umber of groups: 2 tumor : Yoshida-ascites (hemorrhagic) Mummer of cells upon tumor inoculation: approx, 23~000 Group A : chondroitin polysulfate 12 mg/kg -I trypsin my c~clophosphamide 25 mg~kg Group : control 1 Temporal sequence ox the experiment:
tart ox the therapy (1. application of the therapeutically active substances 2 days after tumor transmission 2. application 3 days after tumor transmission, 3. application 4 days after tumor transmission, 4 application 5 days after tumor transmission, 5. application 6 days after tumor transmission
6. application 7 days alter tumor transmission).
Examination of the results 21 days after inoculation of lo the tumor.
table has been drawn up ox the results.
Table Group with alive tree prom a dead having a 12 animals tumor in this tumor f~Sroup _ . _ _ Jo tumor could be found in the deceased animal of group AD
the cause ox death has not been cleared the results of the experiments show that the experimental animals exclusively treated Thea the cytostatic drug cycle-phosphamide have died of the growth of the tumor in the course of the experiment similar to the control group The experimental animals which have been given the cytostatic drug cyclophosphamide together with a ~lycosaminoglycan polysul~ate and in addition trypsin have shown a significantly lengthened lifetime and partly, no growth ox a tumor. When the group By D and E in experiment 1 as jell as group in experiment 3 and group C in experiment 4 30 are compared with the groups A and G in experiment 1, group :13 in experiment 3, group in experiment 4 an group A in experiment 5 the synergistic effect owe the preparation r7 I
awkward; to the invention dental roulettes,.
histological and cytochemical e2~minatio3ls carried out parallel to the animal e~eriment~ show that a largely selective effect to malignaIIt cell con be obtained 5 by the combination OX the substances applied Experiment 6 60 female rat (Sprague Hawley) were classified into tree groups (randomized).
wind of tumor: ~oshida-ascit~s (hemorrhagic) 10 Fumier of cells of the ~roshida-ascites inoculation: appear.
2û,~)00 tart of the Thorpe: 24 hours after i~oclllation Group JO cho~droitin polysulfate c;srclophosphamide + to in 15 Group B: chondroitin polysulfate + cyclopho~pha~ide Group C: control Doses of the pharmacological active substances:
chondroiti~ pol~sul~ate 12 go per kg c~5rclopho~phamide (trademark: Endoxan) 24 go per kg Tropez 6 go / per kg temporal sequence of the application:
application of the aforementioned combination 24 hours after tumor inoculation. P~rther applications daily ox the whole sever applications.
table 6 has been drawn up of the results.
1';"~7 l Table 6 -Group with alive free from ahead having a 20 animals tutor tumor _ . .
this experiment was repeated. table 7 has been drawn up of the results.
able Z
10 Group with alive free from a dead having a 20 animals tumor tumor I_ __ As is especially shown by the results of experiment 6 a particular synergistic effect results prom the combination of the cytostatic drug cyclophosphamide and chondroiti~
polysulfate and trypsinr It seems that a still not entirely understood reciprocity between the chondroitin polysulfate and trypsin entails an increased permeability of the malignant cells to the cytostatic drugs.
The experiments 3 to 6, in which the composition: cho~droitin polysul~ate + cyclophosphamide + trypsin was respectively compared with either chondroitin polysulfa~e trypsin or c~clophosphamide or sully with a control or with chondroitin I
'7 1 polysulfate + cyclophosphamide definitely prove that the combination according to the invention is surprisingly superior Each of -the experiments 3 to 6 individually shows that the chance of survival of the experimental animals is increased to a disproportionately high degree when the active substance combination of chondroitin polysulfate, trypsin and cyclophosphamide is administered.
In addition to the particular effectiveness to tumors having a great number of cells, it has been observed as has already been mentioned, that the aggravating secondary effects of the cytostatic drugs could be substantially reduced - and this is an absolutely decisive innovation -yin particular, younger women did oft or not or only slightly surfer from loss of hair furthermore, twerp was generally no sickness, no vomiting and no diarrhea.
What has to be particularly emphasized is the fact that the injuries of the medulla of a bone caused by -the cytostatic drugs could be remarkably reduced.
Examination of the results 21 days after inoculation of lo the tumor.
table has been drawn up ox the results.
Table Group with alive tree prom a dead having a 12 animals tumor in this tumor f~Sroup _ . _ _ Jo tumor could be found in the deceased animal of group AD
the cause ox death has not been cleared the results of the experiments show that the experimental animals exclusively treated Thea the cytostatic drug cycle-phosphamide have died of the growth of the tumor in the course of the experiment similar to the control group The experimental animals which have been given the cytostatic drug cyclophosphamide together with a ~lycosaminoglycan polysul~ate and in addition trypsin have shown a significantly lengthened lifetime and partly, no growth ox a tumor. When the group By D and E in experiment 1 as jell as group in experiment 3 and group C in experiment 4 30 are compared with the groups A and G in experiment 1, group :13 in experiment 3, group in experiment 4 an group A in experiment 5 the synergistic effect owe the preparation r7 I
awkward; to the invention dental roulettes,.
histological and cytochemical e2~minatio3ls carried out parallel to the animal e~eriment~ show that a largely selective effect to malignaIIt cell con be obtained 5 by the combination OX the substances applied Experiment 6 60 female rat (Sprague Hawley) were classified into tree groups (randomized).
wind of tumor: ~oshida-ascit~s (hemorrhagic) 10 Fumier of cells of the ~roshida-ascites inoculation: appear.
2û,~)00 tart of the Thorpe: 24 hours after i~oclllation Group JO cho~droitin polysulfate c;srclophosphamide + to in 15 Group B: chondroitin polysulfate + cyclopho~pha~ide Group C: control Doses of the pharmacological active substances:
chondroiti~ pol~sul~ate 12 go per kg c~5rclopho~phamide (trademark: Endoxan) 24 go per kg Tropez 6 go / per kg temporal sequence of the application:
application of the aforementioned combination 24 hours after tumor inoculation. P~rther applications daily ox the whole sever applications.
table 6 has been drawn up of the results.
1';"~7 l Table 6 -Group with alive free from ahead having a 20 animals tutor tumor _ . .
this experiment was repeated. table 7 has been drawn up of the results.
able Z
10 Group with alive free from a dead having a 20 animals tumor tumor I_ __ As is especially shown by the results of experiment 6 a particular synergistic effect results prom the combination of the cytostatic drug cyclophosphamide and chondroiti~
polysulfate and trypsinr It seems that a still not entirely understood reciprocity between the chondroitin polysulfate and trypsin entails an increased permeability of the malignant cells to the cytostatic drugs.
The experiments 3 to 6, in which the composition: cho~droitin polysul~ate + cyclophosphamide + trypsin was respectively compared with either chondroitin polysulfa~e trypsin or c~clophosphamide or sully with a control or with chondroitin I
'7 1 polysulfate + cyclophosphamide definitely prove that the combination according to the invention is surprisingly superior Each of -the experiments 3 to 6 individually shows that the chance of survival of the experimental animals is increased to a disproportionately high degree when the active substance combination of chondroitin polysulfate, trypsin and cyclophosphamide is administered.
In addition to the particular effectiveness to tumors having a great number of cells, it has been observed as has already been mentioned, that the aggravating secondary effects of the cytostatic drugs could be substantially reduced - and this is an absolutely decisive innovation -yin particular, younger women did oft or not or only slightly surfer from loss of hair furthermore, twerp was generally no sickness, no vomiting and no diarrhea.
What has to be particularly emphasized is the fact that the injuries of the medulla of a bone caused by -the cytostatic drugs could be remarkably reduced.
Claims (4)
1. A therapeutic preparation which comprises at least one glycosaminoglycan polysulfate, except heparin, and at least one cytostatic drug besides other common carriers and companion substances.
2. A therapeutic preparation according to claim 1 characterized in that the glycosaminoglycan polysulfate is chondroitin polysulfate.
3. A therapeutic preparation according to claim 1 or claim 2 characterized in that trypsin is additionally contained in said preparation.
4. A therapeutic preparation according to claim 1 characterized in that the quantity ratio of the glycosaminoglycan polysulfate to the cytostatic drug ranges from 10:1 to 1:10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000461144A CA1227427A (en) | 1984-08-16 | 1984-08-16 | Therapeutic agent for the use in cancer treatment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000461144A CA1227427A (en) | 1984-08-16 | 1984-08-16 | Therapeutic agent for the use in cancer treatment |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1227427A true CA1227427A (en) | 1987-09-29 |
Family
ID=4128538
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000461144A Expired CA1227427A (en) | 1984-08-16 | 1984-08-16 | Therapeutic agent for the use in cancer treatment |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1227427A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000041730A1 (en) * | 1999-01-13 | 2000-07-20 | Meditech Research Limited | A composition and method for the enhancement of the efficacy of drugs |
| US8287894B2 (en) | 2000-07-14 | 2012-10-16 | Alchemia Oncology Pty Limited | Hyaluronan as a drug pre-sensitizer and chemo-sensitizer in the treatment of disease |
| US8623354B2 (en) | 2005-09-07 | 2014-01-07 | Alchemia Oncology Pty Limited | Therapeutic compositions comprising hyaluronan and therapeutic antibodies as well as methods of treatment |
| US8937052B2 (en) | 2005-07-27 | 2015-01-20 | Alchemia Oncology Pty Limited | Therapeutic protocols using hyaluronan |
| US9066919B2 (en) | 2000-07-14 | 2015-06-30 | Alchemia Oncology Pty Limited | Hyaluronan as a chemo-sensitizer in the treatment of cancer |
-
1984
- 1984-08-16 CA CA000461144A patent/CA1227427A/en not_active Expired
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000041730A1 (en) * | 1999-01-13 | 2000-07-20 | Meditech Research Limited | A composition and method for the enhancement of the efficacy of drugs |
| US8741970B2 (en) | 1999-01-13 | 2014-06-03 | Alchemia Oncology Pty Limited | Composition and method for the enhancement of the efficacy of drugs |
| US8287894B2 (en) | 2000-07-14 | 2012-10-16 | Alchemia Oncology Pty Limited | Hyaluronan as a drug pre-sensitizer and chemo-sensitizer in the treatment of disease |
| US8388993B2 (en) | 2000-07-14 | 2013-03-05 | Alchemia Oncology Pty Limited | Hyaluronan-chemotherapeutic agent formulations for the treatment of colon cancer |
| US9066919B2 (en) | 2000-07-14 | 2015-06-30 | Alchemia Oncology Pty Limited | Hyaluronan as a chemo-sensitizer in the treatment of cancer |
| US8937052B2 (en) | 2005-07-27 | 2015-01-20 | Alchemia Oncology Pty Limited | Therapeutic protocols using hyaluronan |
| US8623354B2 (en) | 2005-09-07 | 2014-01-07 | Alchemia Oncology Pty Limited | Therapeutic compositions comprising hyaluronan and therapeutic antibodies as well as methods of treatment |
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