CA1194802A - Pharmaceutical composition possessing antitumor activity - Google Patents
Pharmaceutical composition possessing antitumor activityInfo
- Publication number
- CA1194802A CA1194802A CA000413032A CA413032A CA1194802A CA 1194802 A CA1194802 A CA 1194802A CA 000413032 A CA000413032 A CA 000413032A CA 413032 A CA413032 A CA 413032A CA 1194802 A CA1194802 A CA 1194802A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- pharmaceutical
- tion
- tumor
- antitumor activity
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition possessing antitumor activity and comprising as an active principle, polyhexa-methyleneguanidine phosphate of the general formula:
wherein n = 2-5, R is NH2; R1 is NH2;
A pharmaceutical composition possessing antitumor activity and comprising as an active principle, polyhexa-methyleneguanidine phosphate of the general formula:
wherein n = 2-5, R is NH2; R1 is NH2;
Description
PHA~.~ACEU'~ICI~I. CO~POSI'~IOI~ POSSESSING A~
~ lOR ACq'IVITY
'I'he present invention relates to pharmacautical eom-positions aLlcl 7 More speci~ically, -to a novel pharmacelltie-al composition porsessing anti-tumor aetivitg and ''n-tended ~or the trea-tment o~ gastro-intestina:l anc~ breas-t eaneer 3 as well as for the trea-tLnent o~ wounds a~'-ter -the radieal opera-tion of a tumor.
At present various an-titumor preparations are known in the ar-t. Aceording to the meehanism Oe thei:r aetion, -they are elassiL'ied in-to 4 groups: an-timetabolites, alk~l-ating agents 9 iL~tercalatlng agen-ts and mitosis inhibi-tors.
The meehaL1isln Oe aetion o:~ these eompounds is associated with their eefeet on the synthesis and ~unetionin~ o~ LlU-eleie aeids (e~. t'Chemotherapy O:e ~alignan-t T~lmors"1 ed.
by N~N. Blol~hin, ~lioscow9 I~,'leditsina Publishin~ House9~1977).
In mos-t eases seleetivity Oe -the prior art prepara-tions e~iIeet on -tumor cells is lo-ii, since they a~'~ect me-tabolism o~ normal cells as well 9 thus causin,~ toxic phe-nomerla at their elinieal adminis-tration. ~ur-thermore~ J~hese prepara-tions do not render any no-tieeable e~eet on eer-tain kinds of ~requently encountered tumors ~such as lung7 stomaeh ancl panereas eaneer).
~ no-wn in the art are certaiLl polycations such as poly-e-thylenimine ~ polypropyleneiLIline 9 polyly~ine and -the like which e~ert direct electrosta-tic ancl cytostatie e~Leet on tumor eells carryin~ a higher negative e~large as eompared .~
to normal cells (cfo H. Morosow, Polycation treated tumor cells in vivo and in vitro, Cancer Res~, 1971, v. 31, No. 3, p. 373-383, J.M. Mehrishi, Effect of lysine polypeptides on the surface change of normal and cancer cells, Rur. JO Can-cer, 1969, v. 5, No~ 3, p. 427-435).
These compounds, however, have not obtained any prac-tical application due to their insufficient efficiency and a number of side effects.
The pharmaceu-tical composition according to the pre-sent invention is novel hitherto unknown in the literature.
It is the main object of the present invention to provide a novel antitumor preparation of a broad range of action which could be effective with respect to tumor forms resistant to known preparations and possessing a contact effect on the cancer cellO
This object is achieved by that a pharmaceutical composition possessing antitumor effect and containing an active principle and a pharmaceutical vehicle, in accord-ance with the present invention, includes as an active principle, polyhexamethyleneguanidine phosphate of the following general formula:
r t~H Ic~ (CH2) ~ R' o (~ po ) ~H
wherein n = 2 to 5, R is ~H2, NH2 ~ C - MH -Il ~H
R = NH, NH -- C - ~I --
~ lOR ACq'IVITY
'I'he present invention relates to pharmacautical eom-positions aLlcl 7 More speci~ically, -to a novel pharmacelltie-al composition porsessing anti-tumor aetivitg and ''n-tended ~or the trea-tment o~ gastro-intestina:l anc~ breas-t eaneer 3 as well as for the trea-tLnent o~ wounds a~'-ter -the radieal opera-tion of a tumor.
At present various an-titumor preparations are known in the ar-t. Aceording to the meehanism Oe thei:r aetion, -they are elassiL'ied in-to 4 groups: an-timetabolites, alk~l-ating agents 9 iL~tercalatlng agen-ts and mitosis inhibi-tors.
The meehaL1isln Oe aetion o:~ these eompounds is associated with their eefeet on the synthesis and ~unetionin~ o~ LlU-eleie aeids (e~. t'Chemotherapy O:e ~alignan-t T~lmors"1 ed.
by N~N. Blol~hin, ~lioscow9 I~,'leditsina Publishin~ House9~1977).
In mos-t eases seleetivity Oe -the prior art prepara-tions e~iIeet on -tumor cells is lo-ii, since they a~'~ect me-tabolism o~ normal cells as well 9 thus causin,~ toxic phe-nomerla at their elinieal adminis-tration. ~ur-thermore~ J~hese prepara-tions do not render any no-tieeable e~eet on eer-tain kinds of ~requently encountered tumors ~such as lung7 stomaeh ancl panereas eaneer).
~ no-wn in the art are certaiLl polycations such as poly-e-thylenimine ~ polypropyleneiLIline 9 polyly~ine and -the like which e~ert direct electrosta-tic ancl cytostatie e~Leet on tumor eells carryin~ a higher negative e~large as eompared .~
to normal cells (cfo H. Morosow, Polycation treated tumor cells in vivo and in vitro, Cancer Res~, 1971, v. 31, No. 3, p. 373-383, J.M. Mehrishi, Effect of lysine polypeptides on the surface change of normal and cancer cells, Rur. JO Can-cer, 1969, v. 5, No~ 3, p. 427-435).
These compounds, however, have not obtained any prac-tical application due to their insufficient efficiency and a number of side effects.
The pharmaceu-tical composition according to the pre-sent invention is novel hitherto unknown in the literature.
It is the main object of the present invention to provide a novel antitumor preparation of a broad range of action which could be effective with respect to tumor forms resistant to known preparations and possessing a contact effect on the cancer cellO
This object is achieved by that a pharmaceutical composition possessing antitumor effect and containing an active principle and a pharmaceutical vehicle, in accord-ance with the present invention, includes as an active principle, polyhexamethyleneguanidine phosphate of the following general formula:
r t~H Ic~ (CH2) ~ R' o (~ po ) ~H
wherein n = 2 to 5, R is ~H2, NH2 ~ C - MH -Il ~H
R = NH, NH -- C - ~I --
2 2 11 ~H
8q~
The pharMaceutical com~osi-tion accordirl~, to the present inverl~ion can be used in clieeerent prepara-tive orlns (inj~-~,ctions, solu-tlon.s, ointments~ supposi-toria).
It is p-l-eeerab]e -to use the pnarmaceutical composition o~ this inventiorl irl-the :!'Orm 0~' injection solu-tions ~i-th a con-tent o~ the active principle o~ 1.5% by weight. It is also pre~erable -that the phaLmaceutical composition ac-cor~ing to the present invention should include distilled water or pi~siolor,ical solution as a pharmaceutical solvent.
The pharmaceutical composi-tion O:e this inven-tion is intended ~'or the -treatment of gastro-in-te5-tinal and breast cancer. It is e~'ective with respect to turnor ~orms resist-ant to known preparations. The prepara-tion also ~laS a con-tact ef~ect on the ca~cer cell and can be used for direct -treatment o~ -the wound after opera-tion oP -the -tumorO
qlhe antitumor activity o~' the pharmaceutical compo-si-tion according to -the preserl-t invention has been studied in six -test systems: lymphoid leukerrlia L 1210, INalker car-cinosarcorDa9 adenocarcinoma 755~ ~a~Conla 37, Lewis lung carcinoma9 melanoma B16. Lymphoid leukemia L-1210 was im~
planted intraperitoneally to BDF mice o~ bo-th sexes~ a-t a rate o~ 106 cells per rnouse. Adenocarcinoma 755 and mela-noma B16 we:re gral-'ted -to ~emale mice BD~9 at a rate of 5 Mg 0~' the tumor suspension per mouse, Sarcorrra 37 was im-plan-ted in-traperitoneally to albino mon~Jrel rrlice o~ botih se~es at a ra-'-e o~ 106 cells per mou5e. Lewis lung carci-noma was gra~-ted to BU~ mice hypodermally at a rate of 50 mg o~ -the tumor suspension per mouse~ i~alker carcinoma was ~rafted hypodermall~ to albino mongrel ra-ts at a rate o~ I00 mg o~ the tumor suspension per rat. ~he ~irst ad~
ministratîo~ of the preparation o~ the inventio~ was per~
formed 24 hour~ a~ter implantation of the tumor or leuko-~ he compo~nd was dissolved i~ distilled water ex tem-pore ~d administered intr~peritoneall~ or intravenously once a daya ~he results of ~he stud~ o~ the obtained anti-tumor ef~ect are shown in Table 1 hereinbelQw.
~able 1 T Si~le Da~5 ~ife Administra-umor dose of ad~ inC~ea~ tion route 1 ~umphoid leuke mia 24.9 1 175 intraperi~o~
n~ ally 2 L-1210 4.2 1~2~3t4t7 125 ditto
8q~
The pharMaceutical com~osi-tion accordirl~, to the present inverl~ion can be used in clieeerent prepara-tive orlns (inj~-~,ctions, solu-tlon.s, ointments~ supposi-toria).
It is p-l-eeerab]e -to use the pnarmaceutical composition o~ this inventiorl irl-the :!'Orm 0~' injection solu-tions ~i-th a con-tent o~ the active principle o~ 1.5% by weight. It is also pre~erable -that the phaLmaceutical composition ac-cor~ing to the present invention should include distilled water or pi~siolor,ical solution as a pharmaceutical solvent.
The pharmaceutical composi-tion O:e this inven-tion is intended ~'or the -treatment of gastro-in-te5-tinal and breast cancer. It is e~'ective with respect to turnor ~orms resist-ant to known preparations. The prepara-tion also ~laS a con-tact ef~ect on the ca~cer cell and can be used for direct -treatment o~ -the wound after opera-tion oP -the -tumorO
qlhe antitumor activity o~' the pharmaceutical compo-si-tion according to -the preserl-t invention has been studied in six -test systems: lymphoid leukerrlia L 1210, INalker car-cinosarcorDa9 adenocarcinoma 755~ ~a~Conla 37, Lewis lung carcinoma9 melanoma B16. Lymphoid leukemia L-1210 was im~
planted intraperitoneally to BDF mice o~ bo-th sexes~ a-t a rate o~ 106 cells per rnouse. Adenocarcinoma 755 and mela-noma B16 we:re gral-'ted -to ~emale mice BD~9 at a rate of 5 Mg 0~' the tumor suspension per mouse, Sarcorrra 37 was im-plan-ted in-traperitoneally to albino mon~Jrel rrlice o~ botih se~es at a ra-'-e o~ 106 cells per mou5e. Lewis lung carci-noma was gra~-ted to BU~ mice hypodermally at a rate of 50 mg o~ -the tumor suspension per mouse~ i~alker carcinoma was ~rafted hypodermall~ to albino mongrel ra-ts at a rate o~ I00 mg o~ the tumor suspension per rat. ~he ~irst ad~
ministratîo~ of the preparation o~ the inventio~ was per~
formed 24 hour~ a~ter implantation of the tumor or leuko-~ he compo~nd was dissolved i~ distilled water ex tem-pore ~d administered intr~peritoneall~ or intravenously once a daya ~he results of ~he stud~ o~ the obtained anti-tumor ef~ect are shown in Table 1 hereinbelQw.
~able 1 T Si~le Da~5 ~ife Administra-umor dose of ad~ inC~ea~ tion route 1 ~umphoid leuke mia 24.9 1 175 intraperi~o~
n~ ally 2 L-1210 4.2 1~2~3t4t7 125 ditto
3 Sar~oma 37 ~.0 1 85 ditto
4 Di~to 1o8 1,2,3,4t7 48 di~to Ditto 200 1,5,9 40 intrave~ous~
~umor gro-wth m -hibition, 6 ~alker car~ raperito-~i:nosarcoma2~3 1,,2,,3,4~ 7 55 neall~
7 Adenocarcino-ma 755 5"0 192,3"4,7 68 ditto 8 ~deno¢arci:~o~
ma 755 5c,o 1,5, 9 55 ~tra~renous-9 ~qela~oma B16 50 ~,475~6,7 53 i~traperito~
I0 ~ewi~ l~g carcinQma 20 intra~rerlou~-fi~he arl-l;i'ur~qor properties of' -the cornpound accordis.
to t,he present invention have been studied in ,nodels o~
subrencll h~t~rotransplantants oi' human tumors. 'rhere were used the ~`ollowin,, clinical rnaterials: breast cancer - 4 sarnple~,; stornach cancer - 2; rec-ta' eancer ~ 2, lu.ng cancer - 2, wherefroLn a rnicroL`ragment OL` .l03 cells was implanted under kidney capsule to ~3DFl mice. The pharma-ceutical composition o:L' the present invention was adsrlinis-tered on day 2,4,6 a~ter -transplan-tation Oe the tumor a-t a single dose o1 `12 rng/kg. r~umor ~,ro~rth inhibi-tion b~ 50--100% was regi~sterecl in ~ eases o~ 'breast cancer out oP
L~ 2~'2 in the case o.LI s-tomach eancer asld ~/2 - in the ease o~' reetal cancer. In the ease oP lung cancer the inhibi-ci~
on is but insi.gnii'iean-t.
'~he sensitivitD of tumor cells (taken during opera-tion ~Prom 22 patients ~vith pulmonar,q eancer) was s-tuclied wi-th respect -to -the pharsnaceutieal composi-tion o-f the pre-sent invention~
~ ter ineubation Oe the tumor cell~s suspension in the presence o~ the pharmaceu-tieal eomposition o~ the pre-sent invention at a dose eorrespondi.ng to the single dose reeomr~ended ~or elinieal pu:rposes~ i.e~ 5 mgjkg3 -the de-gree Oe disturbanee o~ ~NA and ~'~ syn-thesis proessses in -tu.mor cells as eompared to the con-trol was determiaed by means Oe a liquid sci.ntillation rneter ancl introduetiosl o~
label.led thymidine and uricline.' Sensit-ivity Oe tumor cells depanding on the histolo-gieal strueture of' -the tuL,lor is shown in '~able 2.
l'he total toxicity of' the preparation o~ the pre-sent invention has been al.so studied. r~lh9 ~:D50 in mice is 70 m~/kg.
'l'able 2 ... . 'l'otal Sampl.es Sarnpl~s insensitive ~llstolo~ caL nurnber o~' sensi-tive to the preparatio~
orm o. un~ studied to the pre~
~ancer samples paratlon i.:Flat-cell carcino~a 14 9 5 2.Adenocarcinoma 6 1 5 3.~o~dif:Eerentia-ted cancer 2 2 ~ 'he results oi -the biochernical ef~ect of tlie oharma-ceu-tical composi-tion according to the present invention i~
hybrid 'nice with ascites ~orm of l~rnpholeukosis ~-5178y and l~mpholeukosis 1,-1~10 have shown that a sin~;le intraperi-toneal administration o~ a therapeutical c~ose (5 mg/kg) inhibits biosynthesis o~ DNAg ~A and protein in tu~no:r c:ells to a graater e~-tent than in normal cells o~' tissues:
liver, spleen, ~ucows membrane o~ small intestine.
In e~periments ln vitro it has been al~o demonst-rated that -the pharmaceutical compositi.on ol~ this in~en-tion at concentrations of 1.10 ~ to 1.10 6M inhibits con-siderably (by 60% as co[npared to -tile contr~ol) biosynthesis of DNA9 ~IA and protein in ce~lls of' Ehrlich adenocarcir.~oma and lym~holeukosis ~ 10 whLch is due to dis-turbance o~
.,: :
tranSpOrt o,~'' radioactive precursors Oe macromolecu:Les biosyntllesis into tumor ceLls~
The investigation of t,he e~'Lect renclered b~ -the phar-maceutical compositi.orl accorcl.ing -to the preserlt inventi.on on the ceLls oi: ly,nphol~ukosis ï.~l7~y has sho~i-in t'ha-l at COr1CentratiOnS O:L' 2~ and 50 Ju~j/ml it decreases -the nega--tive charge oi~ the plasmatic melnbxane o:~ tumor cells, while a-t concentra-tions o:~ 75 to 500 m~kg it rechar~es the memb-ra.ne sur~ace.
At -the same concen-trations i-t causes displacement of and Na~ ions .~rom -the cell in-to the non-cellular liquid.
'I'he above-mentioned studies have also shown that -the mechanisrn O:e -the e~/ect OI` the pharmacèu~tical compo3ition orf -the present invention is associated wi-th its action on the cancer cell membrane.
'I'he pharrr~aceu-tical composition o~ the present inven-tion decreases the negative charge o~ -the cell plasmatic me~brane~ thus disturbinK ~ransport of macromolecules syn-thesis precursors into -the tumor cell, whereas the mecha-nism o~ the antitumor e~ect Oe the prior art preparations is due to their e~.~ec-t on ~\IA (they are ei-ther analogs o~
su'bstrates or attached to -the basic ~NA cen-tres thus chang-ing i-ts syrnmetry~.
The experiments which have beerl carried ou-t enable a conclusion -that due -to the above mechanis~D O:e action the pharmaceu-tical composition o~ the presen-t inven-tion will be ef:Pective ~vith respect -to -tu.mor ~or~s resistarl-t -to known prepara-tions. As co~apared to the prior art preparations~
, .
- ~L~ 8 ~ ~
it has a contact ef-Eect on the cancer cell and can be used for direct treatment of the wound after the oper~-tion of a tumor.
The pharmaceutical composition according to the present invention is intended for intravenous and intra-muscular administration, as well as for treatment of operation wounds. It can be used in the form of solutions, injection solutions, suppositoria, ointments.
Any pharmaceutically acceptable solvent or base can be used ~s ~ solvent or an ointment base. The adminis-tration of the pr~parat-ion in the form of injections is preferable. Injection so~utions are prepared with a content of the active principle of 1~5% by weight. It is preferable to use distilled water or physiological solution as a solvent. The daily dose of the preparation according to the present invention is 150 mg, the course dose is 1,500 mg.
The pharmaceutical composition i~ prepared by conventional methods.
The active principle of the preparation - polyhexa-methyleneguanidine phosphate is prepared in the following manner.
Equimolar amounts of hexamethyleneguanidine and guanidine hydrochloride are polymerized at a temperature 160 to 170C for 23 hours to produce polyhexamethylene-guanidine hydrochloride in the form of viscous mass which solidifies after cooling. Polyhexamethylene-guanidine hydrochloride is dissolv~d in ethanol andto the resulting solution ethanol solution of sodium ethylate is added in the -~r .
ratio to polyhe~amethyleneguarlldine hy~rochloride o~ l~lo~he re~ultin~ residue o~ sodiulll chloxicle is ~ilterecl o~
and phosphoric acld is added to the ~iltrate so that the ra-tio between the ~il.trate aL~cl phosphoric acid is egual to 1:5, I~sp~ctively~
'L'he precipitated polyhe~rLIethyleneguanîdine phosphate is filtered of~ washed with ether and dried in vacuum. Pu-ri~ica-tion of the product is e~l~ected by reprecipitation (water,e-tnanol). 'I`he g~oal produc-t is :~iltered o~, washed on a Iil-ter with ether and driecl in vacuulil to ~isld 71.6~
oI the p,oal procluc-t (as calculated ~or oolyhexamethylenegua-nidine h~drochloride).
Ths resul-tin~ polyhexamethylsneguanidine phosphate is white solid ~ine-crystal subs-tance having no odour;
its mean ~olecular mass is 1.070 -to 1,130~ it is readily soluble in water 9 insoluble in organic solven-ts 9 stable in s-torap~e and upon lyophilization of its aa,ueouS solutions~
~umor gro-wth m -hibition, 6 ~alker car~ raperito-~i:nosarcoma2~3 1,,2,,3,4~ 7 55 neall~
7 Adenocarcino-ma 755 5"0 192,3"4,7 68 ditto 8 ~deno¢arci:~o~
ma 755 5c,o 1,5, 9 55 ~tra~renous-9 ~qela~oma B16 50 ~,475~6,7 53 i~traperito~
I0 ~ewi~ l~g carcinQma 20 intra~rerlou~-fi~he arl-l;i'ur~qor properties of' -the cornpound accordis.
to t,he present invention have been studied in ,nodels o~
subrencll h~t~rotransplantants oi' human tumors. 'rhere were used the ~`ollowin,, clinical rnaterials: breast cancer - 4 sarnple~,; stornach cancer - 2; rec-ta' eancer ~ 2, lu.ng cancer - 2, wherefroLn a rnicroL`ragment OL` .l03 cells was implanted under kidney capsule to ~3DFl mice. The pharma-ceutical composition o:L' the present invention was adsrlinis-tered on day 2,4,6 a~ter -transplan-tation Oe the tumor a-t a single dose o1 `12 rng/kg. r~umor ~,ro~rth inhibi-tion b~ 50--100% was regi~sterecl in ~ eases o~ 'breast cancer out oP
L~ 2~'2 in the case o.LI s-tomach eancer asld ~/2 - in the ease o~' reetal cancer. In the ease oP lung cancer the inhibi-ci~
on is but insi.gnii'iean-t.
'~he sensitivitD of tumor cells (taken during opera-tion ~Prom 22 patients ~vith pulmonar,q eancer) was s-tuclied wi-th respect -to -the pharsnaceutieal composi-tion o-f the pre-sent invention~
~ ter ineubation Oe the tumor cell~s suspension in the presence o~ the pharmaceu-tieal eomposition o~ the pre-sent invention at a dose eorrespondi.ng to the single dose reeomr~ended ~or elinieal pu:rposes~ i.e~ 5 mgjkg3 -the de-gree Oe disturbanee o~ ~NA and ~'~ syn-thesis proessses in -tu.mor cells as eompared to the con-trol was determiaed by means Oe a liquid sci.ntillation rneter ancl introduetiosl o~
label.led thymidine and uricline.' Sensit-ivity Oe tumor cells depanding on the histolo-gieal strueture of' -the tuL,lor is shown in '~able 2.
l'he total toxicity of' the preparation o~ the pre-sent invention has been al.so studied. r~lh9 ~:D50 in mice is 70 m~/kg.
'l'able 2 ... . 'l'otal Sampl.es Sarnpl~s insensitive ~llstolo~ caL nurnber o~' sensi-tive to the preparatio~
orm o. un~ studied to the pre~
~ancer samples paratlon i.:Flat-cell carcino~a 14 9 5 2.Adenocarcinoma 6 1 5 3.~o~dif:Eerentia-ted cancer 2 2 ~ 'he results oi -the biochernical ef~ect of tlie oharma-ceu-tical composi-tion according to the present invention i~
hybrid 'nice with ascites ~orm of l~rnpholeukosis ~-5178y and l~mpholeukosis 1,-1~10 have shown that a sin~;le intraperi-toneal administration o~ a therapeutical c~ose (5 mg/kg) inhibits biosynthesis o~ DNAg ~A and protein in tu~no:r c:ells to a graater e~-tent than in normal cells o~' tissues:
liver, spleen, ~ucows membrane o~ small intestine.
In e~periments ln vitro it has been al~o demonst-rated that -the pharmaceutical compositi.on ol~ this in~en-tion at concentrations of 1.10 ~ to 1.10 6M inhibits con-siderably (by 60% as co[npared to -tile contr~ol) biosynthesis of DNA9 ~IA and protein in ce~lls of' Ehrlich adenocarcir.~oma and lym~holeukosis ~ 10 whLch is due to dis-turbance o~
.,: :
tranSpOrt o,~'' radioactive precursors Oe macromolecu:Les biosyntllesis into tumor ceLls~
The investigation of t,he e~'Lect renclered b~ -the phar-maceutical compositi.orl accorcl.ing -to the preserlt inventi.on on the ceLls oi: ly,nphol~ukosis ï.~l7~y has sho~i-in t'ha-l at COr1CentratiOnS O:L' 2~ and 50 Ju~j/ml it decreases -the nega--tive charge oi~ the plasmatic melnbxane o:~ tumor cells, while a-t concentra-tions o:~ 75 to 500 m~kg it rechar~es the memb-ra.ne sur~ace.
At -the same concen-trations i-t causes displacement of and Na~ ions .~rom -the cell in-to the non-cellular liquid.
'I'he above-mentioned studies have also shown that -the mechanisrn O:e -the e~/ect OI` the pharmacèu~tical compo3ition orf -the present invention is associated wi-th its action on the cancer cell membrane.
'I'he pharrr~aceu-tical composition o~ the present inven-tion decreases the negative charge o~ -the cell plasmatic me~brane~ thus disturbinK ~ransport of macromolecules syn-thesis precursors into -the tumor cell, whereas the mecha-nism o~ the antitumor e~ect Oe the prior art preparations is due to their e~.~ec-t on ~\IA (they are ei-ther analogs o~
su'bstrates or attached to -the basic ~NA cen-tres thus chang-ing i-ts syrnmetry~.
The experiments which have beerl carried ou-t enable a conclusion -that due -to the above mechanis~D O:e action the pharmaceu-tical composition o~ the presen-t inven-tion will be ef:Pective ~vith respect -to -tu.mor ~or~s resistarl-t -to known prepara-tions. As co~apared to the prior art preparations~
, .
- ~L~ 8 ~ ~
it has a contact ef-Eect on the cancer cell and can be used for direct treatment of the wound after the oper~-tion of a tumor.
The pharmaceutical composition according to the present invention is intended for intravenous and intra-muscular administration, as well as for treatment of operation wounds. It can be used in the form of solutions, injection solutions, suppositoria, ointments.
Any pharmaceutically acceptable solvent or base can be used ~s ~ solvent or an ointment base. The adminis-tration of the pr~parat-ion in the form of injections is preferable. Injection so~utions are prepared with a content of the active principle of 1~5% by weight. It is preferable to use distilled water or physiological solution as a solvent. The daily dose of the preparation according to the present invention is 150 mg, the course dose is 1,500 mg.
The pharmaceutical composition i~ prepared by conventional methods.
The active principle of the preparation - polyhexa-methyleneguanidine phosphate is prepared in the following manner.
Equimolar amounts of hexamethyleneguanidine and guanidine hydrochloride are polymerized at a temperature 160 to 170C for 23 hours to produce polyhexamethylene-guanidine hydrochloride in the form of viscous mass which solidifies after cooling. Polyhexamethylene-guanidine hydrochloride is dissolv~d in ethanol andto the resulting solution ethanol solution of sodium ethylate is added in the -~r .
ratio to polyhe~amethyleneguarlldine hy~rochloride o~ l~lo~he re~ultin~ residue o~ sodiulll chloxicle is ~ilterecl o~
and phosphoric acld is added to the ~iltrate so that the ra-tio between the ~il.trate aL~cl phosphoric acid is egual to 1:5, I~sp~ctively~
'L'he precipitated polyhe~rLIethyleneguanîdine phosphate is filtered of~ washed with ether and dried in vacuum. Pu-ri~ica-tion of the product is e~l~ected by reprecipitation (water,e-tnanol). 'I`he g~oal produc-t is :~iltered o~, washed on a Iil-ter with ether and driecl in vacuulil to ~isld 71.6~
oI the p,oal procluc-t (as calculated ~or oolyhexamethylenegua-nidine h~drochloride).
Ths resul-tin~ polyhexamethylsneguanidine phosphate is white solid ~ine-crystal subs-tance having no odour;
its mean ~olecular mass is 1.070 -to 1,130~ it is readily soluble in water 9 insoluble in organic solven-ts 9 stable in s-torap~e and upon lyophilization of its aa,ueouS solutions~
Claims (4)
1. A pharmaceutical composition possessing anti-tumor activity comprising as an active principle, poly-hexamethyleneguanidine phosphate of the following general formula:
wherein n = 2-5; R is NH2; R1 is NH2; and a pharmaceutical vehicle.
wherein n = 2-5; R is NH2; R1 is NH2; and a pharmaceutical vehicle.
2. A pharmaceutical composition according to claim 1 in the form of injection solutions which comprises the active principle in the amount of 1.5%
by weight.
by weight.
3. A pharmaceutical composition according to claims 1 and 2, wherein the pharmaceutical vehicle comprises a solvent.
4. A pharmaceutical composition according to claims 1 and 2, wherein the pharmaceutical vehicle comprises distilled water or a physiological solution.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SU1982/000020 WO1984000105A1 (en) | 1982-06-21 | 1982-06-21 | Medicinal preparation having antitumoral effect |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1194802A true CA1194802A (en) | 1985-10-08 |
Family
ID=21616776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000413032A Expired CA1194802A (en) | 1982-06-21 | 1982-10-07 | Pharmaceutical composition possessing antitumor activity |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS59501110A (en) |
| CA (1) | CA1194802A (en) |
| CH (1) | CH660964A5 (en) |
| DE (1) | DE3249514T1 (en) |
| FR (1) | FR2535609A1 (en) |
| GB (1) | GB2134783B (en) |
| NL (1) | NL8220420A (en) |
| SE (1) | SE437931B (en) |
| WO (1) | WO1984000105A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5344846A (en) * | 1992-12-30 | 1994-09-06 | The United States Of America As Represented By The Department Of Health And Human Services | Compositions and methods for inhibiting deoxyhypusine synthase and the growth of cells |
| DE19628641C2 (en) * | 1996-07-16 | 1998-12-17 | Fresenius Ag | Use of PHMB for the treatment of tumor diseases |
| KR100557559B1 (en) * | 1999-12-20 | 2006-03-03 | 에스케이 주식회사 | Polyhexamethyleneguanidine phosphate powder, method of making the same and antibiotic resin containing the same |
| KR100725004B1 (en) * | 1999-12-24 | 2007-06-04 | 에스케이 주식회사 | Sterilization composition and method of using the same |
| AT505312A1 (en) | 2007-05-15 | 2008-12-15 | Recticel Schlafkomfort Gmbh Sc | POLYURETHANE MATERIAL WITH BIOCIDAL EQUIPMENT |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3824288A (en) * | 1961-06-09 | 1974-07-16 | Hoffmann La Roche | Substituted hydrazine derivatives and process for the manufacture thereof |
| BR6457241D0 (en) * | 1963-12-23 | 1973-06-26 | Rohm & Haas | PROCESS FOR THE PREPARATION OF T-OCTIL-GUANIDINES |
| GB1492678A (en) * | 1975-08-11 | 1977-11-23 | Ici Ltd | Guanidine derivatives |
| JPS5341426A (en) * | 1976-09-27 | 1978-04-14 | Asahi Chem Ind Co Ltd | Fungicidal and bactericidal agents |
-
1982
- 1982-06-21 CH CH90284A patent/CH660964A5/en not_active IP Right Cessation
- 1982-06-21 DE DE19823249514 patent/DE3249514T1/en not_active Withdrawn
- 1982-06-21 WO PCT/SU1982/000020 patent/WO1984000105A1/en active Application Filing
- 1982-06-21 NL NL8220420A patent/NL8220420A/en not_active Application Discontinuation
- 1982-06-21 JP JP57503491A patent/JPS59501110A/en active Pending
- 1982-06-21 GB GB08403257A patent/GB2134783B/en not_active Expired
- 1982-10-07 CA CA000413032A patent/CA1194802A/en not_active Expired
- 1982-11-04 FR FR8218494A patent/FR2535609A1/en active Granted
-
1984
- 1984-01-30 SE SE8400453A patent/SE437931B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SE8400453L (en) | 1985-03-25 |
| WO1984000105A1 (en) | 1984-01-19 |
| GB8403257D0 (en) | 1984-03-14 |
| SE437931B (en) | 1985-03-25 |
| NL8220420A (en) | 1984-05-01 |
| CH660964A5 (en) | 1987-06-30 |
| JPS59501110A (en) | 1984-06-28 |
| DE3249514T1 (en) | 1984-05-17 |
| FR2535609A1 (en) | 1984-05-11 |
| SE8400453D0 (en) | 1984-01-30 |
| FR2535609B1 (en) | 1985-03-15 |
| GB2134783B (en) | 1985-10-30 |
| GB2134783A (en) | 1984-08-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7169412B2 (en) | Methods for production of the oxidized glutathione composite with cis-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells | |
| CN111909155A (en) | Proteolysis targeting chimera, prodrug molecule for improving oral bioavailability thereof and application | |
| CN101254308A (en) | Biogastrone acid-polyethyleneglycol /chitosan liver target composite drug administration system and preparation thereof | |
| US6312734B1 (en) | Methods for production of the oxidized glutathione composite with cis-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells | |
| Kovach et al. | Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine N-oxide, in humans | |
| US7371411B2 (en) | Methods for production of the oxidized glutathione composite with CIS-diamminedichloroplatinum and pharmaceutical compositions based thereof regulating metabolism, proliferation, differentiation and apoptotic mechanisms for normal and transformed cells | |
| CA1194802A (en) | Pharmaceutical composition possessing antitumor activity | |
| Prakash et al. | Cell-specific delivery of a transforming growth factor-beta type I receptor kinase inhibitor to proximal tubular cells for the treatment of renal fibrosis | |
| AU2003251159B2 (en) | Ruthenium anticancer complexes | |
| KR100808630B1 (en) | Antitumoric compositions for oral administration comprising chlorin compounds | |
| US5219846A (en) | Treatment of human tumors utilizing compounds having a phosphoamides linkage or enol phosphate linkage | |
| ALL | On para-endocrine cancer syndromes | |
| US20200330374A1 (en) | Rectal mucosal administration preparation of pulsatilla chinensis saponin b4 and preparation method therefor | |
| US20220387334A1 (en) | Nanoparticles for preventing peri/post-menopausal bone loss and/or obesity | |
| CN114028579A (en) | Application of aptamer-drug conjugate PTK7-GEMs in preparation of drugs for treating bladder cancer | |
| JPH08310944A (en) | Therapeutic agent for hepatopathy | |
| CN106344930B (en) | Preparation and application of molecular site-specific targeting and activating short peptide adriamycin | |
| CN110183504A (en) | A kind of gemcitabine pro-drug and its preparation method and application with tumor-targeting | |
| KR20010079680A (en) | Medicament containing platinum complex compounds and the use thereof | |
| Swain et al. | Preparation of dendritic carboranyl glycoconjugates as potential anticancer therapeutics | |
| US20230391808A1 (en) | Phosphaphenalene-gold(i) complexes as chemotherapeutic agents against glioblastoma | |
| CN115611926B (en) | Non-sensitive bond bridged SN38 dimer prodrug, self-assembled nanoparticle thereof and application thereof | |
| WO2023088062A1 (en) | Anti-hypoxic/anoxic injury use of magnolol and/or honokiol aromatic ring amino-substituted derivative, and pharmaceutical composition | |
| Liao et al. | Emodin induces osteosarcoma cell apoptosis by promoting ATM protein cleavage | |
| CN109265487B (en) | Iridium complex with chemotherapy and phototherapy synergistic anti-tumor effect and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |