DE19842578A1 - Use of nucleosides and nucleobases for reducing thrombocytopenic side effects caused by cytostatic agents, e.g. carboplatin - Google Patents

Use of nucleosides and nucleobases for reducing thrombocytopenic side effects caused by cytostatic agents, e.g. carboplatin

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Publication number
DE19842578A1
DE19842578A1 DE1998142578 DE19842578A DE19842578A1 DE 19842578 A1 DE19842578 A1 DE 19842578A1 DE 1998142578 DE1998142578 DE 1998142578 DE 19842578 A DE19842578 A DE 19842578A DE 19842578 A1 DE19842578 A1 DE 19842578A1
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DE
Germany
Prior art keywords
methyluracil
side effects
alkyl
nucleosides
carboplatin
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE1998142578
Other languages
German (de)
Inventor
Iduna Fichtner
Peter Langen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Priority to DE1998142578 priority Critical patent/DE19842578A1/en
Priority to EP99969331A priority patent/EP1037618A1/en
Priority to PCT/DE1999/002944 priority patent/WO2000016753A2/en
Publication of DE19842578A1 publication Critical patent/DE19842578A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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)

Abstract

The use of nucleosides and nucleobases and their derivatives (I) is claimed for reducing thrombocytopenic side effects caused by cytostatic agents. The use of nucleosides and nucleobases and their derivatives of formula (I) is claimed for reducing thrombocytopenic side effects caused by cytostatic agents. R1 = OH or NH2; R2 = H or alkyl; R3 = H, alkyl or COOH; R4 = H or optionally substituted deoxyribosyl, ribosyl or arabinosyl.

Description

Die Erfindung betrifft die Verwendung von Nucleosiden, Nucle­ obasen und deren Derivaten, insbesondere von 6-Methyluracil, zum Herabsetzen thrombocytopenischer Nebenwirkungen von Cyto­ statika sowie Kombinationspräparate von Nucleosiden, Nucle­ obasen und deren Derivaten und Cytostatika, insbesondere ein Kombinationspräparat, das mindestens ein Cytostatikum und 6- Methyluracil enthält.The invention relates to the use of nucleosides, nucleus obases and their derivatives, especially of 6-methyluracil, to reduce the thrombocytopenic side effects of Cyto statics and combination preparations of nucleosides, nucleus obases and their derivatives and cytostatics, in particular a Combination preparation containing at least one cytostatic and 6- Contains methyluracil.

Bekanntermaßen weisen die zur Behandlung von Tumorerkrankun­ gen eingesetzten Cytostatika neben ihrer gewünschten anti- Tumorwirkung in der Regel toxische, die Dosis limitierende Nebenwirkungen auf. Da die Dosis-Effekt-Kurve bei Cytostatika besonders steil ist, wäre die Wahl einer möglichst hohen Do­ sis angezeigt, wie sie aber wegen dann gravierenden Nebenwir­ kungen im allgemeinen nicht appliziert werden kann.As is known, they are used to treat tumor diseases cytostatics used in addition to their desired anti- Tumor effects are usually toxic and limit the dose Side effects. Since the dose-effect curve for cytostatics is particularly steep, the choice would be the highest possible do sis displayed, but because of serious side effects cations can generally not be applied.

Im Vordergrund der Nebenwirkungen stehen starke Hemmwirkungen auf die Hämopoese, die zu einer Verminderung der Leukozyten und Thrombozyten führt (Leukopenie, e. g. Granulocytopenie, mit der Folge einer erhöhten Infektionsgefahr; Thrombocytope­ nie mit der Folge einer bedrohlichen Verringerung der Blutge­ rinnung).The main side effects are strong inhibitory effects on hemopoiesis, which leads to a decrease in leukocytes and platelets (leukopenia, e.g. granulocytopenia, with the consequence of an increased risk of infection; Thrombocytope never with the consequence of a threatening decrease in blood coagulation).

Durch den Einsatz von gentechnisch produzierten hämopoeti­ schen Wachstumsfaktoren (e. g. für die Stammzellen von Granu­ locyten und Macrophagen) konnte die Dauer der Leukopenie- Periode und damit die Gefahr einer Infektion verringert und die Therapie durch Dosiserhöhung bei den Cytostatika opti­ miert werden (F. Hansen: Hemopoietic growth and inhibitory factors in treatment of malignancies. A review. Acta Oncol. 34, 453-68 (1995)). Through the use of genetically engineered hemopoeti growth factors (e.g. for the stem cells of Granu locytes and macrophages), the duration of the leukopenia Period and thus the risk of infection is reduced and the therapy by increasing the dose of the cytostatics opti (F. Hansen: Hemopoietic growth and inhibitory factors in treatment of malignancies. A review. Acta Oncol. 34, 453-68 (1995)).  

Anders sieht die Situation bei der Thrombocytopenie aus. Die­ se ist z. B. insbesondere bei neuen Cytostatica, wie den Pla­ tin-Derivaten, z. B. Carboplatin, eine besonders gravierende Nebenwirkung (e. g. J. F. Delaloy, L. Tran, S. Leyvraz, J. Bau­ er, P. De-Grandl: Intraperitoneal carboplatin in advanced ovarian carcinoma. Gynecol-Geburtshilfliche-Rundschau 33, 25-­ 30 (1993); K. Bertelsen, L. Basthold: High-dose platinium chemotherapy in advanced ovarian cancer. Gynecol-Oncol. 44, 79-82 (1992)).The situation is different with thrombocytopenia. The se is e.g. B. especially with new cytostatics, such as the Pla tin derivatives, e.g. B. carboplatin, a particularly serious Side effect (e.g. J. F. Delaloy, L. Tran, S. Leyvraz, J. Bau er, P. De-Grandl: Intraperitoneal carboplatin in advanced ovarian carcinoma. Gynecol Obstetrics Review 33, 25 30 (1993); K. Bertelsen, L. Basthold: High-dose platinium chemotherapy in advanced ovarian cancer. Gynecol-Oncol. 44, 79-82 (1992)).

Versuche, Zeit und Schwere der Thrombocytopenie durch adju­ vante Arzneimittelgabe zu begrenzen sind z. Zt. noch im expe­ rimentellen Stadium. In analoger Weise zu dem Vorgehen bei Leukozyten befindet sich der Wachstumsfaktor für Thrombo­ zyten-Stammzellen, das Thrombopoetin, in experimenteller Er­ probung. In gleicher Weise wird auch IL 2 eingesetzt (R. Hoffman, M. W. Long: Control of thrombocytoiesis. Cancer- Treat-Res. 80, 25-48 (1995); T-P. McDonald: Throinbopoietin. Its biology, clinical aspects and possibilities. Am-J- Pediatr-Hematol-Oncol. 14, 8-21 (1992).Attempts, time and severity of thrombocytopenia by adju To limit vante drug administration z. Currently still in expe experimental stage. In an analogous manner to the procedure at Leukocytes are the growth factor for thrombo Cytic stem cells, thrombopoietin, in an experimental experiment rehearsal. IL 2 is used in the same way (R. Hoffman, M.W. Long: Control of thrombocytoiesis. Cancer Treat Res. 80: 25-48 (1995); T-P. McDonald: Throinbopoietin. Its biology, clinical aspects and possibilities. Am-J- Pediatr-Hematol-Oncol. 14: 8-21 (1992).

Es ist festzustellen, daß es heute noch kein anerkanntes bzw. klinisch zugelassenes Mittel zur Begrenzung der Cytostatica­ bedingten Thrombocytopenie gibt.It should be noted that there is still no recognized or clinically approved agent to limit cytostatics conditional thrombocytopenia there.

In unseren früheren Untersuchungen hatten sich Nucleobasen, Nucleoside und deren Derivate davon als Stimulatoren der Ver­ mehrung von Stammzellen von Granulocyten und Macrophagen und deren Reneration nach Cytostatica-Behandlung (Endoxan) erwie­ sen (P. Langen, H. Schunk, B. Hunger, M. Schütt, O. D. Laerum: Adherent-cell-dependent stimulation of CFU-GM by nucleobases, nucleosides, their analogues and the hemoregulatory peptide dimer. Exp. Hematol. 20, 196-200 (1993). Das war verbunden mit einer drastischen Verringerung der letalen Wirkung hoch­ toxischer Dosen.In our previous research, nucleobases, Nucleosides and their derivatives thereof as stimulators of ver proliferation of stem cells from granulocytes and macrophages and Renewed after cytostatica treatment (Endoxan) sen (P. Langen, H. Schunk, B. Hunger, M. Schütt, O. D. Laerum: Adherent-cell-dependent stimulation of CFU-GM by nucleobases, nucleosides, their analogues and the hemoregulatory peptide dimer. Exp. Hematol. 20, 196-200 (1993). That was connected with a drastic reduction in lethal effects toxic doses.

Ein besonders geeigneter Vertreter der genannten Substanz­ gruppe ist das 6-Methyluracil. A particularly suitable representative of the substance mentioned group is the 6-methyluracil.  

Es wurde überraschend gefunden, daß 6-Methyluracil und wei­ tere Vertreter von Verbindungen gemäß Formel I auch die durch Cytostatica bedingte Thrombopenie verringern. Eine solche Wirkung konnte weder nach den eigenen, noch nach Literatur- Befunden erwartet werden.
It has surprisingly been found that 6-methyluracil and other representatives of compounds of the formula I also reduce the thrombopenia caused by cytostatics. Such an effect could not be expected based on our own or literature findings.

in der
R1 = OH oder NH2,
R2 = H oder Alkyl,
R3 = H, Alkyl oder COOH und
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl -ribosyl oder -arabinosyl
bedeuten.
(6-Methyluracil R1 = OH, R2 = H, R3 = Methyl, R4 = H)in the
R 1 = OH or NH 2 ,
R 2 = H or alkyl,
R 3 = H, alkyl or COOH and
R 4 = H or optionally substituted deoxyribosyl-ribosyl or -arabinosyl
mean.
(6-methyluracil R 1 = OH, R 2 = H, R 3 = methyl, R 4 = H)

Die der Erfindung zugrunde liegenden Befunde wurden mit Car­ boplatin erhoben, dessen thrombocytopenische Wirkung beson­ ders negativ für seine Anwendung ist.The findings on which the invention is based were carried out using Car boplatin raised, the thrombocytopenic effect particular which is negative for its application.

6-Methyluracil ist oral anwendbar, billig und Nebenwirkungen wurden bisher weder nach eigenen Versuchen beobachtet noch in der Literatur beschrieben. Seine Anwendung in Kombination mit Cytostatica ist nach den bisher vorliegenden Befunden ein wichtiger Beitrag zur Optimierung der Krebs-Chemotherapie.6-Methyluracil is oral, cheap and has side effects have so far been observed neither after own experiments nor in described in the literature. Its application in combination with According to the findings available so far, cytostatica is a important contribution to optimizing cancer chemotherapy.

Die bevorzugten Dosierungen für 6-Methyluracil liegen erfin­ dungsgemäß bei 150 bis 600 mg/kg.Tag, wobei sich gezeigt hat, daß eine Dosis von 300 mg/kg.Tag deutlich besser wirkt als die Hälfte, während eine weitere Verdoppelung 600 mg/kg. Tag zu keinen eindeutigen Verbesserungen führt. Daher wird besonders bevorzugt eine Dosis von 300 mg/kg.Tag 6- Methyluracil appliziert. 6-Methyluracil wird dabei vorzugs­ weise oral angewendet, wobei es auch einem Getränk beige­ mischt werden kann.The preferred dosages for 6-methyluracil are invented according to 150 to 600 mg / kg. day, whereby it was shown has that a dose of 300 mg / kg.day works much better than half while doubling another 600 mg / kg. Day does not lead to any clear improvements. Therefore particularly preferably a dose of 300 mg / kg. Day 6-  Methyluracil applied. 6-Methyluracil is preferred wisely used orally, including a beige drink can be mixed.

Gegenstand der Erfindung ist auch ein Kombinationspräparat, das mindestens ein Cytostatikum und ein Nucleosid, eine Nucleobase oder deren Derivate der allgemeinen Formel I
The invention also relates to a combination preparation which contains at least one cytostatic and one nucleoside, a nucleobase or derivatives thereof of the general formula I.

in der
R1 = OH oder NH2,
R2 = H oder Alkyl,
R3 = H, Alkyl oder COOH und
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl -ribosyl oder -arabinosyl
bedeuten,
vorzugsweise in getrennten und gegebenenfalls in unterschied­ lichen Darreichungsformen, enthält.in the
R 1 = OH or NH 2 ,
R 2 = H or alkyl,
R 3 = H, alkyl or COOH and
R 4 = H or optionally substituted deoxyribosyl-ribosyl or -arabinosyl
mean,
preferably in separate and possibly in different administration forms.

In einer bevorzugten Ausführungsvariante enthält das Kombina­ tionspräparat Carboplatin mit gegebenenfalls an sich üblichen Hilfs-, Träger- und Zusatzstoffen und 6-Methyluracil eben­ falls mit gegebenenfalls an sich üblichen Hilfs-, Träger- und Zusatzstoffen.In a preferred embodiment, the Kombina contains tion preparation carboplatin with optionally conventional per se Auxiliaries, carriers and additives and 6-methyluracil if with possibly conventional auxiliary, carrier and Additives.

Anschließend wird die Erfindung an Hand von Abbildungen näher erläutert. The invention is then explained in more detail with the aid of illustrations explained.  

Legende zu Abb. 1Legend to Fig. 1

Weibliche B6D2F1 Mäuse (8/Versuchsgruppe) wurden einen Tag nach i.m. Inokulation von Lewis lung Carcinom-Zellen mit Car­ boplatin i.p. behandelt. Je eine Versuchsgruppe erhielt 100, 150 oder 175 mg/kg, wobei die höchste Dosierung etwa einer LD40 entsprach. Weitere Carboplatin-behandelten Versuchsgrup­ pen erhielten in das normalerweise verabreichte Trinkwasser einen Zusatz von 2,4 mg/ml 6-Methyluracil. 10 Tage nach Car­ boplatin-Behandlung wurde den Mäusen Blut aus der retroorbi­ talen Vene entnommen. Die Bestimmung der Thombozytenzahlen erfolgte mittels Coulter Counter.Female B6D2F1 mice (8 / experimental group) were treated with car boplatin ip one day after inoculating Lewis lung carcinoma cells. One test group each received 100, 150 or 175 mg / kg, the highest dose corresponding approximately to an LD 40 . Further carboplatin-treated test groups received an addition of 2.4 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein in the mice 10 days after treatment with carboplatin. The platelet count was determined using a Coulter Counter.

Legende zu Abb. 2Legend to Fig. 2

Weibliche B6D2F1 Mäuse (8/Versuchsgruppe) wurden einen Tag nach i.m. Inokulation von B16Melanom-Zellen mit Carboplatin i.p. behandelt. Je eine Versuchsgruppe erhielt 100 oder 150 mg/kg, wobei die höchste Dosierung etwa einer LD10 entsprach. Weitere Carboplatin-behandelten Versuchsgruppen erhielten in das normalerweise verabreichte Trinkwasser einen Zusatz von 1,2 mg/ml 6-Methyluracil. 10 Tage nach Carboplatin-Behandlung wurde den Mäusen Blut aus der retroorbitalen Vene entnommen. Die Bestimmung der Thombozytenzahlen erfolgte mittels Coulter Counter.Female B6D2F1 mice (8 / experimental group) were treated with carboplatin ip one day after inoculating B16 melanoma cells. One test group each received 100 or 150 mg / kg, the highest dose corresponding approximately to an LD 10 . Further carboplatin-treated test groups received an addition of 1.2 mg / ml 6-methyluracil in the drinking water normally administered. Blood was drawn from the retroorbital vein from the mice 10 days after carboplatin treatment. The platelet count was determined using a Coulter Counter.

Claims (7)

1. Verwendung von Nucleosiden, Nucleobasen und deren Deriva­ ten der allgemeinen Formel I
in der
R1 = OH oder NH2,
R2 = H oder Alkyl,
R3 = H, Alkyl oder COOH und
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl -ribosyl oder -arabinosyl
bedeuten,
zum Herabsenken thrombocytopenischer Nebenwirkungen von Cytostatika.1. Use of nucleosides, nucleobases and their derivatives of the general formula I
in the
R 1 = OH or NH 2 ,
R 2 = H or alkyl,
R 3 = H, alkyl or COOH and
R 4 = H or optionally substituted deoxyribosyl-ribosyl or -arabinosyl
mean,
to reduce thrombocytopenic side effects of cytostatics. 2. Verwendung nach Anspruch 1, dadurch gekennzeichnet, daß 6-Methyluracil I, R1 = OH, R2 = H, R3 Methyl, R4 = H eingesetzt wird.2. Use according to claim 1, characterized in that 6-methyluracil I, R 1 = OH, R 2 = H, R 3 methyl, R 4 = H is used. 3. Verwendung nach Anspruch 2, dadurch gekennzeichnet, daß das 6-Methyluracil oral appliziert wird.3. Use according to claim 2, characterized in that the 6-methyluracil is administered orally. 4. Verwendung nach einem der Ansprüche 1 bis 3, dadurch ge­ kennzeichnet, daß 6-Methyluracil in einer Dosis von 150 bis 600 mg/kg.Tag, vorzugsweise 300 mg/kg.Tag appli­ ziert wird. 4. Use according to one of claims 1 to 3, characterized ge indicates that 6-methyluracil at a dose of 150 up to 600 mg / kg.day, preferably 300 mg / kg.day appli is decorated.   5. Kombinationspräparat enthaltend mindestens ein Cytostati­ kum und ein Nucleosid, eine Nucleobase oder deren Deriva­ te der allgemeinen Formel I
in der
R1 = OH oder NH2,
R2 = H oder Alkyl,
R3 = H, Alkyl oder COOH und
R4 = H oder gegebenenfalls substituiertes Desoxyribosyl -ribosyl oder -arabinosyl
bedeuten,
zum Herabsenken der thrombocytopenischen Nebenwirkungen der Cytostatika.5. Combination preparation containing at least one cytostatic kum and a nucleoside, a nucleobase or their derivatives of the general formula I.
in the
R 1 = OH or NH 2 ,
R 2 = H or alkyl,
R 3 = H, alkyl or COOH and
R 4 = H or optionally substituted deoxyribosyl-ribosyl or -arabinosyl
mean,
to reduce the thrombocytopenic side effects of the cytostatics. 6. Kombinationspräparat nach Anspruch 5, dadurch gekenn­ zeichnet, daß es Carboplatin und 6-Methyluracil enthält.6. Combination preparation according to claim 5, characterized records that it contains carboplatin and 6-methyluracil. 7. Kombinationspräparat nach Anspruch 5 oder 6, dadurch ge­ kennzeichnet, daß es Cytostatika und ein Nucleosid, eine Nucleobase oder deren Derivate gemäß Anspruch 5 in ge­ trennten und gegebenenfalls unterschiedlichen Darrei­ chungsformen mit an sich üblichen pharmazeutischen Hilfs-, Träger- und Zusatzstoffen enthält.7. Combination preparation according to claim 5 or 6, characterized ge indicates that it is cytostatics and a nucleoside, a Nucleobase or its derivatives according to claim 5 in ge separated and possibly different darrei Forms with conventional pharmaceuticals Contains auxiliaries, carriers and additives.
DE1998142578 1998-09-17 1998-09-17 Use of nucleosides and nucleobases for reducing thrombocytopenic side effects caused by cytostatic agents, e.g. carboplatin Withdrawn DE19842578A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
DE1998142578 DE19842578A1 (en) 1998-09-17 1998-09-17 Use of nucleosides and nucleobases for reducing thrombocytopenic side effects caused by cytostatic agents, e.g. carboplatin
EP99969331A EP1037618A1 (en) 1998-09-17 1999-09-16 Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents
PCT/DE1999/002944 WO2000016753A2 (en) 1998-09-17 1999-09-16 Use of nucleosides, nucleobases and their derivatives for reducing the thrombocytopenic side effects of cytostatic agents

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE1998142578 DE19842578A1 (en) 1998-09-17 1998-09-17 Use of nucleosides and nucleobases for reducing thrombocytopenic side effects caused by cytostatic agents, e.g. carboplatin

Publications (1)

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DE19842578A1 true DE19842578A1 (en) 2000-03-23

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Country Link
EP (1) EP1037618A1 (en)
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WO (1) WO2000016753A2 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10117615A1 (en) * 2001-04-07 2002-10-10 Max Delbrueck Centrum Use of nucleosides, nucleobases and their derivatives for the improved production of adult stem cells

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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DK0806956T3 (en) * 1995-02-01 2003-01-06 Resprotect Gmbh Use of 5-substituted nucleosides to inhibit resistance formation by cytostatic therapy

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WO2000016753A3 (en) 2000-09-14
EP1037618A1 (en) 2000-09-27
WO2000016753A2 (en) 2000-03-30

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