WO2000050032A1 - Antitumour synergistic composition - Google Patents

Antitumour synergistic composition Download PDF

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Publication number
WO2000050032A1
WO2000050032A1 PCT/EP2000/000745 EP0000745W WO0050032A1 WO 2000050032 A1 WO2000050032 A1 WO 2000050032A1 EP 0000745 W EP0000745 W EP 0000745W WO 0050032 A1 WO0050032 A1 WO 0050032A1
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Prior art keywords
inhibitor
topoisomerase
treatment
antineoplastic
formula
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PCT/EP2000/000745
Other languages
French (fr)
Inventor
Cristina Geroni
Marina Ripamonti
Michele Caruso
Antonino Suarato
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Pharmacia & Upjohn S.P.A.
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Priority to BR0008453-0A priority Critical patent/BR0008453A/en
Priority to AT00903657T priority patent/ATE279190T1/en
Priority to EP00903657A priority patent/EP1165069B1/en
Priority to DK00903657T priority patent/DK1165069T3/en
Priority to KR1020017010757A priority patent/KR20010102364A/en
Priority to JP2000600643A priority patent/JP2002537333A/en
Priority to CA002361826A priority patent/CA2361826A1/en
Priority to DE60014873T priority patent/DE60014873T2/en
Priority to AU25459/00A priority patent/AU773506B2/en
Publication of WO2000050032A1 publication Critical patent/WO2000050032A1/en
Priority to HK02106054.8A priority patent/HK1044466A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates in general to the field of cancer treatment and, more particularly, provides an antitumor composition comprising an alkylating anthracycline and a topoisomerase II inhibitor, having a synergistic or additive antineoplastic effect.
  • the present invention provides, in a first aspect, a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, comprising - an alkylating anthracycline of formula la or lb :
  • an antineoplastic topoisomerase II inhibitor and a pharmaceutically acceptable carrier or excipient.
  • alkylating anthracyclines of formula la and lb are 4-demethoxy-3' -deamino-3' -aziridinyl- 4' - ethansulfonyl daunorubicin (la) and 4-demethoxy-N, N- bis (2-chloroethyl) -4' -methansulfonyl daunorubicin (lb).
  • alkylating anthracyclines were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in US-A-5, 532, 218 and US-A-5, 496, 800.
  • Topoisomerase II inhibitors are described in various scientific publications.
  • the main representatives of this wide class of drugs are: the anthracycline derivatives such as doxorubicin, daunorubicin, epirubicin, nemorubicin and idarubicin; the podophyllotoxin compounds etoposide and teniposide; the anthraquinone derivative like mitoxantrone and amsacrine. See for example the review: Cancer,
  • Doxorubicin and etoposide are the preferred topoisomerase II inhibitors to be used in the present invention.
  • the present invention also provides a product comprising an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor, as combined preparation for simultaneous, separate or sequential use in antitumor therapy.
  • a further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neoplastic disease state comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor, in amounts effective to produce a synergistic antineoplastic effect.
  • the present invention also provides a method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent in mammals, including humans, in need thereof, the method comprising administering to said mammal a combination preparation comprising an antineoplastic topoisomerase II inhibitor as defined above and an alkylating anthracycline of formula la or lb, as defined above, in amounts effective to produce a synergistic antineoplastic effect.
  • a synergistic antineoplastic effect as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an alkylating anthracycline of formula la or lb as defined above and a topoisomerase II inhibitor to mammals, including human.
  • * administered w or * administering as used herein is meant parenteral and /or oral administration.
  • w parenteral is meant intravenous, subcutaneus and intramuscolar administration.
  • the alkylating anthracycline may be administered simultaneously with the compound with the topoisomerase II inhibitor activity, for example of the anthracycline or etoposide class, or the compounds may be administered sequentially, in either order.
  • the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the alkylating anthracycline of formula la or lb being utilized, the particular formulation of the topoisomerase II inhibitor, such as one of the anthracycline or etoposide class, being utilized, the particular tumor model being treated, and the particular host being treated.
  • the course of therapy generally employed is from about 0.1 to about 200 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m 2 of body surface area.
  • the course of therapy generally employed is from about 1 to about 1000 mg/m 2 of body surface area. More preferably, the course therapy employed is from about 10 to about 500 mg/m 2 of body surface area.
  • the antineoplastic therapy of the present invention is in particular suitable for treating breast, ovary lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors in mammals, including humans.
  • the present invention is directed to the preparation of a pharmaceutical composition containing an effective amount of an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor in the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis .
  • the effect of an alkylating anthracycline of formula la or lb and a topoisomerase II inhibitor, such as an anthracycline or etoposide derivative is significantly increased without a parallel increased toxicity.
  • the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline and of the topoisomerase II inhibitor and thus yields the most effective and least toxic treatment for tumors.
  • the superadditive actions of the combination preparation of the present invention are shown for instance by the following in vi vo tests, which are intended to illustrate but not to limit the present invention.
  • Table 1 shows the antileukemic activity on disseminated L1210 murine leukemia obtained combining la with etoposide.
  • etoposide alone day +3
  • 1 mg/kg of la alone days +1,2
  • ILS° values 100 and 67
  • Table 2 shows the antileukemic activity on disseminated L1210 murine leukemia obtained combining la with doxorubicin.
  • doxorubicin alone (day +3) and at the dose of 1.5 mg/kg of la alone (days +1,2) were associated, without toxicity, with ILS° values of 50 and 67, respectively.
  • ILS° values 50 and 67, respectively.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

There are provided the combined use of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methansulfonyl daunorubicin or 4-demethoxy-N,N-bis(2-chloroethyl)-4'-methansulfonyl daunorubicin and an antineoplastic topoisomerase II inhibitor in the treatment of tumors and the use of said combination in the treatment or prevention of metastasis or in the treatment of tumors by inhibition of angiogenesis.

Description

Anti umour Synergistic Composition
The present invention relates in general to the field of cancer treatment and, more particularly, provides an antitumor composition comprising an alkylating anthracycline and a topoisomerase II inhibitor, having a synergistic or additive antineoplastic effect. The present invention provides, in a first aspect, a pharmaceutical composition for use in antineoplastic therapy in mammals, including humans, comprising - an alkylating anthracycline of formula la or lb :
Figure imgf000003_0001
an antineoplastic topoisomerase II inhibitor, and a pharmaceutically acceptable carrier or excipient.
The chemical names of the alkylating anthracyclines of formula la and lb are 4-demethoxy-3' -deamino-3' -aziridinyl- 4' - ethansulfonyl daunorubicin (la) and 4-demethoxy-N, N- bis (2-chloroethyl) -4' -methansulfonyl daunorubicin (lb). These alkylating anthracyclines were described in Anticancer Drug Design (1995), vol. 10, 641-653, and claimed respectively in US-A-5, 532, 218 and US-A-5, 496, 800. Both compounds intercalate into DNA via the chromophore and alkylate guanine at N7 position in DNA minor groove via their reactive moiety on position 3' of the amino sugar. Compounds la and lb are able to circumvent the resistance to all major classes of cytotoxics, indicating that the compounds represent a new class of cytotoxic antitumor drugs .
Topoisomerase II inhibitors are described in various scientific publications. The main representatives of this wide class of drugs are: the anthracycline derivatives such as doxorubicin, daunorubicin, epirubicin, nemorubicin and idarubicin; the podophyllotoxin compounds etoposide and teniposide; the anthraquinone derivative like mitoxantrone and amsacrine. See for example the review: Cancer,
Principles and Practice of Oncology, Lippincott-Raven Ed.
(1997), 452-467. Doxorubicin and etoposide are the preferred topoisomerase II inhibitors to be used in the present invention. The present invention also provides a product comprising an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor, as combined preparation for simultaneous, separate or sequential use in antitumor therapy. A further aspect of the present invention is to provide a method of treating a mammal including humans, suffering from a neoplastic disease state comprising administering to said mammal an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor, in amounts effective to produce a synergistic antineoplastic effect.
The present invention also provides a method for lowering the side effects caused by antineoplastic therapy with an antineoplastic agent in mammals, including humans, in need thereof, the method comprising administering to said mammal a combination preparation comprising an antineoplastic topoisomerase II inhibitor as defined above and an alkylating anthracycline of formula la or lb, as defined above, in amounts effective to produce a synergistic antineoplastic effect.
By the term *a synergistic antineoplastic effect" as used herein is meant the inhibition of the growth tumor, preferably the complete regression of the tumor, administering an effective amount of the combination of an alkylating anthracycline of formula la or lb as defined above and a topoisomerase II inhibitor to mammals, including human. By the term * administered w or * administering" as used herein is meant parenteral and /or oral administration. By wparenteral" is meant intravenous, subcutaneus and intramuscolar administration. In the method of the subject invention, the alkylating anthracycline may be administered simultaneously with the compound with the topoisomerase II inhibitor activity, for example of the anthracycline or etoposide class, or the compounds may be administered sequentially, in either order. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the alkylating anthracycline of formula la or lb being utilized, the particular formulation of the topoisomerase II inhibitor, such as one of the anthracycline or etoposide class, being utilized, the particular tumor model being treated, and the particular host being treated.
In the method of the subject invention, for the administration of the alkylating anthracycline of formula la or lb, the course of therapy generally employed is from about 0.1 to about 200 mg/m2 of body surface area. More preferably, the course therapy employed is from about 1 to about 50 mg/m2 of body surface area.
In the method of the subject invention, for the administration of the topoisomerase II inhibitor the course of therapy generally employed is from about 1 to about 1000 mg/m2 of body surface area. More preferably, the course therapy employed is from about 10 to about 500 mg/m2 of body surface area. The antineoplastic therapy of the present invention is in particular suitable for treating breast, ovary lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors in mammals, including humans. In a further aspect, the present invention is directed to the preparation of a pharmaceutical composition containing an effective amount of an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor in the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an alkylating anthracycline of formula la or lb as defined above and an antineoplastic topoisomerase II inhibitor for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis . As stated above, the effect of an alkylating anthracycline of formula la or lb and a topoisomerase II inhibitor, such as an anthracycline or etoposide derivative, is significantly increased without a parallel increased toxicity. In other words, the combined therapy of the present invention enhances the antitumoral effects of the alkylating anthracycline and of the topoisomerase II inhibitor and thus yields the most effective and least toxic treatment for tumors. The superadditive actions of the combination preparation of the present invention are shown for instance by the following in vi vo tests, which are intended to illustrate but not to limit the present invention.
Table 1 shows the antileukemic activity on disseminated L1210 murine leukemia obtained combining la with etoposide. At the dose of 30 mg/kg of etoposide alone (day +3) and at the dose of 1 mg/kg of la alone (days +1,2) were associated, without toxicity, with ILS° values of 100 and 67, respectively. Combining etoposide and la at the same doses with the same schedule an increase of activity with ILS% values of 450 was observed, indicating a synergistic effect .
Table 2 shows the antileukemic activity on disseminated L1210 murine leukemia obtained combining la with doxorubicin. At the dose of 13 mg/kg of doxorubicin alone (day +3) and at the dose of 1.5 mg/kg of la alone (days +1,2) were associated, without toxicity, with ILS° values of 50 and 67, respectively. Combining doxorubicin and la at the same doses with the same schedule an increase of activity with ILS% values of 150 was observed, indicating a synergistic effect.
For these experiments la was solubilized in [Cremophor® /EtOH= 6.5:3.5] / [normal saline] =20/80 v/v, while standard etoposide pharmaceutical preparation and doxorubicin solubilized in water were used.
Table 1: Antileukemic activity against disseminated L12101 murine leukemia of la in combination with Etoposide
Figure imgf000007_0001
Table 2: Antileukemic activity against disseminated L1210:ι murine leukemia of la in combination with Doxorubicin
Figure imgf000007_0002
Figure imgf000008_0001
1)L1210 leukemia cells (lOVmouse) are injected iv on day
0.
2) Treatment is given starting on day 1 after tumor transplantation (day 0) .
3) Increase in life span: [(median survival time of treated mice/median survival time of controls) x 100] -100
4) Number of toxic deaths/number of mice.
5) Long Term Survivors (>60 days) at the end the experiment.

Claims

Claims
1. Products containing an alkylating anthracycline of formula la or lb:
Figure imgf000009_0001
and an antineoplastic topoisomerase II inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of tumors.
2. Products according to claim 1 wherein the alkylating anthracycline is 4-demethoxy-3' -deamino-3' -aziridinyl-4' - methansulfonyl daunorubicin.
3. Products according to claim 1 or 2 wherein the topoisomerase II inhibitor is etoposide.
4. Products according to claim 1 or 2 wherein the topoisomerase II inhibitor is doxorubicin.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an alkylating anthracycline of formula la or lb as defined in claim 1 and an antineoplastic topoisomerase II inhibitor.
6. A composition according to claim 5 wherein the topoisomerase II inhibitor is doxorubicin or etoposide.
7. Use of an alkylating anthracycline of formula la or lb as defined in claim 1 and an antineoplastic topoisomerase II inhibitor in the preparation of a medicament for use in the treatment of tumors.
8. Use according to claim 7 wherein the topoisomerase II inhibitor is etoposide or doxorubicin.
9. Use of an alkylating anthracycline of formula la or lb as defined in claim 1 and an antineoplastic topoisomerase II inhibitor in the preparation of a medicament for use in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.
PCT/EP2000/000745 1999-02-25 2000-01-31 Antitumour synergistic composition WO2000050032A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR0008453-0A BR0008453A (en) 1999-02-25 2000-01-31 Synergistically anti-tumor composition
AT00903657T ATE279190T1 (en) 1999-02-25 2000-01-31 SYNERGISTIC COMPOSITIONS FOR CANCER TREATMENT
EP00903657A EP1165069B1 (en) 1999-02-25 2000-01-31 Antitumour synergistic composition
DK00903657T DK1165069T3 (en) 2000-01-31 2000-01-31 Synergistic antitumor preparation
KR1020017010757A KR20010102364A (en) 1999-02-25 2000-01-31 Antitumour synergistic composition
JP2000600643A JP2002537333A (en) 1999-02-25 2000-01-31 Synergistic antitumor composition
CA002361826A CA2361826A1 (en) 1999-02-25 2000-01-31 Antitumour synergistic composition
DE60014873T DE60014873T2 (en) 1999-02-25 2000-01-31 SYNERGISTIC COMPOSITIONS FOR CANCER TREATMENT
AU25459/00A AU773506B2 (en) 1999-02-25 2000-01-31 Antitumour synergistic composition
HK02106054.8A HK1044466A1 (en) 1999-02-25 2002-08-20 Antitumour synergistic composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9904387.9 1999-02-25
GBGB9904387.9A GB9904387D0 (en) 1999-02-25 1999-02-25 Antitumour synergistic composition

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KR (1) KR20010102364A (en)
CN (1) CN1155378C (en)
AR (1) AR043082A1 (en)
AT (1) ATE279190T1 (en)
AU (1) AU773506B2 (en)
BR (1) BR0008453A (en)
CA (1) CA2361826A1 (en)
DE (1) DE60014873T2 (en)
ES (1) ES2230060T3 (en)
GB (1) GB9904387D0 (en)
HK (1) HK1044466A1 (en)
MY (1) MY135985A (en)
PT (1) PT1165069E (en)
TW (1) TW518223B (en)
WO (1) WO2000050032A1 (en)
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