WO2000050033A2 - Anti-tumor synergetic composition - Google Patents

Anti-tumor synergetic composition Download PDF

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Publication number
WO2000050033A2
WO2000050033A2 PCT/EP2000/000746 EP0000746W WO0050033A2 WO 2000050033 A2 WO2000050033 A2 WO 2000050033A2 EP 0000746 W EP0000746 W EP 0000746W WO 0050033 A2 WO0050033 A2 WO 0050033A2
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Prior art keywords
treatment
tumor
anthracyclme
neoplastic
platinum derivative
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PCT/EP2000/000746
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French (fr)
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WO2000050033A3 (en
Inventor
Cristina Geroni
Marina Ripamonti
Michele Caruso
Antonino Suarato
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Pfizer Italia SRL
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Pharmacia and Upjohn SpA
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Priority to AU26681/00A priority Critical patent/AU774393B2/en
Priority to KR1020017010871A priority patent/KR20010102402A/en
Priority to NZ513352A priority patent/NZ513352A/en
Priority to AT00904990T priority patent/ATE286391T1/en
Priority to DE60017250T priority patent/DE60017250D1/en
Priority to US09/926,055 priority patent/US6593303B1/en
Priority to CA002361828A priority patent/CA2361828A1/en
Priority to EP00904990A priority patent/EP1169035B1/en
Priority to BR0008454-9A priority patent/BR0008454A/en
Priority to JP2000600644A priority patent/JP2002537334A/en
Priority to HK02104132.9A priority patent/HK1042249A1/en
Publication of WO2000050033A2 publication Critical patent/WO2000050033A2/en
Publication of WO2000050033A3 publication Critical patent/WO2000050033A3/en
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 m general to the field of cancer treatment and, more particularly, provides an anti- tumor composition comprising an alkylatmg anthracyclme and an anti-mitotic compound and/or a platinum derivative, having a synergistic or additive anti-neoplastic effect.
  • the present invention provides, m a first aspect, a pharmaceutical composition for use m anti-neoplastic therapy m mammals, including humans, comprising - an anthracyclme of formula la or lb :
  • an anti-neoplastic anti-mitotic compound and/or a platinum derivative an anti-neoplastic anti-mitotic compound and/or a platinum derivative, and a pharmaceutically acceptable carrier or excipient.
  • the chemical names of the anthracyclmes of formula la and lb are 4-demethoxy-3' -deammo-3' -az ⁇ r ⁇ dmyl-4 ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl) -4' -methansulfonyl daunorubicin (lb). These anthracyclmes were described m Anticancer Drug Design
  • the mam representatives of the anti-mitotic class are: Paclitaxel, Docetaxel, Vmblastme, Vmcristme, Vmdesme and Vmorelbme; see for example the review: Cancer, Principles and Practice of Oncology, Lippmcott-Raven Ed.
  • 4-Demethoxy-3' -deammo-3' -az ⁇ dmyl-4' -methansulfonyl daunorubicin is the preferred compound to be used m the present invention, more preferably m combination with oxaliplatm docetaxel or paclitaxel.
  • the present invention also provides a product comprising an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, as combined preparation for simultaneous, separate or sequential use m antitu or 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 anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, m amounts effective to produce a synergetic anti-neoplastic effect.
  • the present invention also provides a method for lowering the side effects caused by anti-neoplastic therapy with an anti-neoplastic agent m mammals, including humans, m need thereof, the method comprising administering to said mammal a combination preparation comprising an anti-neoplastic anti-mitotic compound and/or a platinum derivative as defined above and an anthracyclme of formula la or lb, as defined above, m amounts effective to produce a synergistic anti-neoplastic effect.
  • a synergistic anti-neoplastic 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 anthracyclme of formula la or lb as defined above and an anti-mitotic compound and/or a platinum derivative to mammals, including human.
  • V ⁇ administered w or * administering as used herein is meant parenteral and /or oral administration.
  • X parenteral is meant intravenous, subcutaneous and mtramuscolar administration.
  • the anthracyclme may be administered simultaneously with the compound with anti-mitotic activity, and/or a platinum derivative, or the compounds may be administered sequentially, m either order.
  • 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 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 " of body surface area. In the method of the subject invention, for the administration of the platinum derivative 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 100 to about 500 mg/m of body surface area.
  • the anti-neoplastic therapy of the present invention is m particular suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m mammals, including humans .
  • the present invention is directed to the preparation of a pharmaceutical composition containing an effective amount of an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative m the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an anthracyclme of formula I_a or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis.
  • an anthracyclme of formula la or lb and an anti-neoplastic anti-mitotic compounds, such as taxane derivatives, and/or a platinum 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/or of the anti-mitotic compound and/or of the platinum derivative and thus yields the most effective and less 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 oxaliplatinum.
  • oxaliplatmum alone day +3
  • I_a alone day +1,2
  • increase in life span ILS?>
  • L1210 leukemia cells (10 5 /mouse) are injected iv on day 0 2) Treatment is given starting on day 1 after tumor transplantation (day 0).
  • Table 2 shows the antitumor effect on subcutaneous implanted A549 human lung carcinoma obtained combining la with CisPlatin. At the doses of 3 mg/kg of CisPlatin alone (q4dx2) and at the dose of 1.5 mg/kg of la alone (q4dx3) were associated, without toxicity, with T.I.o values of 16 and 48, respectively. Combining CisPlatin and I_a, a significant increase in tumor growth delay was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone.
  • T median time to reach a tumor size of 1 g treated nude mice
  • C median time to reach a tumor size of 1 g in control nude mice.
  • Table 3 shows the antitumor effect on subcutaneus implanted A549 human lung carcinoma obtained combining la with paclitaxel.
  • paclitaxel alone days +9, 13, 17
  • 2 mg/kg of la. alone days +7, 11, 15
  • T.I.% values 69,90 and 93
  • T median time to reach a tumor size of 1 g treated nude mice
  • C median time to reach a tumor size of 1 g in control nude mice.
  • Table 4 shows the antitumor effect on subcutaneous implanted H207 human ovarian carcinoma obtained combining la with paclitaxel.
  • paclitaxel at the doses of 22 and 33 mg/kg of paclitaxel alone (q4dx3)and at the dose of 1.5 mg/kg of la. alone (q4dx3) were associated, without toxicity, with T . I . % values of 100,80 and 86, respectively.
  • T . I . % values 100,80 and 86, respectively.
  • Combining paclitaxel and I_a a significant increase in tumor growth delay and the appearance of the tumor free survivors (1/7 and 4/7) was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone.
  • T median time to reach a tumor size of 1 g treated nude mice
  • C median time to reach a tumor size of 1 g in control nude mice.
  • Table 5 shows the antitumor effect on subcutaneous injected MX1 mammary carcinoma obtained combining la with docetaxel.
  • docetaxel alone q4dx3
  • I_a alone q4dx3
  • T . I . % values 60,99 and 46,94 respectively.
  • docetaxel and la a significant increase in tumor growth delay and of the tumor free survivors (3/8, 5/8 and 7/8) was observed indicating a therapeutic advantage of the combination m comparison with the administration of the drug alone.
  • TGD Tumor growth delay treated - Tumor growth delay control

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  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
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  • 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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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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 anti-neoplastic anti-mitotic compound and/or a platinum derivative in the treatment of tumors, as well as in the prevention or treatment of metastasis or in the treatment of tumors by inhibition of angiogenesis.

Description

Anti-tumor Synergetic Composition
The present invention relates m general to the field of cancer treatment and, more particularly, provides an anti- tumor composition comprising an alkylatmg anthracyclme and an anti-mitotic compound and/or a platinum derivative, having a synergistic or additive anti-neoplastic effect. The present invention provides, m a first aspect, a pharmaceutical composition for use m anti-neoplastic therapy m mammals, including humans, comprising - an anthracyclme of formula la or lb :
Figure imgf000003_0001
- an anti-neoplastic anti-mitotic compound and/or a platinum derivative, and a pharmaceutically acceptable carrier or excipient.
The chemical names of the anthracyclmes of formula la and lb are 4-demethoxy-3' -deammo-3' -azιrιdmyl-4 ' - methansulfonyl daunorubicin (la) and 4-demethoxy-N, N-bis (2- chloroethyl) -4' -methansulfonyl daunorubicin (lb). These anthracyclmes were described m Anticancer Drug Design
(1995), vol. 10, 641-653, and claimed respectively m US-A-
5,532,218 and US-A-5, 496, 800. Both compounds intercalate into DNA via the chromophore and alkylate guanme at N position m DNA minor groove via their reactive moiety on position 3' of the ammo 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 anti-tumor drugs. Anti-mitotic and platinum derivatives anti-neoplastic agents are described m various scientific publications. The mam representatives of the anti-mitotic class are: Paclitaxel, Docetaxel, Vmblastme, Vmcristme, Vmdesme and Vmorelbme; see for example the review: Cancer, Principles and Practice of Oncology, Lippmcott-Raven Ed.
(1997), 467-483. Platinum derivatives used m clinical practice are: CisPlatm, Carboplatm, Oxaliplatm,
Nedaplatm and Lobaplatm; see review Cancer, Principles and Practice of Oncology, Lippmcott-Raven Ed. (1997), 418- 432.
4-Demethoxy-3' -deammo-3' -azιπdmyl-4' -methansulfonyl daunorubicin is the preferred compound to be used m the present invention, more preferably m combination with oxaliplatm docetaxel or paclitaxel. The present invention also provides a product comprising an anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, as combined preparation for simultaneous, separate or sequential use m antitu or 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 anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative, m amounts effective to produce a synergetic anti-neoplastic effect.
The present invention also provides a method for lowering the side effects caused by anti-neoplastic therapy with an anti-neoplastic agent m mammals, including humans, m need thereof, the method comprising administering to said mammal a combination preparation comprising an anti-neoplastic anti-mitotic compound and/or a platinum derivative as defined above and an anthracyclme of formula la or lb, as defined above, m amounts effective to produce a synergistic anti-neoplastic effect.
By the term *a synergistic anti-neoplastic 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 anthracyclme of formula la or lb as defined above and an anti-mitotic compound and/or a platinum derivative to mammals, including human. By the term Vλ administered w or * administering" as used herein is meant parenteral and /or oral administration. By Xparenteral" is meant intravenous, subcutaneous and mtramuscolar administration. In the method of the subject invention, the anthracyclme may be administered simultaneously with the compound with anti-mitotic activity, and/or a platinum derivative, or the compounds may be administered sequentially, m 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 anthracyclme of formula la or lb being utilized, the particular formulation of the anti-mitotic compound, such as one of taxane analog class and of the platinum derivative 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 anthracyclme 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/m of body surface area.
In the method of the subject invention, for the administration of the anti-mitotic compounds 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/m" of body surface area. In the method of the subject invention, for the administration of the platinum derivative 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 100 to about 500 mg/m of body surface area. The anti-neoplastic therapy of the present invention is m particular suitable for treating breast, ovary, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemia and brain tumors m 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 anthracyclme of formula la or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative m the prevention or treatment of metastasis or for the treatment of tumors by angiogenesis inhibition, as well as to the use of an anthracyclme of formula I_a or lb as defined above and an anti-neoplastic anti-mitotic compound and/or a platinum derivative for the treatment of tumors by angiogenesis inhibition or for the treatment or prevention of metastasis.
As stated above, the effect of an anthracyclme of formula la or lb and an anti-neoplastic anti-mitotic compounds, such as taxane derivatives, and/or a platinum 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/or of the anti-mitotic compound and/or of the platinum derivative and thus yields the most effective and less 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 oxaliplatinum. At the dose of 8 mg/kg of oxaliplatmum alone (day +3) and at the dose of 1 mg/kg of I_a alone (day +1,2) were associated, without toxicity, with increase in life span (ILS?>) values of 83 for both. Combining oxaliplatinum and la at the same doses with the same schedule an increase antitu or activity with ILS° value of 125 was observed, indicating a synergistic effect of the combination. For these experiments la was solubilized in [Cremophor® /EtOH= 6.5:3.5]/ [normal saline] =20/80 v/v, while oxaliplatinum was solubilized in saline solution.
Table 1: Antileukemic activity against disseminated L12101 murine leukemia of la in combination with Oxaliplatinum
Figure imgf000007_0001
1) L1210 leukemia cells (105/mouse) 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.
Table 2 shows the antitumor effect on subcutaneous implanted A549 human lung carcinoma obtained combining la with CisPlatin. At the doses of 3 mg/kg of CisPlatin alone (q4dx2) and at the dose of 1.5 mg/kg of la alone (q4dx3) were associated, without toxicity, with T.I.o values of 16 and 48, respectively. Combining CisPlatin and I_a, a significant increase in tumor growth delay was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone.
Table 2: Antitumor activity on A549 human lung carcinoma1 of la in combination with CisPlatin
Figure imgf000008_0001
1) Tumor fragments are implanted s.c.
2) Treatment is given starting when the tumor is palpable.
3) Tumor inhibiton.
4) Number of toxic deaths/number of mice.
5 ) umor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice.
6) reatment with CisPlatin started two days after treatment with la Table 3 shows the antitumor effect on subcutaneus implanted A549 human lung carcinoma obtained combining la with paclitaxel. At the doses of 22 and 33 mg/kg of paclitaxel alone (days +9, 13, 17) and at the dose of 2 mg/kg of la. alone (days +7, 11, 15) were associated, without toxicity, with T.I.% values of 69,90 and 93, respectively. Combining paclitaxel and la., a significant increase in tumour growth delay was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone.
Table 3: Antitumor activity on A549 human lung carcinoma1 of la in combination with paclitaxel
Figure imgf000009_0001
1) Tumor fragments are implanted s.c.
2) Treatment is given starting when the tumor is palpable.
3) Tumor inhibiton.
4) Number of toxic deaths/number of mice.
5) Tumor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice.
Table 4 shows the antitumor effect on subcutaneous implanted H207 human ovarian carcinoma obtained combining la with paclitaxel. At the doses of 22 and 33 mg/kg of paclitaxel alone (q4dx3)and at the dose of 1.5 mg/kg of la. alone (q4dx3) were associated, without toxicity, with T . I . % values of 100,80 and 86, respectively. Combining paclitaxel and I_a, a significant increase in tumor growth delay and the appearance of the tumor free survivors (1/7 and 4/7) was observed indicating a therapeutic advantage of the combination in comparison with the administration of the drug alone.
Table 4: Antitumor activity on H207 human ovarian carcinoma1 of la in combination with paclitaxel
Figure imgf000010_0001
1) Tumor fragments are implanted s.c.
2) Treatment is given starting when the tumor is palpable.
3) Tumor inhibiton.
4) Number of toxic deaths/number of mice.
5) Tumor growth delay; T, median time to reach a tumor size of 1 g treated nude mice; C, median time to reach a tumor size of 1 g in control nude mice.
6) Treatment with paclitaxel started two days after treatment with la
Table 5 shows the antitumor effect on subcutaneous injected MX1 mammary carcinoma obtained combining la with docetaxel. At the doses of 5 and 10 mg/kg of docetaxel alone (q4dx3)and at the dose of 0.5 and 1 mq/kg of I_a alone (q4dx3) were associated, without toxicity, with T . I . % values of 60,99 and 46,94 respectively. Combining docetaxel and la, a significant increase in tumor growth delay and of the tumor free survivors (3/8, 5/8 and 7/8) was observed indicating a therapeutic advantage of the combination m comparison with the administration of the drug alone.
Table 5: Antitumor activity on MXl mammary carcinoma1 of la m combination with paclitaxel
Figure imgf000011_0001
1) Tumor fragments were injected s.c.
2) Treatment is given starting when the tumor is palpable.
3) Tumor mhibiton.
4) Number of toxic deaths/number of mice.
5) TGD : Tumor growth delay treated - Tumor growth delay control

Claims

Claims
1. Products containing an anthracyclme of formula la or lb :
Figure imgf000012_0001
and an anti-neoplastic anti-mitotic compound and/or a platinum derivative as a combined preparation for simultaneous, separate or sequential use m the treatment of tumors.
2. Products according to claim 1 wherein the anthracyclme is 4-demethoxy-3' -deammo-3' -azιπdmyl-4' -methansulfonyl daunorubicin .
3. Products according to claim 1 or 2 wherein the anti- mitotic compound is paclitaxel or docetaxel.
4. Products according to claim 1 or 2 wherein the platinum derivative is oxaliplatm.
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and, as active ingredient, an anthracyclme of formula la or lb as defined claim 1 and an anti-neoplastic anti-mitotic compound and/or a platinum derivative .
6. A composition according to claim 5 wherein the anthracyclme is 4-demethoxy-3' -deammo-3' -azιrιdmyl-4' - methansulfonyl daunorubicin.
7. Use of an anthracycline of formula la or lb as defined in claim 1 and an anti-neoplastic anti-mitotic compound and/or a platinum derivative in the preparation of a medicament for use in the treatment of tumors.
8. Use according to claim 7 wherein the anthracycline is 4- demethoxy-3' -deamino-3' -aziridinyl-4' -methansulfonyl daunorubicin .
9. Use of a product as defined in claim 1 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/EP2000/000746 1999-02-25 2000-01-31 Anti-tumor synergetic composition Ceased WO2000050033A2 (en)

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Application Number Priority Date Filing Date Title
AU26681/00A AU774393B2 (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
KR1020017010871A KR20010102402A (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
NZ513352A NZ513352A (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
AT00904990T ATE286391T1 (en) 1999-02-25 2000-01-31 SYNERGISTIC COMPOSITION FOR CANCER TREATMENT
DE60017250T DE60017250D1 (en) 1999-02-25 2000-01-31 SYNERGISTIC COMPOSITION FOR CANCER TREATMENT
US09/926,055 US6593303B1 (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
CA002361828A CA2361828A1 (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
EP00904990A EP1169035B1 (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition
BR0008454-9A BR0008454A (en) 1999-02-25 2000-01-31 Synergistically anti-tumor composition
JP2000600644A JP2002537334A (en) 1999-02-25 2000-01-31 Synergistic antitumor composition
HK02104132.9A HK1042249A1 (en) 1999-02-25 2000-01-31 Anti-tumor synergetic composition

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GBGB9904386.1A GB9904386D0 (en) 1999-02-25 1999-02-25 Antitumour synergistic composition
GB9904386.1 1999-02-25

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EP3909998A2 (en) 2005-04-22 2021-11-17 Mitsubishi Chemical Corporation Biomass-resource-derived polyester and production process thereof

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EP3909998A2 (en) 2005-04-22 2021-11-17 Mitsubishi Chemical Corporation Biomass-resource-derived polyester and production process thereof
EP3919543A2 (en) 2005-04-22 2021-12-08 Mitsubishi Chemical Corporation Biomass-resource-derived polyester and production process thereof
EP3925996A2 (en) 2005-04-22 2021-12-22 Mitsubishi Chemical Corporation Biomass-resource-derived polyester and production process thereof
EP3925997A2 (en) 2005-04-22 2021-12-22 Mitsubishi Chemical Corporation Biomass-resource-derived polyester and production process thereof

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ATE286391T1 (en) 2005-01-15
US6593303B1 (en) 2003-07-15
AR022719A1 (en) 2002-09-04
BR0008454A (en) 2002-01-29
WO2000050033A3 (en) 2000-12-21
KR20010102402A (en) 2001-11-15
GB9904386D0 (en) 1999-04-21
AU774393B2 (en) 2004-06-24
MY125222A (en) 2006-07-31
CN1341020A (en) 2002-03-20
NZ513352A (en) 2003-08-29
JP2002537334A (en) 2002-11-05
HK1042249A1 (en) 2002-08-09
CA2361828A1 (en) 2000-08-31
EP1169035A2 (en) 2002-01-09
ZA200106210B (en) 2002-10-28

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