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WO1997034627A2 - Protection de cellules hematopoietiques durant une chimiotherapie ou une radiotherapie - Google Patents

Protection de cellules hematopoietiques durant une chimiotherapie ou une radiotherapie Download PDF

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Publication number
WO1997034627A2
WO1997034627A2 PCT/IB1997/000499 IB9700499W WO9734627A2 WO 1997034627 A2 WO1997034627 A2 WO 1997034627A2 IB 9700499 W IB9700499 W IB 9700499W WO 9734627 A2 WO9734627 A2 WO 9734627A2
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WO
WIPO (PCT)
Prior art keywords
subject
radiotherapy
chemotherapy
hemopoiesis
cytotoxic agent
Prior art date
Application number
PCT/IB1997/000499
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English (en)
Other versions
WO1997034627A3 (fr
Inventor
Joanna Wdzieczak-Bakala
Anne Rousseau-Plasse
Maryse Lenfant
Pierre Corvol
Marie-Therese Chauvet
Original Assignee
Societe De Conseils De Recherches Et D'applications Scientifiques S.A.
Institut National De La Sante Et De La Recherche Medicale
Priority date (The priority date 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 date listed.)
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Application filed by Societe De Conseils De Recherches Et D'applications Scientifiques S.A., Institut National De La Sante Et De La Recherche Medicale filed Critical Societe De Conseils De Recherches Et D'applications Scientifiques S.A.
Publication of WO1997034627A2 publication Critical patent/WO1997034627A2/fr
Publication of WO1997034627A3 publication Critical patent/WO1997034627A3/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • BflgKqrpu,nd of the invention
  • Acute and chronic bone marrow toxicities are the major limiting factors in the treatment of cancer. They are both related to (1) a decrease in the number of hemopoietic cells (e.g., pluripotent stem cells and other progenitor cells) caused by both a lethal effect of cytotoxic agents or radiation on these cells and by differentiation of stem cells provoked by a feed-back mechanism induced by the depletion of more mature marrow compartments and (2) a reduction in self-renewal capacity of stem cells, which is also related to both direct (mutation) and indirect (aging of stem cell population) effects.
  • Acute myelosuppression as a consequence of cytotoxic chemotherapy is well recognized as a dose-limiting factor in cancer treatment. Although other normal tissues may be adversely affected, bone marrow is particularly sensitive to the proliferation-specific treatment such as chemotherapy or radiotherapy.
  • Angiotensin I-Converting Enzyme (peptidyl dipeptidase A, kininase II, EC 3.4.15.1) is a zinc- dipeptidyl carboxypeptidase, whose major physiological function is to cleave the C-terminal dipeptide of angiotensin I (AI) leading to the production of the potent vasoconstrictor angiotensin II (A l) (Skeggs, LT, et al., J. Exp. Med. 103:295 (1956)).
  • ACE Angiotensin I-Converting Enzyme
  • the present invention relates to a method of promoting regeneration of hemopoietic cells in a subject undergoing chemotherapy or radiotherapy.
  • the present invention features a method of promoting regeneration of hemopoietic cells in a subject undergoing chemotherapy or radiotherapy, the method comprising administering to the subject an angiotensin- converting enzyme inhibitor, the amount being effective to reduce the proliferation of hemopoietic cells during or after the chemotherapy or radiotherapy.
  • the method further comprises administering to the subject a hemopoiesis growth factor after the administration of angiotensin-converting enzyme inhibitor and chemotherapy or radiotherapy, the amount being effective to stimulate the proliferation or differentiation of hemopoietic cells.
  • chemotherapy is meant a process of killing proliferating cells using a cytotoxic agent and by “radiotherapy” is meant a process of killing proliferating cells by using irradiation.
  • the subject may intentionally or unintentionally be exposed to said cytotoxic agents or irradiation.
  • the phrase “during the chemotherapy” or “during the radiotherapy” above refers to the period in which the ef ect of the administered cytotoxic agent or irradiation lasts.
  • the phrase “after the chemotherapy” or “after the radiotherapy” above is meant to cover all situations in which an angiotensin converting enzyme inhibitor is administered after the administration of a cytotoxic agent or irradiation regardless of any prior administration of the same or another angiotensin converting enzyme inhibitor and also regardless of the persistence of the effect of the administered cytotoxic agent or irradiation.
  • angiotensin converting enzyme inhibitor By angiotensin converting enzyme inhibitor (“ACE inhibitor”) is meant a compound which is capable of inhibiting the binding to ACE of its substrates.
  • ACE inhibitors include, but are not limited to, lisinopril, captopril, enalapril, and fosinopril.
  • hemopoiesis growth factor examples include, but are not limited to, cytokines or agonists thereof, such as natural, synthetic or modified interleukins (e.g., IL-1, IL-3, IL-6, IL-11, or its agonist), G-CSF (i.e., granulocyte colony- stimulating factor), GH-CSF (i.e., granulocyte/ macrophage- colony stimulating factor) , erythropoietin, stem cell factor, and leukemia inhibitory factor.
  • cytokines or agonists thereof such as natural, synthetic or modified interleukins (e.g., IL-1, IL-3, IL-6, IL-11, or its agonist), G-CSF (i.e., granulocyte colony- stimulating factor), GH-CSF (i.e., granulocyte/ macrophage- colony stimulating factor) , erythropoietin, stem cell factor, and leukemia inhibitory factor.
  • cytotoxic agent an agent which kills proliferating cells, e.g., tumor cells, virally infected cells, or hemopoietic progenitor cells.
  • cytotoxic agent which can be used to practice the above method include, but are not limited to, cyclophosphamide, taxol, daunorubicine, 5-fluorouracil, adriamycin, cisplatinum, methotrexate, cytosine arabino ⁇ ide, mitomycin C, prednisone, vindesine, carboplatinum, vincristine, and an agonist of any of the above compounds.
  • a cytotoxic agent can also be an antiviral agent, e.g., AZT (i.e., 3 # -a*ido- 3'-deoxythymidine) .
  • the subject is undergoing radiotherapy.
  • chemotherapy and “radiotherapy” used herein refer to the process of killing proliferating cells by administration of a cytotoxic agent or by irradiation. Radiotherapy includes only exposure to potentially harmful irradiation.
  • the ACE inhibitor can be administered prior to, during, or subsequent to the chemotherapy or radiotherapy (i.e., prior to, during, or subsequent to the administration of a cytotoxic agent or irradiation) .
  • a he opoiesis growth factor be administered subsequent to the administration of the ACE inhibitor.
  • the timing of when to administer an ACE inhibitor depends on the half life of the compound, the duration of its inhibitory activity, the administration route, etc., as well as the conditions of the chemotherapy or radiotherapy (e.g., the half life of the cytotoxic agent which is used in chemotherapy) .
  • the effective amount of the ACE inhibitor or growth factor used to practice the present invention varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated. Ultimately, it will be decided by the attending veterinarian or physician. Any such amount of the ACE inhibitor or the growth factor as determined by the attending veterinarian or physician is referred to herein as "effective amount”.
  • the ACE inhibitor and the hemopoiesis growth factor may be administered by any route appropriate to the condition being treated. Preferably, it is administered orally or injected into the bloodstream of the subject being treated.
  • the route such as intravenous, subcutaneous, intramuscular, intraperitoneal, nasal, oral, etc., will vary with the condition being treated and the activity of the compound being used.
  • continuous administration using a subcutaneous infusion pump may be desirable when the compound to be used has a rather short half life or lacks long-lasting activity.
  • single or intermittent administration is acceptable or even preferable when the factor to be used has a long half life or long-lasting activity.
  • the ACE inhibitor or the growth factor may be conveniently presented as an ingredient of a pharmaceutical composition in unit dosage form according to any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier which constitutes one or more accessory ingredients.
  • the formulations for tablets or powders are prepared by uniformly and intimately blending the active ingredient with finely divided solid carriers, and then, if necessary as in the case of tablets, forming the product into the desired shape and size.
  • the method further comprises administering a hemopoiesis inhibitory factor.
  • the hemopoiesis inhibitory factor may be administered prior, after, or during the administration of the ACE inhibitor. If a hemopoiesis growth factor is also administered, the hemopoiesis inhibitory factor should be administered prior to the administration of the growth factor.
  • a hemopoiesis inhibitory factor which can be used to practice the above method include, but are not limited to, a transforming growth factor, an interferon, a macrophage inflammatory protein, a tumor necrosis factor, pEEDCK (i.e., pyroGlu-Glu-Asp-Cys-Ly ⁇ ) , AcSDKP (i.e., N-Acetyl-Ser-A ⁇ p- Ly ⁇ -Pro), and an agonist of any of the above factors.
  • pEEDCK i.e., pyroGlu-Glu-Asp-Cys-Ly ⁇
  • AcSDKP i.e., N-Acetyl-Ser-A ⁇ p- Ly ⁇ -Pro
  • agonist is meant an analog (with one or more modifications) or a fragment of that factor with the same desired activity, i.e., inhibiting the proliferation of hemopoietic cells.
  • angiotensin-converting enzyme (ACE) inhibitors examples include ⁇ ulfhydryl-containing inhibitors (e.g., captopril, f ⁇ ntiapril, pivalpril, zefenopril, ano- alacepril) , dicarboxyl-containing ACE inhibitors (e.g., enalapril, lisinopril, benzepril, indolapril, pentopril, indalapril, and ciazlapril) , and phosphorus-containing ACE inhibitors (e.g., fo ⁇ inopril) .
  • ⁇ ulfhydryl-containing inhibitors e.g., captopril, f ⁇ ntiapril, pivalpril, zefenopril, ano- alacepril
  • dicarboxyl-containing ACE inhibitors e.g., enalapril, lisinopril, benz
  • the hemopoiesis growth factor which can be used to practice this invention is a compound capable of stimulating the proliferation of hemopoietic cells, such a ⁇ cytokines.
  • Preferred cytokines include interleukins, GM-CSF, and G-CSF. E.g., see R. Van Furth (ed.), Hemopoietic Growth Factors and Mononuclear Phagocytes (Karges 1993) and Moore, M. article cited in the preceding paragraph.
  • Interleukin-l has shown dramatic hemopoietic protective and restorative effects against lethal doses of irradiation either alone (Neta, R. et al., J. Immunol. 136:2483, 1986) or in concert with bone marrow transfer (Oppenheim, J.J., et al. , Blood 74:2257, 1989), and against chemotherapeutic drugs such as cyclophosphamide (Castelli, M.P., et al., J. Immunol. 140:3830, 1988; Futami, H. , et al., J. Immunol.
  • GM-CSF and G-CSF have also been found to have marked restorative effects after irradiation (Tanikawa, S. , et al., Exp. Hematol. 17:883, 1989; Schuening, F.G. , et al., Blood 74:1308, 1989) or treatment with chemotherapeutic drugs both in preclinical models
  • hemopoiesis inhibitory factors see Thierry, et al., J. Med. Chem. 33:2122 (1990); Robinson, et al.. Stem Cells 11:422 (1993); Paukovits, et al.. Blood 81:1755 (1993); and Moore, et al..
  • the cytotoxic agent which can be used include cyclophosphamide, taxol, daunorubicine, 5-fluorouraeil, adriamycin, cisplatinum, methotrexate, cytosine arabino ⁇ ide, mitomycin C, prednisone, vindesine, carboplatinum, and vincristine.
  • the cytotoxic agent can also be an antiviral compound which is capable of destroying proliferating cells.
  • the method of this invention can also be applied to radiotherapy, which may comprise of either ionizing waves or particles.
  • ionizing waves include x-rays and gamma rays.
  • ionizing particles include alpha rays, beta rays, neutrons, electrons, and protons.
  • Radiotherapy may be administered externally or internally.
  • external radiotherapy include x-ray units, gamma ray units, electron beams, and neutron beams.
  • Internal radiotherapy includes both sealed and unsealed sources. Examples of sealed sources include cobalt beam units, caesium beam units, strontium applicators, yttrium rods or pellets, gold grains, or radium, cobalt or caesium needles or tubes.
  • unsealed sources include iodine, phosphorous, gold, and yttrium. See Walter, J., Cancer and Radiotherapy (Churchill Livingstone 1977) ; Ed. N.J. McNally, The Scientific Basis of Modern Radiotherapy (British Institute of Radiology 1989); and Franz Buschke and Robert G. Parker, Radiation Therapy in Cancer Management (Grove & Stratton 1972).
  • the subject undergoes repeated cycles of treatment according to the method of this invention.
  • a subsequent cycle commences only after the administration of the hemopoiesis growth factor has been terminated and the subject's blood cell counts (e.g., white blood cell count) have returned to a therapeutically acceptable level (as determined by the attending veterinarian or physician) , permitting the repeated chemotherapy or radiotherapy.
  • the subject is exposed to a hazardous level of irr diation.
  • the method of this invention can also be applied to treatment in which radiotherapy and chemotherapy are performed in conjunction.
  • mice (Charles River Laboratory, Wilmington, MA) were exposed to 2 Gy Whole-Body ⁇ -irradiation (CIS Bio International IBL 437C 137 Cs ⁇ -radiation source, Gif-Sur- Yvette, France; dose rate: 4.66 Gy/min) and received one hour later an i.p. injection of lisinopril (10 mg/kg body weight) in saline vehicle. Appropriate saline injected controls were used. At specific times after irradiation, mice were sacrificed by cervical dislocation, the thoracic cavity was rapidly entered, the heart punctured, and blood draining into the thoracic cavity was removed using a
  • Pasteur pipette Blood was immediately collected on lithium heparin at 4 ⁇ c and centrifuged at 3000 rpm for 15 min., and plasma was removed, aliquoted, and frozen (-20 ⁇ c) .
  • HPP-CFC high proliferative potential colony- forming cell assays

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

L'invention porte sur un procédé permettant de stimuler la régénération de cellules hématopoïétiques chez un patient soumis à une chimiothérapie ou à une radiothérapie. Ce procédé consiste à administrer à ce patient un inhibiteur de l'enzyme de conversion de l'angiotensine, ceci sous un volume propre à réduire la prolifération de cellules hématopoïétiques durant la chimiothérapie ou la radiothérapie ou à la suite de celles-ci.
PCT/IB1997/000499 1996-03-19 1997-03-19 Protection de cellules hematopoietiques durant une chimiotherapie ou une radiotherapie WO1997034627A2 (fr)

Applications Claiming Priority (2)

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US61648996A 1996-03-19 1996-03-19
US08/616,489 1996-03-19

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WO1997034627A2 true WO1997034627A2 (fr) 1997-09-25
WO1997034627A3 WO1997034627A3 (fr) 1997-12-18

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045945A1 (fr) * 1998-03-10 1999-09-16 University Of Southern California Methodes ameliorees de radiotherapie
WO1999058140A1 (fr) * 1998-05-11 1999-11-18 University Of Southern California Procede d'augmentation du taux de survie des globules blancs apres une chimiotherapie
WO2000010590A3 (fr) * 1998-08-18 2000-05-18 Queen Mary & Westfield College Traitement anticancereux
US6335195B1 (en) 1997-01-28 2002-01-01 Maret Corporation Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation
US6455500B1 (en) 1998-03-10 2002-09-24 University Of Southern California Radiation therapy methods
US6762167B1 (en) 1998-05-11 2004-07-13 University Of Southern California Methods for treating a patient undergoing chemotherapy
US7173011B2 (en) 2000-11-20 2007-02-06 University Of Southern California Radiation therapy methods
US7338938B2 (en) 1999-05-10 2008-03-04 University Of Southern California Methods for treating a patient undergoing chemotherapy

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2601678B1 (fr) * 1986-07-18 1989-11-24 Inst Nat Sante Rech Med Peptides comprenant la sequence seryl-aspartyl-lysyl-prolyle, procede pour l'extraction du tetrapeptide correspondant, et applications, notamment a la protection de la moelle osseuse au cours de traitements anticancereux par la chimiotherapie

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7744927B2 (en) 1997-01-28 2010-06-29 University Of Southern California Methods of promoting hematopoietic and mesenchymal cell proliferation and differentiation
US6335195B1 (en) 1997-01-28 2002-01-01 Maret Corporation Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation
WO1999045945A1 (fr) * 1998-03-10 1999-09-16 University Of Southern California Methodes ameliorees de radiotherapie
US7776828B2 (en) 1998-03-10 2010-08-17 University Of Southern California Radiation therapy methods
US6455500B1 (en) 1998-03-10 2002-09-24 University Of Southern California Radiation therapy methods
US6762167B1 (en) 1998-05-11 2004-07-13 University Of Southern California Methods for treating a patient undergoing chemotherapy
US6475988B1 (en) 1998-05-11 2002-11-05 University Of Southern California Methods to increase white blood cell survival after chemotherapy
WO1999058140A1 (fr) * 1998-05-11 1999-11-18 University Of Southern California Procede d'augmentation du taux de survie des globules blancs apres une chimiotherapie
US6852316B2 (en) 1998-08-18 2005-02-08 Queen Mary & Westfield College Cancer treatment
WO2000010590A3 (fr) * 1998-08-18 2000-05-18 Queen Mary & Westfield College Traitement anticancereux
US7338938B2 (en) 1999-05-10 2008-03-04 University Of Southern California Methods for treating a patient undergoing chemotherapy
US7786085B2 (en) 1999-05-10 2010-08-31 University Of Southern California Method for treating a patient undergoing chemotherapy
US7173011B2 (en) 2000-11-20 2007-02-06 University Of Southern California Radiation therapy methods

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