WO1991016075A1 - Techniques de traitement de la moelle osseuse - Google Patents

Techniques de traitement de la moelle osseuse Download PDF

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Publication number
WO1991016075A1
WO1991016075A1 PCT/AU1991/000155 AU9100155W WO9116075A1 WO 1991016075 A1 WO1991016075 A1 WO 1991016075A1 AU 9100155 W AU9100155 W AU 9100155W WO 9116075 A1 WO9116075 A1 WO 9116075A1
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WO
WIPO (PCT)
Prior art keywords
bone marrow
pharmaceutical
radiopharmaceutical
radionuclide
melphalan
Prior art date
Application number
PCT/AU1991/000155
Other languages
English (en)
Inventor
Harvey J. Turner
Phillip G. Claringbold
Original Assignee
Australian Nuclear Science & Technology Organisation
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.)
Filing date
Publication date
Application filed by Australian Nuclear Science & Technology Organisation filed Critical Australian Nuclear Science & Technology Organisation
Publication of WO1991016075A1 publication Critical patent/WO1991016075A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to bone marrow treatments, and more particularly, is concerned with a treatment in which ablation of bone marrow is achieved followed by bone marrow transplantation.
  • Such treatment is possible and can be a cure for many patients with haematological malignancy such as acute leukaemia and l p l m v s!o_ns. It has been found' nsce ⁇ ar""- to kill all bone marrow cells. This would be fatal to the patient but for subsequent bone marrow transplantation with healthy bone marrow. If less than all the bone marrow cells are ablated, then natural recovery mechanisms operate through cell regeneration and recurrence of malignancy is likely. Thus, the patient will only enjoy a period of remission.
  • One established technique is to achieve bone marrow ablation with total body irradiation (T.B.I.) . Bone marrow transplantation with healthy bone marrow can then take place almost immediately.
  • the present invention is based on the concept of using a radiopharmaceutical comprising a polyvalent particle-emitting radionuclide and a chelating agent which has strong localisation on bone, the irradiation being less than the level which would be fatal in the absence of further treatment steps; administering a cytotoxic compound which affects bone marrow but at a dosage less than that would be fatal in the absence of other treatment; and after allowing for the effects of the radionuclide and cytotoxic compound to dissipate, effecting a bone marrow transplantation.
  • the invention manifests itself in a method of treatment of an animal such as a human being, and in another aspect, manifests itself in a treatment kit for the procedure.
  • the radiation emits principally beta radiation which is short range but highly effective for cell ablation.
  • radionuclide is samarium-153 b ⁇ t there are many other possible radionuclides such as strontium-89, yttrium-90, ruthenium-103, indium-115, cerium-144, gadolinium-159, holmium-166, ytterbium-175, lutecium-177, and rhenium-186.
  • the selection of chelating agent referably involves a selection of one which can be labelled with strong attachment by the radionuclide, and the resulting complex should be highly specific to bone.
  • polyaminepolyalkylphosphonic acids and derivatives including physiological salts thereof can be selected with advantage.
  • An important example of such a compound is ethylenediaminetetramethylene phosphonate (EDTMP) which is a known chelating agent and is readily labelled with samarium-153 and has been found to localise on the surface of cortical and trabecular bone.
  • ETMP ethylenediaminetetramethylene phosphonate
  • chelating agents in this class are: di ⁇ thylenetria in ⁇ pentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediaminetrimethylenepnosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP) ,
  • cytotoxic compound includes melphalan (described in U.S. patent Nos. 3,032,584 and 3,032,585) and related compounds including equivalent chemotherapeutic agent with a predominantly myelotoxic action.
  • a preferred embodiment of the invention comprises the use of EDTMP labelled with samarium-153 administered at a high but sub-lethal level.
  • samarium-153 labelled EDTMP is myelosuppressive, complete marrow ablation is not achieved even with very high dosage levels.
  • Attempts to produce complete marrow ablation in dogs and rabbits have been reported as not successful, and further studies by the present inventor indicate that in rats samarium-153 EDTMP alone is unlikely to completely ablate red marrow.
  • Another embodiment consists in the use of rhenium-186 labelled HEDP.
  • the treatment comprises delaying administration of the cytotoxic drug for several days to allow substantial radioactive decay of the radiopharmaceutical.
  • the graph illustrates platelet concentration in the blood with time following a lethal total body irradiation in rats.
  • This model established the validity of monitoring platelet concentration as an indicator of bone marrow ablation.
  • Figure 2 demonstrates the viability of marrow transplantation after total body irradiation, i.e. marrow ablation.
  • the control sample with no marrow transplantation showed all rats died within about 10 days but a very high survival rate was achieved with those that received marrow transplantation.
  • Figure 3 is a graph of platelet concentration with time. A lethal total body irradiation is given to the sample and marrow transplantation effected. By day 10, platelet concentration had dropped to a potentially fatal level. However, the increase in platelet concentration demonstrated that the transplantation had been effective and bone marrow cell reproduction had occurred to rescue the animals and a normal platelet concentration was achieved by day 15.
  • Figure 4 demonstrates the use of samarium-153 EDTMP at a rate of 3.5 GBq instead of total body irradiation.
  • Samarium-153 EDTMP was prepared according to published methods (Turner et al 1989 Eur.J.Nucl.Med.15: 784-795) . Briefly, Samarium-153 was prepared by neutron irradiation of S ⁇ O- (enriched to 98% Samarium-152) in the HIFAR Research Reactor, Australian Nuclear Science and
  • Figure 6 demonstrates survival rate after chemo- and/or radiotherapy treatment comprising 9.5 mg/kg Melphalan and samarium-153 EDTMP administered at 555mBq.
  • a control with melphalan alone indicated 100% survival.
  • a sample comprising the samarium and melphalan but without marrow transplantation produced a low survival rate of about 20%.
  • the third line demonstrates a sample of 13 individuals treated with samarium-153, melphalan, and given a marrow transplant at day 3, and again a survival rate of about 20% only was achieved. This result indicates that the transplantation was not successful due to the half-life of the radionuclide, and marrow transplantation needs to be delayed until the effects of the internal endoradiotherapy have diminished.
  • Figure 7 indicates the result of delaying marrow transplant until six days after the commencement of the procedure.
  • the procedure commenced with samarium endoradiotherapy, and five days later the cytotoxic compound melphalan was administered.
  • the survival rate was approximately 20% whereas for those individuals receiving the transplant the survival rate exceeded 90%.

Abstract

On traite une affection hématologique maligne chez un animal en utilisant un radionuclide émetteur de particules polyvalentes, afin de marquer un agent de chélation de localisation de l'os, et en administrant cet agent de façon à affecter la moelle osseuse de l'animal, selon une dose proche mais inférieure à un niveau qui entraînerait une ablation complète de la moelle osseuse, puis en administrant un agent pharmaceutique cytotoxique selon une dose suffisante pour affecter la moelle osseuse de l'animal, cette dose étant proche mais inférieure à un niveau qui entraînerait une ablation complète de la moelle osseuse. On peut par exemple utiliser le samarium-153 comme radionuclide et un agent radiopharmaceutique choisi parmi les composés EDTMP, DTPMP, HEEDTMP, NTMP, TTHMP, HEDP et des sels physiologiquement acceptables de ces composés. Le médicament cytotoxique peut être du melphalan ou l'un de ses dérivés ou analogues.
PCT/AU1991/000155 1990-04-20 1991-04-19 Techniques de traitement de la moelle osseuse WO1991016075A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPJ9726 1990-04-20
AUPJ972690 1990-04-20

Publications (1)

Publication Number Publication Date
WO1991016075A1 true WO1991016075A1 (fr) 1991-10-31

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1991/000155 WO1991016075A1 (fr) 1990-04-20 1991-04-19 Techniques de traitement de la moelle osseuse

Country Status (1)

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WO (1) WO1991016075A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009075A1 (fr) * 1994-09-21 1996-03-28 Keshelava Viktor V Procede de traitement d'affections malignes
US5565184A (en) * 1993-07-02 1996-10-15 Mallinckrodt Medical, Inc. Functionalized tripodal ligands for x-ray & radioactive imaging applications
WO2000076556A2 (fr) * 1999-06-11 2000-12-21 Neorx Corporation Complexe a forte dose de radionucleides destine a la suppression de la moelle osseuse
WO2002062398A2 (fr) * 2001-01-08 2002-08-15 Neorx Corporation Composes, compositions et methodes therapeutiques et diagnostiques
EP1395226A2 (fr) * 2001-06-11 2004-03-10 The University of Miami Complexes radiopharmaceutiques permettant de tolerer une transplantation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965254A (en) * 1973-05-23 1976-06-22 The Procter & Gamble Company Compositions for the treatment of calcific tumors
EP0164843A2 (fr) * 1984-06-04 1985-12-18 The Dow Chemical Company Complexes organiques d'acide aminophosphonique pour le traitement de tumeurs calcifiantes
US4853209A (en) * 1987-05-18 1989-08-01 The Dow Chemical Company Bone marrow suppressing agents
US4882142A (en) * 1988-12-19 1989-11-21 The Dow Chemical Company Bone marrow suppressing agents
EP0375376A2 (fr) * 1988-12-19 1990-06-27 The Dow Chemical Company Complexes macrocycliques d'acides aminophosphoniques, leur préparation, formulations et application
US4976950A (en) * 1988-12-19 1990-12-11 The Dow Chemical Company Bone marrow suppressing agents

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3965254A (en) * 1973-05-23 1976-06-22 The Procter & Gamble Company Compositions for the treatment of calcific tumors
EP0164843A2 (fr) * 1984-06-04 1985-12-18 The Dow Chemical Company Complexes organiques d'acide aminophosphonique pour le traitement de tumeurs calcifiantes
US4853209A (en) * 1987-05-18 1989-08-01 The Dow Chemical Company Bone marrow suppressing agents
US4882142A (en) * 1988-12-19 1989-11-21 The Dow Chemical Company Bone marrow suppressing agents
EP0375376A2 (fr) * 1988-12-19 1990-06-27 The Dow Chemical Company Complexes macrocycliques d'acides aminophosphoniques, leur préparation, formulations et application
US4976950A (en) * 1988-12-19 1990-12-11 The Dow Chemical Company Bone marrow suppressing agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A.G. GILMAN et al., "Goodman and Gilman's The Pharmacological Basis of Therapeutics", Seventh Edition, published 1985, by MACMILLAN PUBLISHING COMPANY (NEW YORK), see pages 1243. *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5565184A (en) * 1993-07-02 1996-10-15 Mallinckrodt Medical, Inc. Functionalized tripodal ligands for x-ray & radioactive imaging applications
WO1996009075A1 (fr) * 1994-09-21 1996-03-28 Keshelava Viktor V Procede de traitement d'affections malignes
WO2000076556A2 (fr) * 1999-06-11 2000-12-21 Neorx Corporation Complexe a forte dose de radionucleides destine a la suppression de la moelle osseuse
JP2003501488A (ja) * 1999-06-11 2003-01-14 ネオルックス コーポレイション 骨髄抑制のための高投与量放射性核種錯体
WO2000076556A3 (fr) * 1999-07-11 2001-10-11 Neorx Corp Complexe a forte dose de radionucleides destine a la suppression de la moelle osseuse
WO2002062398A2 (fr) * 2001-01-08 2002-08-15 Neorx Corporation Composes, compositions et methodes therapeutiques et diagnostiques
WO2002062398A3 (fr) * 2001-01-08 2003-12-18 Neorx Corp Composes, compositions et methodes therapeutiques et diagnostiques
EP1395226A2 (fr) * 2001-06-11 2004-03-10 The University of Miami Complexes radiopharmaceutiques permettant de tolerer une transplantation
EP1395226A4 (fr) * 2001-06-11 2005-03-30 Univ Miami Complexes radiopharmaceutiques permettant de tolerer une transplantation

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