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WO2000078359A2 - Compositions pour traiter des cellules tumorales resistant a la chimiotherapie et compositions de chimiotherapie ciblee - Google Patents

Compositions pour traiter des cellules tumorales resistant a la chimiotherapie et compositions de chimiotherapie ciblee Download PDF

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Publication number
WO2000078359A2
WO2000078359A2 PCT/US2000/016955 US0016955W WO0078359A2 WO 2000078359 A2 WO2000078359 A2 WO 2000078359A2 US 0016955 W US0016955 W US 0016955W WO 0078359 A2 WO0078359 A2 WO 0078359A2
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WO
WIPO (PCT)
Prior art keywords
peptide
doxorubicin
paclitaxel
cys
acm
Prior art date
Application number
PCT/US2000/016955
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English (en)
Other versions
WO2000078359A3 (fr
Inventor
George Tuszynski
Taffy Williams
Paul Actor
Original Assignee
George Tuszynski
Taffy Williams
Paul Actor
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 George Tuszynski, Taffy Williams, Paul Actor filed Critical George Tuszynski
Priority to AU54981/00A priority Critical patent/AU5498100A/en
Publication of WO2000078359A2 publication Critical patent/WO2000078359A2/fr
Publication of WO2000078359A3 publication Critical patent/WO2000078359A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid

Definitions

  • compositions include a
  • compositions of this invention also include a paclitaxel-
  • compositions of the invention are of the same, resistant cancer resistant cancer and those with normal cancer.
  • the compositions of the invention are of the same, resistant cancer, resistant cancer and those with normal cancer.
  • Doxorubicin is the most commonly used anticancer chemotherapeutic
  • doxorubicin PNAS 93:7269-7273 (1996). It is an anthracycline derived from
  • Dox Doxorubicin
  • the cell and reach certain threshold levels.
  • Paclitaxel is a common chemotherapeutic agent often used to treat
  • TAXOLTM is a natural product with antitumor activity. It is obtained via a
  • Taxus baccata the Pacific Yew Tree
  • paclitaxel 5 ⁇ ,20-Epoxy-1 ,2 ⁇ ,4,7 ⁇ ,13 ⁇ -hexahydroxytax-
  • Paclitaxel acts as an antimicrotubule agent by promoting the assembly
  • paclitaxel induces abnormal arrays
  • cancer is the existence of drug resistance in tumors resulting in decreased cytotoxicity of chemotherapy agents. Some cancers are drug resistant prior
  • doxorubicin by a newly developed compound, oxalyl bis(N-phenyl)hydroxamic
  • MDR multidrug resistance
  • Paclitaxel is a substrate for the multidrug resistant pump, which is also
  • gP170 cells selected for high levels of resistance to this drug
  • tubulin genes and mutations in ⁇ -tubulin genes and mutations in ⁇ -tubulin. Id.
  • Other mechanisms for chemotherapy resistance include: glutathione
  • Another strategy proposes the use of liposome encapulated doxorubicin to
  • Doxorubicin conjugates have also been developed. Doxorubicin
  • doxorubicin has previously resulted in severe loss of cytotoxic activity. See
  • doxorubicin A previous paclitaxel-peptide conjugate has been constructed with a
  • bombesin/gastrin-releasing peptide receptor-recognizing peptide Gln-Trp-
  • a cancer chemotherapy agent is
  • a cancer chemotherapy agent is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • a peptide is selected, and the agent and peptide are coadministered
  • composition comprises a
  • FIG. 1 Doxorubicin is a drawing of doxorubicin.
  • FIG. 2 (Paclitaxel) is a drawing of paclitaxel.
  • FIG. 3 Doxorubicin - Peptide Conjugate
  • Dox-P peptide conjugate
  • the linkage is an amide linkage.
  • the peptide's amino terminus is modified with an Acm group
  • FIG. 4 (Paclitaxel - Peptide Conjugate) is a drawing of a paclitaxel-
  • ester-amide linkage with the ester linkage being between paclitaxel and the
  • FIG. 5 (Effect of Dox and Dox-P on Drug-Resistant CHO Cell Viability)
  • doxorubicin alone (Dox) is
  • FIG. 6 (Effect of Dox and Dox-P on CHO Cell Viability) demonstrates
  • FIG. 7 (Effect of Doxorubicin Peptide Conjugate on Adhesion of B16-
  • F10 Melanoma Cells show the effect of Dox-P on adhesion of B16-F10
  • FIG. 8 Effect of Doxorubicin (Dox), Doxorubicin-Peptide (Dox-P) on
  • FIG. 9 (Effect of Ala-Ser-Val-Thr-Ala-Arg on Doxorubicin Toxicity of
  • Doxorubicin Resistant CHO Cells shows the effect of coadministering the
  • doxorubicin and multidrug-resistant cells.
  • the present invention relates to chemotherapeutic agents conjugated
  • conjugates can be produced by linking the chemotherapeutic agent to
  • agents can also be coadministered with peptides of the present invention.
  • chemotherapeutic agents can be used in the present disclosure.
  • preferred compounds include those that
  • Acceptable agents including the following:
  • alkylating agents bisulfan, carboplatin, cisplatin, thiotepa
  • nitrogen mustards melphalan, cyclophospamide, chlorambucil
  • antibiotics • antibiotics (doxorubicin, bleomycin, danuorubicin, actinomycin D,
  • idarubicin idarubicin, fludarabine, floxuradine, 5-flurouracil, antracylcine, plicamycin,
  • vinca alkyloids (vincristine, vinblastine);
  • hormonal agonists and antagonists including: nilutamide
  • antiandrogens including: bicalutamide and flutamide;
  • antiestrogens including: anastrozole, toremitine, letrozole, and tamoxifen;
  • estrogens including: estradiol; gonadotropin releasing hormone analogs
  • leuprolide acetate and goserelin acetate including: leuprolide acetate and goserelin acetate; and progestins including:
  • paclitaxel camphothecan, topotecan, vincristine, vinblastine, colchicine
  • methotrexate methotrexate, mercaptopurine, irinotecan, B-methasone, dicarbazine,
  • vinurelbine L-asparginase, paclitaxel, docetaxal, tretinoin, temiposide, ricin,
  • cytoxin cytoxin, saintopin, ellipticin, azatoxin, SQZ, dinalin, and VP16).
  • This invention is most useful when the chemotherapy agent is highly
  • the invention is useful for treating resistant
  • cancers but it is particularly beneficial to use them to treat nonresistant cancers.
  • chemotherapy agents to the tumor cells
  • this invention allows for more effective treatment at lower doses.
  • composition of the present invention contains doxorubicin.
  • composition contains paclitaxel.
  • Peptides of the present invention include peptide sequences from
  • thrombospondin that bind to the thrombospondin receptor.
  • these include peptides binding to the TSP-1 receptor with an
  • Peptides can also be identified by their capacity to bind to the
  • thrombospondin receptor Such peptides can be developed and identified by
  • phage display peptide library kit such as that available from New
  • Phage display describes a selection
  • Phage display can be used to create a physical linkage between a vast library of random peptide sequences to the DNA
  • biopanning This technique is carried out by incubating a
  • the eluted phage is then amplified and taken
  • random peptides can be screened for their ability to bind
  • doxorubicin paclitaxel or other chemotherapeutic agents when conjugated
  • the peptides can be from 3 to 100 amino acids in length, preferably 3
  • thrombospondin protein include the heparin binding domains of the thrombospondin protein, which flank the Cys-Ser-Val-Thr-Cys-Gly (SEQ ID NO: 1) region.
  • Preferred peptides include the heparin binding domains of the thrombospondin protein, which flank the Cys-Ser-Val-Thr-Cys-Gly (SEQ ID NO: 1) region.
  • Val-Thr-Cys(Acm)-Gly (SEQ ID NO: 6) are expected to behave similarly in the
  • the first peptide is subject to oxidation at the sulfur atoms
  • peptide may be less stable.
  • blocking strategies include alkylation with
  • Peptides of the present invention include those with unnatural or non-
  • Such other moieties could include fluorine, chlorine, organic
  • Amino acids or peptides in the d-orientation can also be used, as can
  • compositions of the present invention was produced by:
  • composition of the invention was produced by linking the
  • thrombospondin can be used to form an amide with one end of a dicarboxylic
  • composition of the present invention was produced by linking
  • the ester linkage is between the paclitaxel and the succinyl linker
  • compositions of the present invention may be formulated in a
  • composition which may include carriers, thickeners, diluents,
  • buffers preservatives, surface active agents, liposomes, or lipid formulations
  • compositions may also include one or more
  • antimicrobial agents antimicrobial agents, antiinflammatory agents, anesthetics, and the like.
  • the pharmaceutical composition may be administered in a number of
  • Administration may be topically (including on the skin,
  • parenterally for example by intravenous drip, subcutaneous, intratumor,
  • formulations for topical administration may include ointments,
  • lotions, creams, gels, drops, suppositories, sprays, liquids and powders are included in the formulation.
  • compositions for oral may be necessary or desirable.
  • Compositions for oral may be necessary or desirable.
  • parenteral administration may include sterile aqueous solutions optionally
  • coadministered compound can then be compared to the chemotherapy agent
  • dosages are generally 10x below the lethal dose.
  • the LD 50 the dose that
  • composition's half life can also be determined in one or more animal models,
  • composition of the present invention can be used to adjust the dosages.
  • the dosages can be reduced in amount or
  • Optimal dosing schedules can also be calculated from measurements
  • Optimum dosages may vary depending on the potency of the composition,
  • Dox-P conjugate dosage is from about 5 mg/kg to about 30 mg/kg
  • compositions may be more preferably about 10 mg/kg to about 15 mg/kg and the compositions may
  • chemotherapy agents is about 60 to about 75 mg/m 2 given every 21 days,
  • paclitaxel-p conjugate dosage is from about 50 mg/m 2 to
  • This dosage can be any dosage that can be administered to a patient.
  • This dosage can be any dosage that can be administered to a patient.
  • compositions may be administered as a
  • paclitaxel-p can also be lower than the standard recommended dosages
  • Dox-P doxorubicin-peptide conjugate
  • the method begins with a derivatized thrombospondin peptide, which
  • the flask was transferred to a room temperature water bath and the
  • the solvent was removed at reduced pressure (about 10 "4 torr) while
  • Doxorubicin and multidrug-resistant CHO cells were cultured using
  • Example 1 at concentrations of 0.25, 0.5, 0.75, and 1.0 mM. Untreated cells
  • the assay incorporates a
  • the system incorporates an oxidation-reduction (redox) indicator that
  • absorbance-based instrumentation 570 nm and 600 nm.
  • Example 3 Effect of DOX and DOX-P on wild-type CHO cell viability
  • Example 2 The study of Example 2 was performed, except wild-type CHO cells
  • nonresistant cells is not hindered by the conjugation with the peptide.
  • the LD 50 the dose at which half of the cells die, was calculated from
  • Dox-P can overcome resistance.
  • F10 melanoma cells (a nonresistant cell line) to doxorubicin and the
  • Gly (SEQ ID NO: 6) peptide with a d orientation, or 1% bovine serum albumin
  • the non-adherent cells were removed and the wells were washed with a
  • the peptide to doxorubicin altered its ability to prevent wild-type, nonresistant
  • mice melanoma tumor cells were injected into mice.
  • the animals (5 in each group) were treated intraperitoneally 24 and 96 hours
  • Val-Thr-Cys(Acm)-Gly SEQ ID NO: 6
  • Dox peptide, or Dox
  • mice 18 ⁇ M/kg.
  • the mice were sacrificed and the melanoma tumor colonies on the
  • mice administered to mice at a concentration of 30 and 68 mg/kg, respectively. Both compound have the same number of doxorubicin molecules per weight
  • Thr-Ala-Arg (SEQ ID NO: 2) peptide shows a dose-response effect when
  • Val-Thr-Ala-Arg (SEQ ID NO: 2) peptide may cause this effect by binding to
  • the MDR pump inactivating it or decreasing its effectiveness. It may also
  • Ala-Ser-Val-Thr-Ala-Arg (SEQ ID NO: 2) peptide may also interact with
  • the membrane of the cell such that it modifies the membrane or MDR pump
  • a peptide's ability to bind to the thrombospondin receptor can be
  • response measure in arc seconds is proportional to receptor-
  • Thrombospondin can be used as a positive control.
  • Bovine Aorta Endothelial Cells (BAEC) and MDA-MB-231 cells, breast
  • carcinoma cells are transfected with purified DNA encoding for the receptor
  • TSP-1 thrombospondin
  • bovine serum albumin BSA
  • the stain is washed off and the cells are counted in a field of 1 mm
  • the data can be
  • paclitaxel-peptide conjugate (“Paclitaxel-P”) was produced by the following steps:
  • TAXOLTM paclitaxel
  • 2'-Succinyltaxol was prepared from paclitaxel by a method similar to
  • the activated ester N-hydroxysuccinimide ester of 2' succinyltaxol
  • a cytotoxicity assay can be used to evaluate the
  • cancer cells such as human breast cancer cells
  • paclitaxel-resistant cells paclitaxel-resistant cells
  • paclitaxel alone or the paclitaxel-
  • Untreated cells can be used as a negative control.
  • the assay quantitatively measures the proliferation of cell lines and can establish the
  • the assay incorporates a
  • the system incorporates an oxidation-reduction (redox) indicator that
  • the LD 50 the dose at which half of the cells die, can be calculated from
  • B16-F10 melanoma including B16-F10 melanoma, lewis lung carcinoma, human breast
  • paclitaxel resistant cells An example of a paclitaxel resistant cell line is the SKOV-3TR
  • F10 melanoma cells (a nonresistant cell line) to paclitaxel and the paclitaxel- peptide conjugate of Example 11. This study could also be performed with a
  • bovine serum albumin (BSA).
  • the stain is washed off and the cells are counted in a field of 1 mm
  • doxorubicin alters its ability to prevent wild-type, nonresistant tumor
  • mice melanoma tumor cells are injected into mice.
  • the melanoma tumor cells are injected into mice.
  • mice (5 in each group) are treated intraperitoneally 24 and 96 hours after
  • Val-Thr-Cys(Acm)-Gly (SEQ ID NO: 6) peptide, or paclitaxel, at a
  • the mice are sacrificed and the melanoma tumor colonies on the lung are counted.
  • the LD 50 can be determined experimentally by treating
  • mice with increasing doses of paclitaxel groups of mice with increasing doses of paclitaxel and identifying the
  • a toxicity study can be performed using mice to evaluate the
  • paclitaxel is administered to mice at a concentration which is lower than the
  • LD 50 which can be determined as in Example 15, preferably 10 fold lower
  • the paclitaxel-p conjugage is administered at a dose that
  • Paclitaxel and multidrug-resistant CHO cells are treated with a
  • peptides are co-administered with paclitaxel.
  • peptides are co-administered with paclitaxel.
  • peptide will not show any effect when coadministered with the paclitaxel.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Cette invention se rapporte à des procédés et à des compositions servant au traitement du cancer et au traitement des cancers résistant à la chimiothérapie, ces compositions contenant un agent chimiothérapeutique conjugué à un peptide ou administré conjointement à un peptide.
PCT/US2000/016955 1999-06-21 2000-06-21 Compositions pour traiter des cellules tumorales resistant a la chimiotherapie et compositions de chimiotherapie ciblee WO2000078359A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54981/00A AU5498100A (en) 1999-06-21 2000-06-21 Compositions for treating chemotherapy-resistant tumor cells and targeted chemotherapy compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14031099P 1999-06-21 1999-06-21
US60/140,310 1999-06-21

Publications (2)

Publication Number Publication Date
WO2000078359A2 true WO2000078359A2 (fr) 2000-12-28
WO2000078359A3 WO2000078359A3 (fr) 2002-01-24

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WO (1) WO2000078359A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035011A2 (fr) * 2001-10-26 2003-05-01 The Uab Research Foundation Conjugues multimedicaments multiligands permettant une administration ciblee de medicaments

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443404A1 (fr) * 1990-02-22 1991-08-28 W.R. Grace & Co.-Conn. Fragments peptidiques et analogues de thrombospondine
EP0478101A2 (fr) * 1990-09-24 1992-04-01 W.R. Grace & Co.-Conn. Peptides ayant une activité de type thrombospondine et leur utilisation thérapeutique
WO1992017499A1 (fr) * 1991-04-08 1992-10-15 Cornell Research Foundation, Inc. Hexapeptide particulier derive de la thrombospondine et utilisation de ce compose
EP0578342A2 (fr) * 1992-05-14 1994-01-12 W.R. Grace & Co.-Conn. Purification et caractérisation d'un récepteur d'adhésion de cellules tumorales reconnaissant la séquence CSVTCG
US5770563A (en) * 1991-12-06 1998-06-23 The United States Of America As Represented By The Department Of Health And Human Services Heparin- and sulfatide binding peptides from the type I repeats of human thrombospondin and conjugates thereof
WO1998035688A1 (fr) * 1997-02-13 1998-08-20 Storz Instrument Company Methode de destruction de cellules epitheliales pigmentaires retiniennes
WO2001005968A1 (fr) * 1999-06-21 2001-01-25 Inkine Pharmaceutical Company, Inc. Angiocidine: recepteur d'adherence des cellules tumorales specifiques cys-ser-val-thr-cys-gly

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443404A1 (fr) * 1990-02-22 1991-08-28 W.R. Grace & Co.-Conn. Fragments peptidiques et analogues de thrombospondine
EP0478101A2 (fr) * 1990-09-24 1992-04-01 W.R. Grace & Co.-Conn. Peptides ayant une activité de type thrombospondine et leur utilisation thérapeutique
WO1992017499A1 (fr) * 1991-04-08 1992-10-15 Cornell Research Foundation, Inc. Hexapeptide particulier derive de la thrombospondine et utilisation de ce compose
US5770563A (en) * 1991-12-06 1998-06-23 The United States Of America As Represented By The Department Of Health And Human Services Heparin- and sulfatide binding peptides from the type I repeats of human thrombospondin and conjugates thereof
EP0578342A2 (fr) * 1992-05-14 1994-01-12 W.R. Grace & Co.-Conn. Purification et caractérisation d'un récepteur d'adhésion de cellules tumorales reconnaissant la séquence CSVTCG
WO1998035688A1 (fr) * 1997-02-13 1998-08-20 Storz Instrument Company Methode de destruction de cellules epitheliales pigmentaires retiniennes
WO2001005968A1 (fr) * 1999-06-21 2001-01-25 Inkine Pharmaceutical Company, Inc. Angiocidine: recepteur d'adherence des cellules tumorales specifiques cys-ser-val-thr-cys-gly

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035011A2 (fr) * 2001-10-26 2003-05-01 The Uab Research Foundation Conjugues multimedicaments multiligands permettant une administration ciblee de medicaments
WO2003035011A3 (fr) * 2001-10-26 2004-02-26 Uab Research Foundation Conjugues multimedicaments multiligands permettant une administration ciblee de medicaments
US7311892B2 (en) 2001-10-26 2007-12-25 The Uab Research Foundation Multidrug multiligand conjugates for targeted drug delivery
US7807134B2 (en) 2001-10-26 2010-10-05 Ahmad Safavy Multidrug multiligand conjugates for targeted drug delivery

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Publication number Publication date
WO2000078359A3 (fr) 2002-01-24
AU5498100A (en) 2001-01-09

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