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WO1997007797A1 - Traitement de l'affection de la prostate chez l'homme au moyen de derives beta-lapachone - Google Patents

Traitement de l'affection de la prostate chez l'homme au moyen de derives beta-lapachone Download PDF

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Publication number
WO1997007797A1
WO1997007797A1 PCT/US1996/013335 US9613335W WO9707797A1 WO 1997007797 A1 WO1997007797 A1 WO 1997007797A1 US 9613335 W US9613335 W US 9613335W WO 9707797 A1 WO9707797 A1 WO 9707797A1
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Prior art keywords
cells
mapachone
lapachone
substituted
human
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PCT/US1996/013335
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English (en)
Inventor
Arthur Pardee
Chiang J. Li
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Dana-Farber Cancer Institute
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Application filed by Dana-Farber Cancer Institute filed Critical Dana-Farber Cancer Institute
Priority to AU67775/96A priority Critical patent/AU6777596A/en
Publication of WO1997007797A1 publication Critical patent/WO1997007797A1/fr
Priority to US09/028,400 priority patent/US6245807B1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Definitions

  • the present invention is directed to a method of treating an individual suffering from benign prostate hyperplasmia and prostate cancer.
  • the prostate gland produces several components of semen in blood and several regulatory peptides.
  • the prostate gland comprises stroma and epithelium cells, the latter group consisting of columnar secretory cells and basal non-secretory cells.
  • the proliferation of these basal cells, as well as stroma cells gives rise to benign prostatic hyperplasmia (BPH) which is one common prostate disease.
  • BPH benign prostatic hyperplasmia
  • BPH is a progressive condition which is characterized by the nodular enlargement of the prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, noncuria, poor urine stream, and hesitation or delay in starting the urine flow.
  • Consequences of BPH can include hypertrophy of bladder smooth muscle, decompensated bladder, and increased incidence of urinary tract infection.
  • BPH is considered to be an escapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently in the United States, the method of choice for treating BPH is surgery, e.g., transurethral recession of the prostate.
  • prostate disease is prostatic adenocarcinoma (CaP) or androgen independent prostate cancer, which involves malignant transformation of epithelial cells in the peripheral region of the prostate gland.
  • Androgen independent prostate cancer is presently the most common cancer in men in the United States with 38,000 deaths anticipated for the USA in 1 994, and is a significant condition worldwide.
  • the only existing treatment for metastatic disease is hormonal therapy, which is not curative. Thus, the metastatic disease is typically fatal.
  • Hormonal therapy consisting of different approaches to blocking the action of androgen on the prostate tumor is effective in controlling only the growth of tumor cells that depend on androgen for growth (hormone-dependent tumor).
  • hormone-dependent tumor inevitably progresses to more advanced hormone-independent tumor, which cannot be controlled by current treatment.
  • Difficulties in treating prostate cancer arise from a variety of reasons. Although such androgen ablation is a standard therapy for metastatic prostate cancer it is rarely entirely successful because in most individuals the cancer is heterogeneous comprising both androgen dependent and androgen independent cancer cells. Thus, the therapy does not eliminate the androgen independent cells.
  • Chemotherapy which has been used to treat a number of other cancers, has not proven successful. This is because the vast majority of these androgen independent cells are not actively proliferating and standard chemotherapeutic agents work by selectively killing actively proliferating cells.
  • Radiotherapy which also is selective for rapidly proliferating cells, has also not proven effective. Surgery has also not proven an effective means for treating advanced disease states. Accordingly, it would be desirable to have new methods for stimulating the death of these slow proliferating cancer cells. It would be particularly desirable to have a new means of treating individuals suffering from prostate cancer, particularly androgen independent cancer.
  • Mapachone (3,4-dihydro-s,3-dimethyl-2H-naphthol[1 ,3-b] pyran- 5,6-clone) is a simple plant product with a chemical structure different from currently used anti-cancer drugs. It is obtained by sulfuric acid treatment of the naturally occurring lapachol, which is readily isolated from Tabebuia avellanedae growing mainly in Brazil, or is easily synthesized from lomatiol, isolated from seeds of lomatia growing in Australia (Hooker, S., et. al., J. Am. Chem. Soc, 58: 1 181-1 190 (1936); Goncalves de Lima, O., et al., Rev. lost. Antibiot. Univ. Recife. 4:3-17 (1962)).
  • Mapachone has been shown to have a variety of pharmacological effects. Mapachone is a topoisomerase I inhibitor but acts by a different mechanism than camptothecin. Numerous /Mapachone derivatives have been synthesized and tested as anti-viral and anti-parasitic agent
  • R and R are each independently selected from the group consisting of hydrogen, hydroxy, thio (SH), halogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted aryl, and substituted and unsubstituted alkoxy, and salts thereof, wherein the dotted double bond between the ring carbons to which R and R, are bonded represent an optional ring double bond.
  • Preferred compounds of formula I include those in which at least one of the substituents R and R, is hydrogen and/or at least one of said substituents is allyl.
  • Mapachone i.e., R and R, both being hydrogen
  • allyl-/?- lapachone particularly 3-allyl-/Mapachone (i.e. R being allyl and R, being hydrogen) and 3-bromo-/Mapachone (i.e. R being bromo and R, being hydrogen).
  • Figure 1 shows the effect of ff-lapachone on survival of human prostate cancer cells O, PC-3 cells; O, DU145 cells. Cell survival was determined by the colony formation assay described below.
  • Figures 2A, 2B, 2C and 2D show induction of apoptosis by ⁇ - lapachone in human prostate cancer cells.
  • DNA laddering typical feature of apoptosis, was induced in PC-3, D 145 (2A) and LNCaP cells (2B).
  • 2A cells were treated with 4 ⁇ W ⁇ /Mapachone for 4 hours, followed by incubation in drug-free medium for 4 hours (lane 2,7), 1 2 hours (lane 3,8), 20 hours (lane 4,9), 44 hours (lane 5, 10).
  • As controls cells were treated with equal volume of DMSO (lane 1 ,6) . DNA was extracted and subjected to electrophoresis.
  • LNCaP cells were treated with /Mapachone for 4 hours at concentrations of O ⁇ M (lane 1 ),
  • LNCaP cells were treated with or DMSO (2C) or 8 ⁇ M /Mapachone (2D) for 1 hour, followed by incubation in drug-free media for 23 hours before they were subjected to flow cytometric analysis.
  • Figure 3 shows lack of correlation between Mapachone induced apoptosis and the expression of p53 and bcl-2.
  • Figures 4A, 4B, and 4C shows induction of apoptosis (A) and differentiation in HL-60 cells (B,C) by /Mapachone.
  • HL-60 cells were treated with 8 ⁇ M /Mapachone for 24 hours (lane 1 ). 16 hours (lane 2), 8 hours (lane 3), 4 hours (lane 4), 2 hours (lane 5), 0 hours
  • Figure 5 shows the effect of /Mapachone on tumor volume.
  • the bar represents episodes of administration of /Mapachone.
  • Figure 6 shows the effect in vivo of /Mapachone on prostate tumors AT-3.1 .
  • Figure 7 shows the effect in vivo of /Mapachone on prostate tumors AT-3.1.
  • R and R are each independently selected from the group consisting of hydrogen, hydroxy, thio (SH), halogen (e.g. fluoro, chloro and bromo), substituted and unsubstituted aryl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkyl and substituted and unsubstituted alkoxy, and salts thereof, wherein the dotted double bond between the ring carbons to which R and R, are bonded represent an optional ring double bond.
  • the alkyl groups preferably have from 1 to about 1 5 carbon atoms, more preferably from
  • alkyl refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Straight or branched chain noncyclic alkyl groups are generally more preferred than cyclic groups.
  • Straight chain alkyl groups are generally more preferred than branched.
  • the alkenyl groups preferably have from 2 to 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to about 6 carbon atoms.
  • alkenyl groups have 3 carbon atoms (i.e., 1 -propenyl or 2-propenyl), with the allyl moiety being particularly preferred.
  • Phenyl and naphthyl are generally preferred aryl groups.
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • Said substituted R and R, groups may be substituted at one or more available positions by one or more suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from 6 to 10 carbon atoms, halogen such as fluoro, chloro and bromo, and N, O and S, including heteroalkyl, e.g., heteroalkyl having one or more of said hetero atom linkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or
  • the compounds of formulae I and II are useful in suppressing survival in human ovary and breast cells, and are thus useful in treating ovarian and breast cancer.
  • Preferred compounds of formula I include /Mapachone, 3-allyl-/?- lapachone, 3-bromo-/Mapachone and 3-OH-/Mapachone, 3-allyl-/?- lapachone and 3-bromo-/Mapachone are more preferred.
  • Preferred compounds of formula II include 3-bromo-alpha- lapocleone (compound 4 of Table 1 ).
  • This compound also causes suppression of survival, albeit at slightly higher concentrations, in human ovary and breast cells.
  • typical apoptosis was not detected in any other human cancer cells of epithelial origins including colon, kidney, lung, breast, or ovary exposed to the drug other than the prostate cells.
  • HL-60 Human hematopoietic leukemia cells
  • a suitable effective dose of one or more compounds of formulae I or II will be preferably in the range of 10 to 500,000 ⁇ g per kilogram body weight of recipient per day, more preferably in the range of 1000 to 50,000 ⁇ g per kilogram body weight per day, most preferably in the range of 5000 to 25,000 ⁇ g per kilogram body weight per day.
  • the desired dose is suitably administered once or several more sub-doses administered at appropriate intervals throughout the day, or other appropriate schedule. These sub-doses may be administered as unit dosage forms, for example, containing 1 to 20,000 ⁇ g, preferably 10 to 10,000 ⁇ g per unit dosage form.
  • the subject is a human. Still more preferably, the human has CaP.
  • Administration of the compounds of the invention may be by any suitable route including oral, rectal, nasal, vaginal, topical (including buccal and sublingual), and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) with oral or parenteral being preferred. It will be appreciated that the preferred route may vary with, for example, the condition and age of the recipient.
  • the administrative ingredients may be used in therapy in conjunction with other medicaments.
  • compositions of the invention comprise at least one compound of formulae I or II together with one or more acceptable carriers thereof and optionally other therapeutic ingredients, including those therapeutic agents discussed supra.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • compositions may conveniently be presented in unit dosage form, e.g., tablets and sustained release capsules, and in liposomes and may be prepared by any methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion or packed in liposomes and as a bolus, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • compositions suitable for topical administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • compositions suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising one or more compounds of formulae I or II and a pharmaceutically acceptable carrier.
  • a suitable topical delivery system is a transdermal patch containing the ingredient to be administered.
  • compositions suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • compositions suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • sterile liquid carrier for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • the compounds are preferably dissolved in a non-ionic solubilizer such as an ethylene oxide ester-ether and fatty acid glycerides commercially available as Cremphor EL (BASF).
  • a non-ionic solubilizer such as an ethylene oxide ester-ether and fatty acid glycerides commercially available as Cremphor EL (BASF).
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • /Mapachone was kindly provided by Dr. A. Matter (CIBA-GEIGY Ltd., Switzerland). It was dissolved in dimethyl sulfoxide (DMSO) at 20 mM concentration, aliquoted, and kept at -20°C.
  • DMSO dimethyl sulfoxide
  • Schlegel (Harvard School of Public Health, Boston, MA), were cultured in Dulbecco's modified Eagle's medium (Life Technologies, Inc.) supplemented with 10% FCS, 2 mM L- glutamine, and 800 //g/ml of G41 8.
  • Exponentially growing cells were seeded (2000 cells/dish) in 60 mm culture dishes and allowed to attach for 48 hours. B-lapachone was added in less than 5 ⁇ volume (corresponding to a final DMSO concentration of less than 0.1 %) directly to dishes from concentrated working solutions in DMSO. Control dishes received DMSO alone at equal volume. After 1 to 4 h, ceils were rinsed and drug free medium was added to the cells. Cultures were observed daily for 10 to 20 days, cells were fixed and stained with modified Wright-Giemsa Stain (Sigma).
  • Colonies of greater than 30 cells were scored as survivors.
  • Nuclear extract was prepared from exponentially growing cells (Dignam, J.D., et al., Nucleic Acids Res., 1 1 : 1475 (1983)).
  • the ECL assay system was used to detect p53 and bcl-2 levels. Briefly, nuclear protein samples (10 ⁇ g per sample) were electrophoresed in a sodium dodecyl sulfate-polyacrylamide gel and then electrophoretically transferred to a nitrocellulose membrane. The blot was blocked, washed, and incubated with p53, bcl-2, or p21 (Cip1 /Waf1 ) antibody (Oncogene Science, Cambridge, MA) at 1 : 1000 dilution.
  • the filter was then incubated with a secondary antibody that was conjugated with horseradish peroxidase. Finally, the filter was developed with detection reagents (RPN 2109:Amersham) and exposed to a hyperfilm-ECL (RPN 2103).
  • Example 1 Effects of ff-Lapachone on Prostate Weight Rats in the treated group received /Mapachone at 50 mg/kg I.p..
  • Example 2 Effects of ff-Lapachone on Survival of Human Cancer Cells Human carcinoma cell lines of different histotypes were used to test the anti-survival effect of Mapachone. Androgen independent human prostate tumor cells PC-3 and DU145 were treated with ⁇ - lapachone in vitro. Cell survival was determined by colony formation assay, /Mapachone inhibits proliferation of both cell lines with an IC 100 of 4 to 8 ⁇ M ( Figure 1 ).
  • LNCaP cells were equally sensitive to Mapachone.
  • 21 MT a human breast carcinoma cell line
  • AD2780s a human ovary carcinoma cell line
  • Other cell lines tested, which included H596, H520 (human lung carcinoma cell lines) and 293 (a human kidney epithelial cell line) were also relatively resistant to /Mapachone (IC 100 > 32 /M).
  • apoptosis occurs in 62% by 24 hours (data not shown). Apoptosis, as determined by DNA laddering and chromosome condensation, was not detected in /Mapachone treated 21 - MT (human breast epithelial cell line), H520 (human lung carcinoma cell lines), SW1 1 16 (human colon adenocarcinoma), A2780s (human ovary carcinoma) cells.
  • Apoptosis Induced by / S-Lapachone is Independent of Expression of p53 and bcl-2.
  • bcl-2 has been implicated in the resistance of cancer cells to chemotherapeutic drugs including prostate cells (Berchem, G.J., et al., Cancer Res. 55:735-738 (1995)) .
  • chemotherapeutic drugs including prostate cells
  • bcl-2 expression was measured by Westem blot assay. As shown in Fig. 3, bcl-2 expression is high in PC-3 and low in DU145 cells, which does not correlate with their sensitivity to /Mapachone induced apoptosis.
  • Hela cells with ectopic overexpression of bcl-2 (hela-bcl-2) (Meikrantz, W., et al., supra) was not significantly resistant to /Mapachone in comparison with its parental cell line (IC100 was 16 ⁇ M in parental cells, and 32 ⁇ M in Hela-bcl-2 cells) (data not shown).
  • p53 status has been shown to be important for apoptosis in cancer cells provoked by ionizing radiation and chemotherapeutic drugs
  • p 53 was expressed in DU145 cells, but was not detectable in PC-3 cells (Fig. 3A), although apoptosis was induced in both cell lines (Fig. 2A). Mapachone treatment did not significantly induce expression of p53 (Fig. 3B). These results suggest that apoptosis induced by /Mapachone is not dependent on P53 expression. Expression of p21 is not significantly upregulated in prostate cancer cells undergoing apoptosis (Fig. 3B).
  • /Mapachone was also tested in hematopoietic cancer cells.
  • Example 5 Inhibition of Human Prostate Tumor Growth In Vivo /Mapachone was tested against human prostate tumor in nude mice.
  • a hormone refractory human prostate adenocarcinoma cell line (PC-3) was inoculated into nude mice.
  • Treatment was initiated when tumor reached 100 to 250 mm 3 . Without drug treatment (mouse 5), the tumor grew rapidly and the mouse died when the tumor reached about 400 mm 3 (Fig. 5).
  • /Mapachone given at 500 mg/kg, stopped tumor growth (mouse 2, Fig. 5).
  • intermediate dosage 250 mg.kg, mouse 1 and 3
  • /Mapachone also showed intermediate inhibition on tumor growth (Fig. 5).
  • Mouse 4 did not develop an appreciable tumor mass under the treatment with /Mapachone (500 mg/kg). No sign of drug toxicity was observed.

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Abstract

Nous savons maintenant que certains composés obtenus par hasard et représentés par les formules (I et II) sont sélectivement utilisables pour stimuler la mort de cellules prostatiques chez des mammifères, ce qui fait que ces composés conviennent au traitement d'affections de la prostate. Dans ces formules, R et R1 sont choisis chacun indépendamment dans le groupe des hydrogène, hydroxy, thio (SH), halogène, alkyles substitué et non substitué, alcényles substitué et non substitué, alcoxy substitué et non substitué, et certains de leurs sels. En outre, dans ces formules, le doublement en pointillé des liaisons entre les groupes carbone auxquels sont liés R et R1 représente une double liaison de groupe facultatif. Parmi les composés préférés représentés par la formule (I), on compte ceux dans lesquels, l'un au moins des substituants de R et R1 sont hydrogène, et/ou l'un au moins desdits substituants est allyle. Parmi les composés spécifiquement préférés, on compte les β-lapachone (R et R1 sont tous les deux hydrogène), allyle-β-lapachone, en particulier 3-allyle-β-lapachone (R est allyle et R1 est hydrogène) et 3-bromo-β-lapachone (R est bromo et R1 est hydrogène).
PCT/US1996/013335 1995-08-24 1996-08-19 Traitement de l'affection de la prostate chez l'homme au moyen de derives beta-lapachone WO1997007797A1 (fr)

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Application Number Priority Date Filing Date Title
AU67775/96A AU6777596A (en) 1995-08-25 1996-08-19 Treatment of human prostate disease with beta-lapachone derivatives
US09/028,400 US6245807B1 (en) 1995-08-24 1998-02-24 Treatment of human prostate disease

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US282995P 1995-08-25 1995-08-25
US60/002,829 1995-08-25

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PCT/US1996/013336 Continuation WO1997007528A1 (fr) 1995-08-15 1996-08-15 Agencement de polarisation pour reseau lineaire de detecteurs

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245807B1 (en) * 1995-08-24 2001-06-12 Dana-Farber Cancer Institute Treatment of human prostate disease
WO2003090710A1 (fr) * 2002-04-23 2003-11-06 Case Western Reserve University Systemes d'administration de lapachone, compositions de lapachone et utilisations associees
EP1420777A4 (fr) * 2001-07-31 2009-03-04 Arqule Inc Compositions pharmaceutiques contenant beta-lapachone ou des derives ou des analogues correspondants, et leurs methodes d'utilisation
WO2012162627A1 (fr) * 2011-05-26 2012-11-29 The General Hospital Corporation Traitement de maladies angiogéniques ou vasculaires associées
CN105503692A (zh) * 2015-12-27 2016-04-20 新乡医学院 一种α-拉帕醇类似物及其合成方法和作为抗肿瘤药物的应用
CN106074492A (zh) * 2016-06-13 2016-11-09 中山大学 9-甲氧基-α-拉帕醌作为吲哚胺2,3-双加氧酶-1抑制剂的用途
WO2016196344A1 (fr) 2015-05-30 2016-12-08 Molecular Templates, Inc. Supports de sous-unité a de toxine de shiga, déimmunisés, et molécules de ciblage de cellule les comprenant

Citations (1)

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WO1994004145A1 (fr) * 1992-08-21 1994-03-03 Dana Farber Cancer Institute Traitement d'infections virales chez l'homme

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WO1994004145A1 (fr) * 1992-08-21 1994-03-03 Dana Farber Cancer Institute Traitement d'infections virales chez l'homme

Non-Patent Citations (3)

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Title
C.J. LI ET AL.: "Induction of apoptosis by beta lapachone in human prostate cancer cells.", CANCER RES., vol. 55, no. 17, 1995, pages 3712 - 3715, XP000611542 *
S.M. PLANCHON ET AL.: "Beta-lapachon-mediated apoptosis in human promyelocytic leukemia(HL-60) and human prostate cancer cells: a P53-dependent response.", CANCER RES., vol. 55, no. 17, 1995, pages 3706- - 3711, XP000611541 *
S.M. PLANCHON ET AL.: "Lack of P53 induction in human prostate cancer cells by beta- lapachone, a catalytic inhibitor of topoisomerase I.", PROC. AM. ASSOC. CANCER RES ANNU. MEET., vol. 37, 1996, pages 429 - 430, XP000611540 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245807B1 (en) * 1995-08-24 2001-06-12 Dana-Farber Cancer Institute Treatment of human prostate disease
EP1420777A4 (fr) * 2001-07-31 2009-03-04 Arqule Inc Compositions pharmaceutiques contenant beta-lapachone ou des derives ou des analogues correspondants, et leurs methodes d'utilisation
WO2003090710A1 (fr) * 2002-04-23 2003-11-06 Case Western Reserve University Systemes d'administration de lapachone, compositions de lapachone et utilisations associees
US6890950B2 (en) 2002-04-23 2005-05-10 Case Western Reserve University Lapachone delivery systems, compositions and uses related thereto
WO2012162627A1 (fr) * 2011-05-26 2012-11-29 The General Hospital Corporation Traitement de maladies angiogéniques ou vasculaires associées
WO2016196344A1 (fr) 2015-05-30 2016-12-08 Molecular Templates, Inc. Supports de sous-unité a de toxine de shiga, déimmunisés, et molécules de ciblage de cellule les comprenant
CN105503692A (zh) * 2015-12-27 2016-04-20 新乡医学院 一种α-拉帕醇类似物及其合成方法和作为抗肿瘤药物的应用
CN105503692B (zh) * 2015-12-27 2017-12-26 新乡医学院 一种α‑拉帕醇类似物及其合成方法和作为抗肿瘤药物的应用
CN106074492A (zh) * 2016-06-13 2016-11-09 中山大学 9-甲氧基-α-拉帕醌作为吲哚胺2,3-双加氧酶-1抑制剂的用途

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