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WO1994008578A2 - Activite tumoricide des ansamycines benzoquinonoides contre le cancer de la prostate et les malignites neurales primitives - Google Patents

Activite tumoricide des ansamycines benzoquinonoides contre le cancer de la prostate et les malignites neurales primitives Download PDF

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Publication number
WO1994008578A2
WO1994008578A2 PCT/US1993/009858 US9309858W WO9408578A2 WO 1994008578 A2 WO1994008578 A2 WO 1994008578A2 US 9309858 W US9309858 W US 9309858W WO 9408578 A2 WO9408578 A2 WO 9408578A2
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group
composition
derivatives
ansamycin
geldanamycin
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PCT/US1993/009858
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English (en)
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WO1994008578A3 (fr
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Luke Whitesell
Leonard Neckers
Jane Trepel
Charles Myers
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The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services
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Application filed by The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services filed Critical The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services
Priority to EP93923891A priority Critical patent/EP0664702A1/fr
Priority to CA002146668A priority patent/CA2146668A1/fr
Priority to AU53606/94A priority patent/AU5360694A/en
Priority to JP6510285A priority patent/JPH08502488A/ja
Publication of WO1994008578A2 publication Critical patent/WO1994008578A2/fr
Publication of WO1994008578A3 publication Critical patent/WO1994008578A3/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Benzoquinonoid ansamycin antibiotics were isolated in the late 1970s from the culture broths of several actinomycete species. Their unusual ansa bridge structure generated considerable interest, and a number of compounds including herbimycin A (HA) and geldanamycin (GA) were screened as possible anti-retroviral and anti-tumor agents. Results against the usual test cell lines of the time such as L1210 leukemia and P-388 were disappointing. The concentrations required for anti-tumor activity were quite toxic in the whole animal and further development was abandoned.
  • HA was able to revert the phenotype of tyrosine kinase oncogene-transformed cell lines at quite modest concentrations. Inhibition of angiogenesis and induction of differentiation in a number of model systems were also reported. HA and GA have been shown to induce differentiation in a number of in vitro model systems, reportedly due to their inhibition of src-family protein tyrosine kinases.
  • the invention provides a method for treating human malignancies selected from the group comprising primitive neuroectodermal tumors, prostate cancer, melanoma, and metastatic Ewing's sarcoma.
  • the method includes administering an effective dosage of an ansamycin benzoquinone to an animal which has the malignancy.
  • the administration is preferably parenteral, such as intravenous.
  • the effective dosage is usually selected from a range of about 0.1 milligram of drug per kilogram body weight of the recipient animal (mg/kg) to about 20 mg/kg. Preferably, the effective dosage is selected from a range of about l mg/kg to about 10 mg/kg. More preferably, the effective dosage is about 5 mg/kg.
  • the ansamycin benzoquinone is typically selected from a group consisting of geldana ycin and its derivatives, herbimycin A and its derivatives, and macbecin I and its derivatives including macbecin II. The general chemical formula for the ansamycin benzoquinones is displayed in Figure 1.
  • the side groups R lf R 2 , R 3 and R 4 are typically a hydrogen, a hydroxyl, an alkyl or an alkoxy.
  • alkyl refers to substituents that are saturated hydrocarbon radicals.
  • the alkyl groups may be straight-chain or branched-chain, limited only by steric hindrance. Shorter alkyl groups, such as 1-4 carbon atoms are preferred.
  • alkoxy is used to refer to an alkyl radical which also bears an oxygen substituent that is capable of covalent attachment to another hydrocarbon radical (for example, a methoxy or ethoxy group) . As with alkyl groups, shorter alkoxy groups are preferred.
  • independently selected is used to indicate that the various R groups, R-. to R 4 , may be identical or different.
  • the invention includes a method for treating human malignancies selected from the group comprising primitive neuroectoder al tumors, prostate cancer, melanoma, and metastatic Ewing's sarcoma comprising parenterally administering to a human an effective dosage of an ansamycin benzoquinone selected from the group consisting of geldanamycin and its derivatives, herbimycin A and its derivatives, macbecin I and its derivatives including macbecin II.
  • the effective dosage is an amount sufficient to ameliorate symptoms or signs of the cancer.
  • the amount is generally a range of from about 0.1 mg/kg to about 20 mg/kg.
  • the geldanamycin derivatives are preferably those in the group consisting of 17-des-0-methylgeldanamycin, geldanamycin acetate, 7 • ,8 • -benzodemethoxygeldanoxazone, hydrogeldanamycin-18,21-diacetate, 7•-(and 8')- fluorodemethoxygeldanazine, 7 l -bromodemethoxygeldanoxazinone, 19-piperidinogeldanamycin, geldampicin, 8'- bromodemethoxygeldanoxazinone, 7' (or 8 1 )- fluorodemethoxygeldanazine, and 17-amino-17- demethoxygeldanamycin.
  • the invention further includes a pharmaceutical composition having at least one pharmaceutically acceptable excipient and an amount of an ansamycin benzoquinone effective to treat cancer in a mammal to whom at least one dose of the composition is administered.
  • the cancer is selected from a group including primitive neuroectodermal tumors, prostate cancer, melanoma, and metastatic Ewing's sarcoma.
  • the mammal is a human and the amount of ansamycin benzoquinone is selected from a range of from about 0.1 mg/kg to about 20 mg/kg.
  • the amount of ansamycin benzoquinone is selected from a range of from about 1 mg/kg to about 10 mg/kg. More preferably, the amount of ansamycin benzoquinone is about 5 mg/kg.
  • the composition is preferably adapted for parenteral administration such as intravenous administration.
  • the ansamycin benzoquinone component of the composition is usually selected from a group consisting of geldanamycin and its derivatives, herbimycin A and its derivatives, macbecin I and its derivatives including macbecin II.
  • the geldanamycin derivative is preferably selected from the group specified above.
  • FIG. 1 is the chemical structure of ansamycin benzoquinones.
  • Fig. 2 graphically shows that benzoquinonoid ansamycins inhibit cell proliferation and survival in a dose dependent fashion.
  • Fig. 3 is a photograph of a DNA electrophoresis assay showing that cycloheximide inhibits HA-induced DNA degradation.
  • Fig. 4 demonstrates lack of benzoquinonoid ansamycin toxicity to primary neurons in culture.
  • Fig. 5 shows HA inhibition of prostate tumor growth in nude mice.
  • Fig. 6 shows that systemic treatment with HA of tumor-bearing mice inhibits tumor growth.
  • the invention shows that benzoquinonoid ansamycins possess very potent cytocidal activity in vitro against a select range of human tumor lines and in vivo in a mouse model of certain human tumors.
  • the invention also found little toxicity on primary neuron cultures, several hematopoietic cell lines and a mouse fibroblast line.
  • Cell lines of the pediatric cancers neuroblastoma, neuroepithelioma and medulloblastoma were used as model systems in which to explore the therapeutic potential of ansamycin benzoquinones.
  • the benzoquinonoid ansamycins are potent cytotoxins in vitro against a panel of highly malignant human tumor cell lines possessing primitive neural features. Proliferation and/or survival of fibroblasts, primary neuronal cultures and several leukemia cell lines are unaffected at concentrations resulting in greater than 99% cell loss in sensitive lines.
  • the tu origenicity in nude mice of sensitive cell lines can also be markedly reduced by either systemic or topical administration of these agents without apparent toxicity to the whole animal.
  • the cytocidal action of these ansamycins is initiated very rapidly, is irreversible and clearly distinct from the delayed inhibition of src-fa ily kinases that has been previously reported.
  • the benzoquinonoid ansamycins are available commercially, or they can be isolated from natural sources.
  • production of geldanamycin is described by DeBoer, et al. "Geldanamycin, A New Antibiotic,” The Journal of Antibiotics 23:9, 442-447 (September 1970).
  • For isolation of herbimycin see Omura, et al. "Herbimycin, A New Antibiotic Produced By A Strain Of Streptomyces, " The Journal of Antibiotics 32:4, 255-261 (April 1979).
  • the ansamycin benzoquinones such as HA and GA, are available from the National Cancer Institute (NCI) Repository for investigational use. They are commercially available from Bethesda Research Lab (BRL) in Rockville, Maryland. When referring to treating a cancer, improved or decreased symptoms are included. That is, “treatment” is not limited to an objective regression of tumor size, but also includes the patient's report of his subjective status.
  • An effective amount of the compound is that amount which provides subjective relief of a symptom, decrease in the tumor burden, or decrease in an identifiable tumor marker.
  • Administration of the compound is by any medically or pharmaceutically accepted route. Typically, the parenteral route is preferred. Examples include intravenous, intramuscular, and subcutaneous administration. Topical application is also effective.
  • the dosing range is preferably from about 0.1 to about 20 mg/kg/day based on the patient's body weight. More specifically, the range is from about 1 to about 10 mg/kg/day.
  • the dosage of the benzoquinonoid ansamycin depends on many factors that are well known to those skilled in the art. The factors include, for example, the route of administration, the potency of the particular compound, the condition being treated, and the patient's age, weight, and general state of health including cardiac, hepatic and renal function.
  • a preferred dosing schedule is a parenteral or topical dose usually once or twice a day for a limited period, typically about 5 to 10 days.
  • the schedule is preferably repeated at a suitable interval, usually at about 14 to 28 days with the first day of the first cycle counted as day one.
  • the does can be given every other day or every three to four days for a total of about three to ten doses.
  • a preferred parenteral route is intravenous (IV) .
  • the IV dose is infused over about 30 to 60 minutes.
  • compositions of the present invention are presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, aqueous solutions or suspensions and water-in-oil emulsions containing suitable quantities or formulations of a benzoquinonoid ansamycin.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • suitable unit dosage forms are tablets, capsules, pills, powder packets, wafers, granules, teaspoonfuls, tablespoonfuls, droppersful, ampoules, and vials.
  • the benzoquinonoid ansamycin may be combined or mixed with various solutions and other compounds as is known in the art. For example, it may be administered in water, saline or buffered vehicles.
  • the benzoquinonoid ansamycin may be administered by any conventional method including oral, topical and parenteral (e.g., intravenous or intramuscular) injection.
  • the treatment may consist of a single dose or a plurality of doses over a period of time.
  • the drugs can be combined with appropriate doses of compounds.
  • a pharmaceutically effective amount of the drugs can be employed with a pharmaceutically acceptable carrier such as an additive or diluent.
  • a preferred formulation for parenteral use is an emulsion including the ansamycin benzoquinone and at least one emulsifying agent.
  • the vehicle Cremophor can be used as an emulsifier.
  • Emulsifiers which are nonionic and which contain complex fatty acids are preferred.
  • detergents may be useful in preparing the emulsion.
  • Another preferred formulation includes modifying the parent compound, such as HA or GA, to a salt which would be soluble in an aqueous solution. For example, esterification of reactive groups can be carried out to produce water soluble homologues or analogues of the ansamycin benzoquinone. Because the parent compounds tend to be insoluble in water, administration as an aqueous solution without modification of the parent is a lesser preferred, although a feasible, alternative.
  • CHP-100 cells were obtained from Dr. A. Evans (Children's Hospital of Philadelphia) .
  • the cell lines TC-32 and NIH3T3 were obtained from Dr. M. Tsokos (NCI, Laboratory of Pathology) . All other cell lines used were purchased from the American Type Culture Collection ATCC,
  • the cell lines CHP-100, TC-32, IMR-32, SKNSH, CEM and HL-60 were grown in RPMI 1640 (Biofluids, Inc., Rockville, MD) .
  • the cell lines D283 Med, D341 Med, SKNMC, SK-MEL-1, SK-MEL-2, and RPMI 7951 were cultured in Eagle's MEM with 1% non-essential amino acids and ImM sodium pyruvate (all from Biofluids, Inc) .
  • NIH3T3 cells were cultured in Dulbecco's MEM with 4.5 g/L glucose (Biofluids, Inc).
  • Herbimycin A National Service Center NSC 305978
  • geldanamycin NSC 122750
  • NCI National Cancer Institute
  • panel A demonstrates potent growth inhibitory activity of HA against the primitive neuroectodermal cell line CHP-100 as measured by inhibition of 3 H-thymidine incorporation after two days of culture with the drug.
  • This cell line is approximately 10-fold more sensitive in vitro to the inhibitory activity of HA than the non-tumorigenic mouse fibroblast cell line NIH3T3.
  • Panel B demonstrates a similar pattern of cell type selectivity for the related ansamycin GA, and GA is approximately ten-fold more potent than HA.
  • Thymidine incorporation studies were performed as previously described (Whitesell L, Rosolen A, Neckers LM, "Episome-generated N-myc antisense RNA restricts the differentiation potential of proimitive neuroectodermal cell lines", Mol . Cell . Biol . 11: 1360-1371 (1991)) except that serial dilutions of HA or GA were added to triplicate wells in 100 ⁇ L of the appropriate growth medium for the cell line being tested.
  • mitochondrial reduction of 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide (MTT) was used (Alley MC, et al., "Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazoliu assay", Cancer Res . , 48: 589-601 (1988)).
  • MTT 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide
  • EXAMPLE 2 Characteristics of HA and GA cvtotoxicity. Having demonstrated that HA and GA are actually cytotoxic to CHP100 cells, characteristics of this cytotoxicity was examined. Cell death can be an active or passive process depending on cell type and initiating stimulus. DNA degradation is often used as an endpoint for both processes. A requirement for ongoing protein synthesis in the transduction of cell death suggests an active type of program.
  • CHP-100 cells (5xl0 6 /10 cm tissue culture dish) were plated in the presence of HA (500 nM) , 80 nM cycloheximide (a concentration previously determined to inhibit protein synthesis by 75% as measured by 3 H-leucine incorporation) or a combination of the two. Sixty-eight hours after plating, the cells were harvested by trypsinization and cell number and viability determined by trypan blue exclusion in a hemocytometer chamber. The cells were washed once in PBS and high molecular weight DNA prepared according to a previously reported method (Rodriguez-Tarduchy G, Lopez-Rivas A. , "Phorbol esters inhibit apoptosis in IL-2 dependent T- lymphocytes", Biochem . Biophys . Res . Comm . , 164: 1069-1075 (1989)).
  • cell pellets were incubated at 37°C for at least 4 hours in 0.5mL of lysis buffer (200mM TRIS pH8.5, 100 mM EDTA, 50 ⁇ g/ml proteinase K, 1% SDS) .
  • the DNA was phenol extracted and the aqueous phase dialyzed overnight against 10 mM TRIS pH7.5, lmM EDTA.
  • the DNA was incubated at 37°C with 50 ⁇ g/mL RNase A. After 5 hours, 120 ⁇ g/mL proteinase K was added and the incubation continued for 5 more hours.
  • DNA was extracted with phenol followed by chloroform and precipitated with ethanol/sodium acetate.
  • Fig. 3 After re-dissolving in water, 5 ⁇ g of DNA was loaded per lane on a 1.4% agarose gel and electrophoresed for 16 hours at 35 volts prior to staining with ethidiu bromide and photography.
  • CTRL indicates a control and no drugs were added.
  • HA means that 500 nM HA were added.
  • CHX means that 80 nM cycloheximide were added.
  • CHX/HA means both drugs were added simultaneously.
  • DNA was isolated and electrophoresed as described above. Degradation of high molecular weight DNA is apparent only in lane HA.
  • Figure 3 demonstrates that protein synthesis is necessary for HA-induced cell death.
  • a panel of primitive neural cell lines was screened using both inhibition of 3 H-thymidine incorporation and reduction of MTT as endpoints. See Table l which is a summary of dose response data obtained by thymidine assay for a variety of both neural and non-neural cell lines.
  • Non-neural cell types such as the hematopoietic lines HL-60 and CEM were quite resistant to growth inhibition by HA and GA.
  • HA at 472 nM or GA at 40 nM was added to established neonatal rat cerebellar neuron cultures. Plates were incubated for a further 4 days and reduction of MTT dye reflecting viable cell number per well was then assayed as optical density at 540 nm. The height of the bars represents the mean absorbance of quadruplicate wells. Error bars indicate the standard deviation of the mean.
  • Figure 4 demonstrates that primary cultures of neonatal rat cerebellar neurons were not affected by culture in 472 nM HA or 40 nM GA. This experiment was also repeated several times with neonatal rat cerebral cortical neurons with the same results.
  • melanoma cell lines SK-MEL-1, SK-MEL-2 and RPMI 7951 were also screened against HA by MTT assay.
  • TABLE 1 Selectivity of growth inhibition by HA and GA Data are derived from dose response curves generated by quantification of 3 H-thymidine incorporation by indicated cell lines 48 hours after plating in various concentrations of the indicated drug. Cell lines are grouped in decreasing order of sensitivity
  • IC 50 Concentration of drug resulting in 50% decrease in mean cpm of triplicate wells relative to untreated control wells.
  • ⁇ c 95 Concentration of drug resulting in a 95% decrement.
  • CHP-100 cells were harvested from subconfluent monolayers and resuspended at 5xl0 7 cells/mL in PBS. 100 ⁇ L were inoculated subcutaneously in the right and left inguinal areas of six week old male athymic nude mice (Frederick Cancer Research Facility, Frederick, MD) on day 0. Therapy with HA or GA was initiated either on the day of tumor inoculation or 10 days post inoculation when palpable tumors were apparent.
  • the drugs were administered either topically by painting 5 ⁇ L of a 2 mg/mL solution of the drug in dimethyl sulfoxide on the site of tumor cell inoculation or systemically by intraperitoneal injection of drug formulated in dimethyl sulfoxide. Control animals received identical treatments with the appropriate vehicle alone. Animals were sacrificed 21 days after cell inoculation and well encapsulated tumors were resected and weighed. All studies involving the use of mice were carried out under protocols reviewed and approved by the Animal Care and Use Sub-committee of the National Cancer Institute.
  • Table 2 depicts the effects of either topical or systemic administration of drugs to animals at the time of tumor cell inoculation.
  • Nude mice were inoculated with tumor cells subcutaneously and therapy begun on the same day.
  • Topical therapy consisted of applying 5 ⁇ L of a 2 mg/mL solution of drug in dimethyl sulfoxide to the skin overlying the tumor inoculation site daily for 5 days.
  • Systemic therapy consisted of intraperitoneal GA injection daily for 5 days at 4.5 mg/kg body weight, or about 90 ⁇ g.
  • Tumor formation as defined by resection of a discrete mass of 100 mg or greater was assessed 21 days after cell inoculation. A marked reduction in subsequent tumor formation was evident following both HA and GA administration.
  • the mean weight of tumors that formed in drug-treated animals was also significantly smaller. No overt toxicity as evidenced by weight loss, decreased motor activity or local skin reaction was noted.
  • the tumors which formed despite topical GA treatment were resected aseptically, disaggregated in tissue culture medium and grown for 9 days in vitro in the presence or absence of GA.
  • the cell cultures recovered in this fashion grew well and, importantly, despite previous in vivo treatment with GA they remained fully sensitive to its cytotoxic action in vitro . This finding suggests that the failure of topical GA to inhibit tumor formation in all animals was a result of inadequate exposure to active drug and not acquired tumor cell resistance.
  • Tumors Mean Tumors Mean
  • nude mice were given a subcutaneous injection of human prostate cancer cells. These mice were treated with 5 mg/kg of HA intraperitoneally (IP) . See Fig. 5. Five million human prostate cancer cells were inoculated subcutaneously. Treatment began on the day of tumor cell inoculation and was repeated every other day for a total of 3 doses. Treatment consisted of 5 mg/kg herbimycin A as an intraperitoneal injection. The animals were sacrificed and the tumors were resected and weighed two weeks after inoculation. The ability of HA to inhibit the growth of established tumors was also examined in the nude mouse model.
  • IP intraperitoneally
  • HA treatment 10 days after tumor cell inoculation at a dose of 1.5 mg/kg, given intraperitoneally every third day for 4 doses resulted in decreased tumor mass as determined on the 21st day after tumor cell inoculation (Fig. 6) .
  • Nude mice with established subcutaneous tumors received intraperitoneal injections of either HA 1.5 mg/kg or an equivalent volume of vehicle on days 10, 13, 16 and 19 post tumor cell inoculation. Each point depicts the weight of an individual tumor mass resected on day 21.
  • HA and GA appear to be selectively cytocidal, it is of great interest to define their precise mechanism of action from the points of view of both basic biology as well as clinical drug development. For example, understanding the mechanism of action of these drugs may allow for identification of other sensitive tumor types. See Whitesell, et al., "Benzoquinonoid Ansamycins Possess Selective Tumoricidal Activity Unrelated to src Kinase Inhibition,"
  • the xenograft tumor results reported suggest promising in vivo anti-tumor activity for the benzoquinonoid ansamycins.
  • the detection of any anti-tumor activity in vivo is encouraging given the near complete lack of baseline pharmacologic information.
  • the antibiotics discussed here are small, lipophilic molecules that should be relatively easy to produce in bulk and, following systemic administration, should readily penetrate solid tumors and even the blood-brain barrier. Compounds such as these may well serve as models for the development of a generation of novel drugs possessing both biologic specificity and tumoricidal pharmacology.

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Abstract

Procédés et compositions pour le traitement de certains malignités chez l'homme, comprenant l'utilisation de certains ansamycine-benzoquinones.
PCT/US1993/009858 1992-10-14 1993-10-14 Activite tumoricide des ansamycines benzoquinonoides contre le cancer de la prostate et les malignites neurales primitives WO1994008578A2 (fr)

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Application Number Priority Date Filing Date Title
EP93923891A EP0664702A1 (fr) 1992-10-14 1993-10-14 Activite tumoricide des ansamycines benzoquinonoides contre le cancer de la prostate et les malignites neurales primitives
CA002146668A CA2146668A1 (fr) 1992-10-14 1993-10-14 Activite tumoricide d'ansamycines benzoquinonoides contre le cancer de la prostate et les tumeurs malignes primitives du systeme nerveux
AU53606/94A AU5360694A (en) 1992-10-14 1993-10-14 Tumoricidal activity of benzoquinonoid ansamycins against prostate cancer and primitive neural malignancies
JP6510285A JPH08502488A (ja) 1992-10-14 1993-10-14 前立腺癌および初期神経悪性疾患に対するベンゾキノイドアンサマイシンの殺腫瘍活性

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US96125092A 1992-10-14 1992-10-14
US07/961,250 1992-10-14

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051223A1 (fr) * 1998-04-03 1999-10-14 University Of Pittsburgh Of The Commonwealth System Of Higher Education Ansamycines benzoquinoides pour le traitement d'une crise ou d'un arret cardiaque
WO2000045805A2 (fr) * 1999-02-08 2000-08-10 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Methodes d'inhibition du reseau de hgf-met-upa-plasmine
US6174875B1 (en) 1999-04-01 2001-01-16 University Of Pittsburgh Benzoquinoid ansamycins for the treatment of cardiac arrest and stroke
US6482943B1 (en) 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
US6649587B1 (en) 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
EP1413885A2 (fr) * 1997-04-02 2004-04-28 Takeda Chemical Industries, Ltd. Utilisation et méthode de criblage d'un activeur d'un produit génétique aberrant
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005095347A1 (fr) * 2004-03-26 2005-10-13 Van Andel Research Institute Geldanamycine et ses derives pouvant inhiber une proliferation cancereuse et identifier de nouvelles cibles
US7241754B2 (en) 2003-06-13 2007-07-10 Kosan Biosciences, Inc. 2-Desmethyl ansamycin compounds
US7259156B2 (en) 2004-05-20 2007-08-21 Kosan Biosciences Incorporated Geldanamycin compounds and method of use
US7279502B2 (en) 1999-04-30 2007-10-09 Cellgate, Inc. Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
WO2007113270A1 (fr) * 2006-03-31 2007-10-11 Biotica Technology Ltd. Dérivés de 15-o-desméthylmacbecine et leur utilisation pour le traitement de cancer ou de malignités touchant les lymphocytes b
WO2007113266A2 (fr) * 2006-03-31 2007-10-11 Biotica Technology Ltd. Nouveaux composés et leurs méthodes de production
WO2007128827A1 (fr) * 2006-05-09 2007-11-15 Biotica Technology Limited Dérivés de 17-oxymacbecin et leur utilisation dans le traitement du cancer et/ou des malignités touchant les lymphocytes b
US7312244B2 (en) 1999-04-30 2007-12-25 Cellgate, Inc. Polyamine analog-amino acid conjugates useful as anticancer agents
WO2008061134A1 (fr) * 2006-11-15 2008-05-22 Abraxis Bioscience, Inc. Dérivés d'analogues de l'hydroquinone de geldamycine substitués par 18-amino présentant une activité cytotoxique pour le traitement du cancer
US7608611B2 (en) * 2005-03-11 2009-10-27 The Regents Of The University Of Colorado Hsp90 inhibitors, methods of making and uses therefor
US7776849B2 (en) 2005-06-29 2010-08-17 Kyowa Hakko Kirin Co., Ltd. Benzenoid ansamycin derivative
US8466140B2 (en) 2007-09-10 2013-06-18 University Of Massachusetts Mitochondria-targeted anti-tumor agents
US8551964B2 (en) 2007-08-23 2013-10-08 The Regents Of The University Of Colorado Hsp90 inhibitors with modified toxicity
US9603829B2 (en) 2011-11-14 2017-03-28 The Regents Of The University Of Colorado, A Body Corporate HSP90 inhibitors with modified toxicity

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2042523A (en) * 1979-02-19 1980-09-24 Kaken Chemical Co Geldanamycin derivatives and anti-tumor drug
DE3234203A1 (de) * 1981-09-17 1983-07-07 Takeda Chemical Industries, Ltd., Osaka Macbecin-derivate und deren herstellung

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2042523A (en) * 1979-02-19 1980-09-24 Kaken Chemical Co Geldanamycin derivatives and anti-tumor drug
DE3234203A1 (de) * 1981-09-17 1983-07-07 Takeda Chemical Industries, Ltd., Osaka Macbecin-derivate und deren herstellung

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CANCER RES., vol.48, no.22, 15 November 1988 pages 6530 - 6534 P.N.PREIS ET AL. 'Neuronal Cell Differentiation of Human Neuroblastoma Cells by Retinoic Acid plus Herbimycin A' *
CANCER RES., vol.52, no.7, 1 April 1992 pages 1721 - 1728 L.WHITESELL ET AL. 'Benzoquinonoid Ansamycins Possess Selective Tumoricidal Activity Unrelated to src Kinase Inhibition' cited in the application *
NIPPON GEKA HOKAN (ARCH. JPN. CHIR.), vol.60, no.2, 1 March 1991 pages 113 - 121 M. MATSUMOTO 'Inhibitors for Protein Tyrosine Kinases, Erbstatin, Genistein and Hernimycin A, Induce Differentiation of Human Neural Tumor Cell Lines' *

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EP0664702A1 (fr) 1995-08-02
CA2146668A1 (fr) 1994-04-28

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