WO2000006546A1 - Compositions pharmaceutiques immunotherapeutiques anticancereuses - Google Patents

Compositions pharmaceutiques immunotherapeutiques anticancereuses Download PDF

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Publication number
WO2000006546A1
WO2000006546A1 PCT/US1998/012198 US9812198W WO0006546A1 WO 2000006546 A1 WO2000006546 A1 WO 2000006546A1 US 9812198 W US9812198 W US 9812198W WO 0006546 A1 WO0006546 A1 WO 0006546A1
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formula
alkyl
compound
alkenyl
group
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PCT/US1998/012198
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English (en)
Inventor
Kevin J. Tracey
Minghuang Zhang
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The Picower Institute For Medical Research
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Priority to PCT/US1998/012198 priority Critical patent/WO2000006546A1/fr
Priority to AU86573/98A priority patent/AU8657398A/en
Publication of WO2000006546A1 publication Critical patent/WO2000006546A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

Definitions

  • Anti-cancer therapy has usually followed the model wherein a cytotoxic agent is administered that kills rapidly dividing cells, which are cancer cells and some rapidly dividing host cells, such as bone marrow cells and gut epithelial cells.
  • a cytotoxic agent is administered that kills rapidly dividing cells, which are cancer cells and some rapidly dividing host cells, such as bone marrow cells and gut epithelial cells.
  • conventional cytotoxic cancer therapies have been limited by their side effects targeting those tissues or organs having rapidly dividing cells, (e.g., bone marrow suppression and mucositis).
  • Advances in cancer therapies have been made to better schedule the dosing of cytotoxic agents in creative combinations and to administer growth factors that are designed to rescue host rapidly dividing cells, such as blood cell growth factors G-CSF, EPO and others.
  • cytokines During the early immune response to infection or injury, macrophages synthesize pro- inflammatory cytokines which orchestrate the inflammatory reaction. Relatively small amounts of these cytokines produced locally in tissues benefit the host by activating antimicrobial pathways and stimulating tissue repair. On the other hand, if the inflammatory stimulus triggers an uncontrolled release of larger amounts of cytokines. the resulting cytokine cascade mediates the development of lethal shock and tissue injury (Tracey et al., Science 234:470-474, 1986; Tracey et al., Nature 330:662-664, 1987; and Tracey in Remnick and Friedland, eds, Tumor Necrosis Factor, Marcel Dekker, inc. 1996).
  • spermine prevents the synthesis of nitric oxide synthase and NO production in macrophages activated by bacterial endotoxin (Southan et al., Biochem. Biophys. Res. Comm. 203:1638-1644, 1944; and Szabe et al., Cancer Res. 52:1891-1894, 1992), down-regulates human neutrophil locomotion (Ferrante, Immunol. 54:785-790, 1985), and is immunosuppressive to T cells (Quan et al., Am. J. Reprod. Immunol. 22:64-69, 1990).
  • spermine levels have been measured in tissues following injury, inflammation, and infection, derived, in part, from a release of intracellular spermine from dying and injured cells.
  • Several theories have been proposed that the accumulation of spermine and the products of its oxidative metabolism via polyamine oxidase mediate anti- inflammatory activity found in inflammatory exudates, human pregnancy serum, plasma from arthritic rats, and human rheumatoid synovial fluid (Ferrante, Immunol. 54:785-790, 1985; Hempel et al., Nature 225:32-35, 1983; Lewis et al., Biochem. Pharmacol. 25:1435, 1976; Persellin, Arthritis Rheum.
  • TNF tumor necrosis factor
  • Macrophages are terminally differentiated immune effector cells that, when activated, can lyse tumor cells.
  • the macrophage lytic activity is mediated, in part, by secreting the cytokine TNF ⁇ .
  • the anti-tumor activity of macrophages is somehow suppressed during tumor growth.
  • Macrophages act by phagocytosis and intracellular disposal. It is a goal of cancer immunotherapy to activate macrophages, since activated macrophages have been shown to lyse tumor cells under both in vitro and in vivo conditions. Macrophages have a continuous function for removal of senescent or damaged red blood cells from the circulation, but this function is constitutive and does not require activation. By contrast, macrophages require activation to perform infrequent functions, such as participation in a host defense against cancer.
  • an activated macrophage may mean any change in behavior of the macrophage, such as increased adherence, altered motility, increased enzymatic activity, or increased phagocytosis.
  • mechanisms that have been studied that can activate macrophages include, for example, bacterial endotoxin, and cytokines such as TNF, GM-CSF, IL-2, IL-1 and others.
  • cytokines such as TNF, GM-CSF, IL-2, IL-1 and others.
  • Subsequent direct tumor cell lysis occurs both by direct macrophage-tumor cell contact and the release of a plethora of cytotoxic molecules from the activated macrophages (e.g., H 2 O 2 , NO, IL-1, TNF, and collagenases).
  • the importance of direct contact of the macrophage to the tumor cell requires that the macrophage be located within or in proximity to tumor cell tissue. If there are substances secreted by tumor cells that deactivate or prevent macrophage activation, the ability to deactivate the deactivators (a double negative makes a positive) represents an important therapeutic advance for immunotherapeutic treatment of cancer.
  • the present invention is based upon the discovery of a group of compounds having such activity, wherein the tumor-secreted deactivating substance is spermine. Summary of the Invention
  • the present invention provides a pharmaceutical composition for cancer immunotherapy treatment comprising a compound selected from formula I and a pharmaceutically acceptable carrier, wherein formula I comprises:
  • the present invention further provides a method for treating a patient with cancer, comprising administering an effective amount of a compound selected from the group consisting of formula I, formula II and formula III, wherein formula I comprises:
  • A is independently -CH 2 -, -O-, -NH-, -CO-, phenyl, or pyrimidnyl; wherein Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rg and R 9 are each independently H, C ⁇ -6 alkyl, C). 6 alkenyl, C ⁇ . 6 alkoxy.
  • formula II comprises: H 2 N-B-D-B-NH 2 II wherein "B” is a linker moiety independently selected from the group consisting of straight or branched Ci-6 alkyl, straight or branched C 2-6 alkenyl, straight or branched C ⁇ -6 alkyl substituted with an amine moiety, and straight or branched C -6 alkenyl substituted with an amine moiety; wherein "D” is a nitrogen-containing moiety selected from the group consisting of pyrimidinyl, piperidyl,
  • Ri is H; R through R 9 is H or Cj. 3 alkyl.
  • the preferred compounds of formula I are:
  • Figure 2 shows that cytotoxic activity of LPS-stimulated monocytes for co-cultured tumor cells is inhibited by spermine, and that this spermine-dependent effect is apparent at several different target celheffector cell ratios.
  • Figure 3 shows that cytotoxic activity of LPS-stimulated monocytes for co-cultured tumor cells is not inhibited by compound Ca38, and that at certain target celheffector cell ratios, cytotoxicity is enhanced.
  • Figure 4 shows that several of the immunomodulatory compounds (compound 38 of formula I, compounds 91 and 94 of formula II) with anti-cancer activity are not themselves directly cytotoxic for tumor cells at their effective immunostimulatory concentrations.
  • Figure 5 shows that compound Ca38 is efficacious in overriding or reversing the spermine-induced suppression of macrophage activation and of macrophage effector functions in vivo, as determined in a carrageenan-induced footpad edema model.
  • Figure 6 shows that in vivo treatment with compound Ca91 increases intra-tumor TNF levels.
  • Figure 7 shows that the inhibitory effects of compound Ca91 on growth of a representative solid tumor in vivo are negated by administration of anti-TNF antibodies, indicating that the anti-cancer effects of compound Ca91 are mediated, at least in part, through an effect on TNF levels in the tumor-bearing animal.
  • Figure 8 shows that compound 38 is effective to delay, inhibit or prevent the establishment of solid tumors from experimentally introduced tumor cell suspensions.
  • the effect in this model of tumor establishment (or metastasis) is dose-sensitive.
  • Figure 9 shows growth curves of solid tumors in animals treated daily with compound Ca91. Tumors were established from experimental engraftment of tumor cell suspensions before initiation of treatment. Administration of compound Ca91 was efficacious in slowing or preventing further tumor growth, and this activity was dose-sensitive.
  • B is a linker moiety independently selected from the group consisting of straight or branched C ⁇ _ 6 alkyl, straight or branched C 2-6 alkenyl, straight or branched C ⁇ -6 alkyl substituted with an amine moiety, and straight or branched C 2 .
  • alkenyl substituted with an amine moiety wherein "D” is a nitrogen-containing moiety selected from the group consisting of pyrimidinyl, piperidyl, pyridinyl, -CH-CH 2 -NH 2 , -CH-CH 2 -CH 2 -NH 2 , -CH-NH 2 , and piprazinyl; wherein formula III comprises: N ⁇ C-B-D-B-D-B-C ⁇ N III wherein "B” and "D" are independently defined as in formula II.
  • the pro-inflammatory cytokines TNF, IL-1, IL-6, MlP-l ⁇ and MlP-l ⁇ play an important role in stimulating the early stages of acute inflammation, including recruitment and activation of inflammatory cells, stimulation of endothelial activation and direct cytotoxicity.
  • cytokines play an important role for recovery from infection or injury, however, normal counter-regulatory mechanisms are also critical to the success of an immune response, because inappropriate or excessive production of pro-inflammatory cytokines can lead to shock or tissue injury.
  • Counter-regulatory mechanism has focused upon the cytokine inhibitory roles of the glucocorticoid hormones, the anti-inflammatory cytokines, such as TGF- ⁇ and IL-10, and prostaglandin PGE 2 .
  • glucocorticoid hormones such as TGF- ⁇ and IL-10
  • PGE 2 prostaglandin PGE 2 .
  • local production of proinflammatory cytokines mediates a host response to inflammation, infection and injury whereas overexpression of these mediators can injure or kill the host.
  • spermine plays an important counter-regulatory role for pro-inflammatory cytokine production and that an excessive counter-regulatory response, mediated by excessive spermine production, can be a mechanism protecting tumors against host defense mechanisms.
  • spermine is an important point of therapeutic intervention for immunotherapy of cancers, particular solid tumors, by inhibiting an excessive counter-regulatory response and allowing endogenous immune and inflammatory mechanisms to take place.
  • local administration of spermine in vivo protected mice against the development of acute footpad inflammation induced by carageenan.
  • Spermine can effectively inhibit cytokine synthesis in serum-free conditions and in the presence of the polyamine oxidase inhibitor aminoguanidine. Oxidative metabolism of spermine is not required for the counter-regulatory activity of spermine on cytokine synthesis.
  • the spermine concentrations are readily achievable in vivo as high spermine concentrations have been reported in tumors and in patients infected with bacteria, mycobacteria and viruses (Kurihara et al., Neurosurg. 32:372-375, 1993; Susuki et al., Experimentia 40:838-839, 1984; Seiler et al., Biochem J. 225:219-226, 1985; and Cipolla et al., Eur.
  • the present compounds that exhibit immunotherapeutic activity have been described structurally according to three formulae.
  • the compounds exhibit cancer immunotherapeutic pharmacologic activity by inhibiting spermine-induced counter-regulatory activity that tumor cells induce to protect themselves from a host defense immune response. Therefore, the inventive pharmaceutical compositions stimulate an immune response of the host against tumor cells by inhibiting an immune-inhibitory response, or a double negative makes a positive.
  • Tumors, particularly solid tumors are typically found to be unaffected by macrophages capable of participating in a vigorous host immune response against the tumor tissue. However, for the most part, these macrophages are not active (i.e., are dormant) against the invading tumor tissue.
  • Compound Synthesis Compound 38 is N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl) hexamethylenediamine.
  • This compound has been used as an ultraviolet stabilizer for polymeric materials.
  • One process to synthesize compound 38 is described in Maiz et al. Chemical Industry v. 47 (Catal. Org. React), 369-371, Marcel Dekker, 1992. Briefly, the synthetic process involves a reductive alkylation of 2,2,6,6-tetramethyl-4-piperdone with hexamethylenediamine.
  • compositions of the present invention may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using pharmaceutically acceptable carriers well-known in the art into dosages suitable for oral administration.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Example 1 Screening assay for compounds active in overriding the spermine-dependent inhibition of macrophage activation in vitro.
  • This example illustrates the in vitro activity of spermine to inhibit the macrophage/monocyte cytokine response to a standardized challenge with bacterial (E. coli) endotoxin (lipopolysaccharide, LPS), and further illustrates the use of a screening assay for compounds that reverse or override such spermine-dependent inhibition of macrophage activation and identifies compounds active in this assay.
  • E. coli bacterial endotoxin
  • Human monocytes were isolated and cultured from aliquots of fresh, EDTA-treated human blood from healthy donors (Long Island Blood Services; Melville, NY, USA) using standard techniques. Briefly, blood cells were fractionated to obtain peripheral blood mononuclear cells (PBMCs) by density gradient centrifugation through Ficoll-Paque (Pharmacia; Upsalla, Sweden). Buffy coat cells were collected, suspended in RPMI 1640 medium (Gibco BRL; Grand Island, NY, USA) supplemented with 10% heat-inactivated human serum, 0.1% L-glutamine and 0.01% gentamycin, and cultured at 37 °C in a humidified atmosphere of 5% CO 2 in air.
  • PBMCs peripheral blood mononuclear cells
  • Buffy coat cells were collected, suspended in RPMI 1640 medium (Gibco BRL; Grand Island, NY, USA) supplemented with 10% heat-inactivated human serum, 0.1% L-glutamine and 0.01% gentamycin, and culture
  • PBMCs peripheral blood mononuclear cells
  • cytokine assay and spermine uptake studies Nonadherent cells were removed by aspiration after overnight culture, and adherent cells (i.e., human monocytes) were then used in experimental procedures.
  • Monocyte cultures were activated with 100 ng/ml sonicated LPS (Sigma; St. Louis, MO, USA), and activation was measured by assaying for the elicited cytokine response; typically, tumor necrosis factor (TNF) levels in culture supernatants were measured by a standard TNF-specific enzyme-linked immunosorbent assay (ELISA).
  • LPS challenge was supplemented with 25 U/ml recombinant human interferon- ⁇ (IFN- ⁇ ; Boehringer Mannheim; Mannheim, Germany); results with LPS alone challenge and LPS/ IFN- ⁇ challenge were comparable.
  • IFN- ⁇ human interferon- ⁇
  • spermine was added to culture wells, typically 30-60 min before LPS challenge.
  • Fresh spermine stock solutions were prepared before each experiment, by dissolving spermine in sterile-filtered deionized water to a concentration of 51.2 mM or 35 mM; further dilution in RPMI 1640 followed by addition to cultured cells gave the final concentrations indicated (range 1-1000 ⁇ M).
  • Control cultures (not spermine-treated) received an equal volume of unadulterated medium.
  • LPS was prepared as a 400 ⁇ g/ml stock solution by sonication for 10 min, then further diluted with RPMI 1640 and by addition to cultures to provide the indicated final concentrations.
  • test compounds Fifty compounds with some molecular resemblance to naturally occurring polyamines (e.g., spermine) were screened for activity in reversing the spermine-dependent suppression of the tumor necrosis factor (TNF) response of monocyte cultures challenged with LPS. Briefly, dilutions of test compounds were pre-incubated at various concentrations with monocyte cultures 30-60 min before the addition of spermine (35 ⁇ M), which was introduced 30-60 min before LPS challenge. Culture supernatants were collected 4 hours after LPS challenge and assayed for TNF by ELISA.
  • TNF tumor necrosis factor
  • the mechanism by which the compounds of the present invention antagonize the macrophage suppressive activity of spermine was further investigated by measuring spermine accumulation in LPS-stimulated human PBMC cultures in the presence or absence of compound 91. Briefly, PBMC cultures were pre-cultured with LPS (100 ng/ml) for two hours, then treated with test compound (or medium as control) for 30-60 min, and then supplemented with 14 C-spermine as tracer. After 30 min, cells were flushed of unincorporated radiolabel, chased with cold spermine, and cell-associated radioactivity was measured by standard methods using a microtiter plate-based detection system.
  • Tumor target cell suspensions were prepared in 2X serial dilutions in RPMI 1640 and 200 ⁇ l aliquots were added to cultures of 3 X 10 5 human monocytes (prepared from human blood samples as described above, except that the PBMC fraction was cultured overnight in the presence of 2 ng/ml human MCSF) to provide effector celhtarget cell ratios of 2:1, 4:1, 8:1, 16:1, 32:1 and 64:1.
  • Example 3 Screening assay for compounds active in overriding the spermine-dependent inhibition of macrophage effector functions in vivo. This example shows that compounds of the instant invention can override the macrophage-suppressive effects of spermine in vivo.
  • Carrageenan-induced edema of the rat footpad is a well-accepted model of inflammation, in which monocytes/macrophages play a pivotal role. Intra-footpad administration of carrageenan causes monocyte/macrophage activation, leading to pro-inflammatory cytokine release (including, importantly, TNF) which is associated with inflammatory cell infiltration, edema and paw swelling.
  • mice Female C3H/HeN mice (20-25 g; Jackson Laboratories, Bar Harbor, ME, USA) were used in experimental groups of five animals.
  • Carrageenan (Sigma) was prepared at a concentration of 1.0% in PBS at 37°C three or more days before use. 50 ⁇ l doses of 0.2% carrageenan were injected into the plantar surface of the left hind paw of animals in the control group, and spermine (at the indicated doses) was co-administered in 50 ⁇ l PBS in three separate spermine-treatment groups.
  • the right hind paw was injected with the same volume of PBS as the matched control in each animal. At between 20-28 hours after footpad injection, the thickness of the left versus the right hind paw was measured by an investigator blinded as to the treatment group. The difference in thickness (in mm) between the left versus right paws was taken as the inflammatory index.
  • This assay is indicative of the activity of the test compound to override or reverse the inhibitory effects of spermine on macrophage activation and macrophage-mediated cytokine responses in vivo, and therapeutically beneficial activity of compounds of the present invention is identified thereby.
  • spermine is effective to suppress macrophage activation and effector functions (measured as footpad swelling) in this in vivo model.
  • Example 4 Anti-cancer activity in vivo.
  • This example shows the effectiveness of the compounds of the present invention to enhance intra-tumor TNF levels, to cause necrosis in established tumors, and to significantly inhibit the growth of experimentally introduced tumors in vivo.
  • TNF expression in B16 melanoma tumors is localized in mononuclear cells (relative hybridization intensity)
  • mice were given B16 Fl melanoma grafts as described above, and animals with size-matched tumors were randomized into treatment groups of five to receive intraperitoneal injections on days 7, 9 and 1 1 as follows: PBS group, 100 ⁇ l PBS vehicle only; Anti-TNF group, 2.0 mg anti-TNF IgG raised in rabbits/mouse; PI-Ca91, 2.0 mg/kg compound 91 ; +Rab IgG group, 2.0 mg/kg compound 91 plus 2.0 mg control rabbit IgG/mouse; +Anti- TNF group, 2.0 mg/kg compound 91 plus 2.0 mg anti-TNF IgG raised in rabbit/mouse. Tumor sizes were measured on day 13 and the average of such tumor sizes for each group are shown in Figure 7.
  • mice were studied in a melanoma engraftment model in which test compound was present from the time of subcutaneous implantation of the tumor cells.
  • Such assays are predictive, among other things, of the therapeutic activity of the test compound against melastases; that is, the activity of the compound to inhibit or prevent establishment of a new tumor by "founder" tumor cells.
  • 16 Fl tumor cells were cultured and isolated as described above for transfer into mice.
  • Stock solutions of compound 38 were prepared to provide final concentrations of 0 ⁇ M. 10 ⁇ M and 100 ⁇ M when mixed with melanoma cell suspensions.
  • compound 38 was efficacious in delaying or preventing the establishment of macroscopically apparent tumors following experimental transfer of tumor cells, and this "anti-melastatic" activity was dose-dependent.
  • animals were given B16 Fl melanoma cells as above, and lumors were allowed to become established for 7-8 days, at which time animals were matched according to tumor size and then distributed in control and treatment groups. Animals were treated daily for eight days and tumor size was estimated from caliper measurements every other day (compound 91 was administered i.p. at 0.5 or 2.0 mg/kg/day; controls received vehicle alone).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un type de compositions pharmaceutiques utiles pour le traitement de cancers, plus particulièrement pour les tumeurs solides et agissant comme antagonistes de la spermine. Ces compositions peuvent empêcher l'effet inhibiteur qu'exerce la spermine sur l'action des macrophages afin d'éviter l'immunosuppression induite par la spermine.
PCT/US1998/012198 1998-07-30 1998-07-30 Compositions pharmaceutiques immunotherapeutiques anticancereuses WO2000006546A1 (fr)

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PCT/US1998/012198 WO2000006546A1 (fr) 1998-07-30 1998-07-30 Compositions pharmaceutiques immunotherapeutiques anticancereuses
AU86573/98A AU8657398A (en) 1998-07-30 1998-07-30 Immunotherapeutic anti-cancer pharmaceutical compositions

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013045826A1 (fr) 2011-09-29 2013-04-04 Nutrialys Medical Nutrition Sa Compositions contenant de la spermine avec cadaverine, putrescine et/ou spermidine.
US8877779B2 (en) 2007-03-01 2014-11-04 Mitsubishi Tanabe Pharma Corporation Benzimidazole compound and pharmaceutical use thereof
WO2017136533A1 (fr) * 2016-02-03 2017-08-10 The Trustees Of The University Of Pennsylvania Méthodes pour traiter, diagnostiquer, et surveiller le traitement des mucopolysaccharidoses

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3352870A (en) * 1965-05-24 1967-11-14 Reilly Tar & Chem Corp Di-(nu-cyanoalkylpiperidyl) alkanes
WO1994007489A1 (fr) * 1992-10-02 1994-04-14 The Salk Institute For Biological Studies Inhibiteurs non competitifs de recepteurs neuronaux de l'acetylcholine nicotinique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3352870A (en) * 1965-05-24 1967-11-14 Reilly Tar & Chem Corp Di-(nu-cyanoalkylpiperidyl) alkanes
WO1994007489A1 (fr) * 1992-10-02 1994-04-14 The Salk Institute For Biological Studies Inhibiteurs non competitifs de recepteurs neuronaux de l'acetylcholine nicotinique

Non-Patent Citations (1)

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Title
BAIR K.W. ET AL.: "(1-Pyrenylmethyl)amino Alcohols, a New Class of Antitumor DNA Intercalators. Discovery and Initial Amine Side Chain Structure-Activity Studies", J. MED. CHEM., vol. 33, 1990, pages 2385 - 2393, XP002912046 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877779B2 (en) 2007-03-01 2014-11-04 Mitsubishi Tanabe Pharma Corporation Benzimidazole compound and pharmaceutical use thereof
WO2013045826A1 (fr) 2011-09-29 2013-04-04 Nutrialys Medical Nutrition Sa Compositions contenant de la spermine avec cadaverine, putrescine et/ou spermidine.
WO2017136533A1 (fr) * 2016-02-03 2017-08-10 The Trustees Of The University Of Pennsylvania Méthodes pour traiter, diagnostiquer, et surveiller le traitement des mucopolysaccharidoses

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