WO2015009956A1 - Utilisation de lipides nitrés pour le traitement d'effets secondaires de thérapies médicales toxiques - Google Patents

Utilisation de lipides nitrés pour le traitement d'effets secondaires de thérapies médicales toxiques Download PDF

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WO2015009956A1
WO2015009956A1 PCT/US2014/047073 US2014047073W WO2015009956A1 WO 2015009956 A1 WO2015009956 A1 WO 2015009956A1 US 2014047073 W US2014047073 W US 2014047073W WO 2015009956 A1 WO2015009956 A1 WO 2015009956A1
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chemotherapy
use according
adr
side effect
acid
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PCT/US2014/047073
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English (en)
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Tianxin Yang
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University Of Utah Research Foundation
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods of treating the side effects of a toxic medical therapy using nitrated lipids.
  • the methods comprise the use of nitrated fatty acids or esters thereof to treat side effects, including organ system damage, caused by chemotherapy, radiotherapy, and the administration of other toxic agents.
  • Chemotherapy and radiotherapy provide an effective means of treating cancer.
  • cisplatin is among of the most successful anticancer drugs and is now being widely used for the treatment of testicular, head and neck, ovarian, cervical, nonsmall cell lung carcinoma, and many other types of cancer.
  • a drawback of both chemotherapy and radiotherapy is the production of toxicity in normal tissues.
  • the clinical use of cisplatin is limited by its severe side effects, including neurotoxicity, ototoxicity, nausea and vomiting, hair loss, and nephrotoxicity.
  • Adriamycin is an anthracycline antibiotic and can cause severe side effects, including podocyte foot process effacement, increase glomerular permeability leading to proteinuria, and inflammation via oxygen free radicals.
  • Other kinds of medical treatment may also involve administration of toxic agents, i.e., those that produce toxicity in normal tissues. Like chemotherapy and radiotherapy, the side effects associated with such treatments may limit the use of the treatment.
  • the present invention attempts to solve these problems, as well as others.
  • methods and medicaments useful in the treatment of the side effects of toxic medical therapies comprise administration of at least one nitrated lipid to a subject in need thereof in amounts effective to treat a side effect of a toxic medical therapy.
  • the side effect is reduced relative to the side effect prior to administration of the nitrated fatty acid or ester thereof.
  • the nitrated lipids may be used to prepare medicaments for treating a side effect of a toxic medical therapy.
  • nitrated lipids may be used in the present methods, including, e.g., nitrated fatty acids and esters thereof.
  • the nitrated fatty acid is a monounsaturated fatty acid (e.g., oleic acid) or a polyunsaturated fatty acid.
  • the oleic acid is selected from 9-nitrooleic acid, 10-nitrooleic acid, or combinations thereof.
  • lipids may be used to form the nitrated lipids, including, but not limited to a fatty acid or an ester thereof.
  • fatty acids are compatible with the disclosed methods, including, but not limited to, monounsaturated and polyunsaturated fatty acids.
  • Procedures for synthesizing nitrated lipids, sources for obtaining the lipids, and administration routes for the nitrated lipids are also provided.
  • the effective amount of the nitrated lipid administered to the subject may vary. In some aspects, the effective amount is that which prevents the subject from experiencing any of the disclosed side effects with any of the disclosed toxic medical therapies. In other aspects, the effective amount is an amount that reduces or eliminates the subject's side effects relative to the subject's side effects prior to administration of the nitrated lipid.
  • the methods disclosed herein may further comprise administrating a variety of therapeutic agents useful in the treatment of the underlying condition, disease, or disorder giving rise to any of the toxic medical therapies disclosed herein.
  • BUN Blood Urea Nitrogen
  • FIG. 2 The nitrated fatty acid OA-NO 2 improves renal morphology in a mouse model of cisplatin-induced toxicity. Shown are representative images of renal morphology at x200 and x400 magnifications.
  • FIG. 6 Bar graphs show the effects of nitrated fatty acid OA-NO 2 on cisplatin-induced apoptosis in vivo and in vitro.
  • FIG. 7 Nitrated fatty acid OA-NO 2 ameliorates albuminuria in Adriamycin (ADR) nephropathy.
  • FIGS. 8a-8b Nitrated fatty acid OA-NO 2 ameliorates hypoalbuminemia and ascites in ADR nephropathy.
  • Fig. 8a is a bar graph of the ELISA analysis of plasma albumin in different groups of mice at day 8 after ADR injection.
  • Fig. 8b is photographs of ascites in different groups of mice at day 8 after ADR injection.
  • Values are means ⁇ SE.
  • FIGS. 9a-9c Nitrated fatty acid OA-NO 2 ameliorates hypertriglyceridemia and renal dysfunction in ADR nephropathy.
  • Fig. 9a is a bar graph of the plasma triglyceride;
  • Fig. 9b is a bar graph of the plasma creatinine;
  • Fig. 9c is a bar graph of the Blood Urea Nitrogen (BUN).
  • FIGS. lOa-lOc Nitrated fatty acid OA-N0 2 ameliorates glomerulosclerosis and tubulointerstitial lesion in ADR nephropathy.
  • Fig. 10a is representative micrographs showing kidney histology in different groups of mice at day 8 after ADR injection. Kidney sections were stained with periodic acid-Schiff reagent (magnification: right x200, left x 1000 shown).
  • FIGS, lla-llf. Nitrated fatty acid OA-N0 2 preserves podocyte markers in ADR nephropathy.
  • Fig. 11a is an immunob lotting analysis of WT1 and ⁇ -actin in the kidneys.
  • Fig. lib is a bar graph of the densitometric analysis of WT1 protein. The densitometric value of WT1 protein was normalized by ⁇ -actin.
  • Fig. 11c is a photograph of the immunohistochemical analysis of WT1 in the kidney.
  • Fig. lid is a bar graph of the number of WT1 positive cells per glomerulus.
  • Fig. lie is a bar graph of the qRT-PCR analysis of ZO-1 in the kidney.
  • FIGS. 12a-12h Nitrated fatty acid OA-N0 2 hampers renal fibrosis in ADR
  • Figs. 12a-12b are bar graphs of the qRT-PCR analysis of renal mRNA levels of FN and collage III.
  • Figs. 12c-12d are representative immunoblots of renal a-SMA and FN. ⁇ - actin served as a loading control.
  • Figs. 12e-12f are bar graphs of the densitometric analysis of immunoblots in C-D.
  • FIGS. 13a-13c Effect of nitrated fatty acid OA-N0 2 on TBARS levels.
  • Fig. 13a is a bar graph of the measurement of plasma thiobarbituric acid-reactive substances (TBARS).
  • Fig. 12b is a bar graph of the measurement of urinary TBARS.
  • Fig. 13c is a bar graph of the measurement of kidney TBARS.
  • Values are means ⁇ SE.
  • FIGS. 14a-14d Effect of nitrated fatty acid OA-N0 2 on renal mRNA expression of NADPH oxidase subunits.
  • Figs. 14a-14b are bar graphs of the qRT-PCR analysis of renal mR A expression of p47 p ox and gp91 p ox .
  • ADR+OA-N0 2 : n 16. Values are means ⁇ SE.
  • Treating means to alleviate, in whole or in part, symptoms associated with a condition or disorder (e.g., disease), or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the condition or disorder.
  • an "effective amount" of a compound disclosed herein refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a condition or disorder, or halts further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder.
  • the prevention of, reduction of, or elimination of the side effect are examples of desirable treatment results.
  • treating does not necessarily occur by administration of one dose of the compound, but often occurs upon administration of a series of doses.
  • an effective amount, an amount sufficient to alleviate, or an amount sufficient to treat a disease, disorder, or condition may be administered in one or more administrations.
  • Pretreatment means to deliver or administer an effective amount of the compound prior to a subject being exposed to a toxic medical therapy. In one embodiment, pretreatment may be between 1-3 hours before a toxic medical therapy, alternatively between 1-3 days before a toxic medical therapy. Posttreatement may be any time after a subject being exposed to a toxic medical therapy. [029]
  • the methods disclosed herein comprise administration of a nitrated lipid.
  • Nitrated lipids are lipids comprising at least one nitro (N0 2 ) group covalently bonded to the lipid.
  • the methods disclosed herein encompass administration of a single type of nitrated lipid or a mixture of two or more different types of nitrated lipids.
  • one type of nitrated lipid is 9-nitro- 9-cis-octadecenoic acid.
  • type identifies the compound by lipid, stereochemistry, and number and position of N0 2 groups.
  • Nitrated lipids include nitrated fatty acids or esters thereof.
  • a fatty acid is a substituted or unsubstituted alkyl or alkenyl having a terminal COOH group.
  • the alkyl or alkenyl is a Cg-C 2 4 alkyl or alkenyl.
  • a wide variety of fatty acids may be used, including, but not limited to monounsaturated fatty acids and polyunsaturated fatty acids.
  • the monounsaturated fatty acid is oleic acid.
  • the oleic acid is 9-nitrooleic acid, 10-nitrooleic acid, or combinations thereof.
  • An ester of a fatty acid is a substituted or unsubstituted alkyl or alkenyl having a terminal COOR group.
  • the alkyl or alkenyl is a Cg-C 2 4 alkyl or alkenyl.
  • R may include, but is not limited to, a Ci_8 alkyl or glyceryl.
  • Nitrated lipids and its derivatives may be synthesized according to known procedures.
  • U.S. Patent Publication No. 2007/0232579 discloses a procedure comprising the steps of reacting a lipid with a mercuric salt, a selenium compound, and a nitrating compound to produce a first intermediate and reacting the first intermediate with an oxidant.
  • Useful mercuric salts, selenium compounds, nitrating compounds, oxidants, relative amounts of reactants, and reaction conditions are also disclosed in U.S. Patent Publication No. 2007/0232579.
  • Nitrated lipids, its derivatives, and other lipids may be synthesized according to other procedures as demonstrated in U.S. Patent Publication Nos. 2009/326070, 2009/326070, 2012/0136034, 2011/0082206, and (incorporated herein by reference in their entireties)
  • lipids described above may be obtained from a variety of sources.
  • lipids may be commercially available or may be obtained from natural sources.
  • Plant oils including, but not limited to olive oil, linseed oil, flaxseed oil, rapeseed oil, and perilla oil are possible natural sources of fatty acid lipids.
  • Fish oils or other marine oils are other possible sources of fatty acids.
  • Nitrated lipids present in any of these or other natural sources may be extracted and/or purified for use in the methods disclosed herein.
  • the disclosed methods involve treatment or pretreatment of a side effect of a toxic medical therapy.
  • a variety of side effects may be treated, including, but not limited to organ system damage, nausea, vomiting, and hair loss.
  • organ system it is meant a group of related organs.
  • the urinary system is an organ system including the kidneys, the ureters, the bladder, and the urethra.
  • Other examples of organ systems include, but are not limited to, the digestive system, the nervous system, the auditory system, the circulatory system, the endocrine system, the excretory system, the skeletal system, the respiratory system, the reproductive system, the muscular system, the lymphatic system, immune system, integumentary system, and the integumentary system.
  • Organ system damage refers to damage to one or more of the organs making up the organ system as a result of a toxic medical therapy.
  • Organ damage may include, but is not limited to, oxidative stress to the organ, cytotoxicity, and necrosis or apoptosis of organ cells.
  • Other organ damage may include Cardiotoxicity (heart damage), Hepatotoxicity (liver damage), Nephrotoxicity (kidney damage), Ototoxicity (damage to the inner ear), producing vertigo, Encephalopathy (brain dysfunction), Immunosuppression and myelosuppression, typhlitis, infertility, immunodepression, tendency to bleed, gasointestinal distress, and the like.
  • organ damage may be readily identified using well-known pathological techniques.
  • kidney damage may be identified by examining the overall renal morphology, the dilation of renal tubules, and the appearance of protein cast.
  • Organ damage may also be identified by measuring certain biomarkers of organ damage in a subject.
  • Useful biomarkers include, but are not limited to biological substances or activities that provide a marker of organ dysfunction, oxidative stress, necrosis or apoptosis.
  • a biomarker of organ dysfunction includes, but is not limited to the rise of plasma creatinine and BUN for renal dysfunction, and the rise of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for hepatic dysfunction.
  • Biomarkers of oxidative stress include, but are not limited to, the NADPH oxidase subunits p47 phox and gp91 phox , and thiobarbituric acid-reactive substances (TBARS).
  • Biomarkers of inflammation include, but are not limited to, Tumor necrosis factor (TNF-a), Interleukin 1 (IL- 1 ⁇ ) and monocyte chemotactic protein-1 (MCP-1).
  • a biomarker of apoptosis includes, but is not limited to, the activity of caspase 3, 6, and 9, NF- ⁇ , peroxisome proliferator-activated receptors (PPARs).
  • Another biomarker of organ damage is myeloperoxidase, MPO.
  • An increase in the level of MPO, BUN, AST, ALT, TBARS, ⁇ l phox , or gp9 Aox in a subject or an increase in the activity of caspase 3, 6, and 9 in the subject may provide an indication of organ damage.
  • Other organ system damage that may be recovered by the nitrated lipids may be found in Wang et al. "Nitro-oleic acid protects against endotoxin-induced endotoxemia and multiorgan injury in mice", AJP- Renal Physiol. 298(3): F754-F762 (2010).
  • the disclosed methods encompass a variety of toxic medical therapies.
  • toxic medical therapy it is meant a medical therapy that involves administration of an agent that is capable of producing toxicity in normal tissues.
  • the agent may be chemical or physical.
  • Chemical agents include, but are not limited to, alkylating agents, anti-metabolites, alkaloids and terpenes, topoisomerase inhibitors, antibiotics, monoclonal antibodies, tyrosine kinase inhibitors, nanoparticles, and hormones.
  • antibiotics include, but are not limited to, actinomycin, anthracyclines, and other cytotoxic antibiotics.
  • Anthracyclines include, but are not limited to, doxorubicin (Adriamycin), daunorubicin, valrubicin, idarubicin, epirubicin, which also inhibit topoisomerase II.
  • Cytotoxic antibiotics include, but are not limited to, bleomycin, plicamycin, mitomycin. Bleomycin acts in a unique way through oxidation of a DNA- bleomycin-Fe(II) complex and forming free radicals, which induce damage and chromosomal aberrations.
  • alkylating agents include, but are not limited to, cisplatin, mechlorethamine, cyclophosphamide, chlorambucil, carboplatin, ifosfamide, and oxaliplatin.
  • antimetabolites include, but are not limited to azathioprine, mercaptopurine, and other purine and pyrimidine analogues.
  • alkaloids and terpenes include, but are not limited to, vinca alkaloids, etoposide, teniposide, paclitaxel, taxanes, podophyllotoxins, and docetaxel.
  • vinca alkaloids include, but are not limited to, vincristine, vinblastine, vinorelbine, and vindesine
  • topoisomerase inhibitors include, but are not limited to, irinotecan, topotecan, etoposide, etoposide phosphate, teniposide, semisynthetic derivatives of epipodophyllotoxins, and amsacrine.
  • monoclonal antibodies include, but are not limited to, trastuzumab, cetuximab, rituximab, and bevacizumab.
  • hormones include, but are not limited to, steroids such as dexamethasone, finasteride, aromatase inhibitors, tamoxifen, and goserelin.
  • chemical agents include, but are not limited to, contrast agents, NSAIDS, COX-2 inhibitors, ACE inhibitors, ARBs, and lithium.
  • An example of a physical agent includes, but is not limited to, radiation.
  • the radiation may be ionizing radiation, proton therapy, electrochemotherapy, or laser radiation.
  • the nitrated lipids are administered to a subject in an effective amount.
  • An effective amount is an amount that 1) prevents the subject from experiencing any of the disclosed side effects associated with any of the disclosed toxic medical therapies; 2) reduces the subject's side effects relative to the subject's side effects prior to administration of the nitrated lipid; and/or eliminates the subject's side effects relative to the subject's side effects prior to administration of the nitrated lipid.
  • the side effect is urinary system damage comprising damage to one or more kidneys.
  • the effective amount is an amount that prevents, reduces, or eliminates the damage to the kidneys.
  • the damage to the kidneys may include, but is not limited to, any of the types of damage described above.
  • the nitrated lipids act as a signaling molecule capable of activating peroxisome proliferator-activated receptors (PPARs), inhibiting nuclear factor kappa-light-chain- enhancer of activated B cells (NF- ⁇ ), and releasing Nitrous Oxide (NO) in response to at least one toxic medical therapy.
  • PPARs peroxisome proliferator-activated receptors
  • NF- ⁇ nuclear factor kappa-light-chain- enhancer of activated B cells
  • NO Nitrous Oxide
  • the nitrated lipids in response to a toxic medical therapy, may attenuate glomerulosclerosis, podocyte loss, and tubulointerstitial fibrosis.
  • the nitrated lipids in response to a toxic medical therapy, reduce oxidative stress including plasma and urinary TBARS, reduce expression of NAD(P)H oxidase p47 phox and gp91 phox , and suppress inflammation including expression of TNF-a, IL- ⁇ and MCP-1 in response to a toxic medical therapy.
  • the nitrated lipids exert a renoprotective action against toxic medical therapies via anti-inflammatory and anti-oxidant properties, as supported by the examples below. All three PPAR subtypes ⁇ , ⁇ , and ⁇ , share anti-inflammatory and antioxidant properties, they may protect against renal I/R injury via different mechanisms.
  • PPARa provided protection likely via activation of fatty acid ⁇ -oxidation, a mechanism that also appeared to protect against cisplatin-induced nephrotoxicity, while PPAR5 may act via activation of the PKB/Akt pathway, leading to the increased spread of renal tubular epithelial cells.
  • the nitrated lipids activate all three PPAR subtypes to provide anti-inflammatory protection against toxic medical therapies.
  • the mechanism of action of the nitrated lipids in response to a toxic medical therapy protects podocytes and prevents albuminuria, hypoalbuminemia, hyperlipidemia and ascites. Podocytes play a crucial role in regulation of glomerular function.
  • WTl is a pivotal transcription factor that is essential for the maintenance of the differentiated features of adult podocytes.
  • nitrated lipids significantly preserve the expression of WTl proteins and prevent downregulation of WTl proteins.
  • nitrated lipids reverse the mRNA reduction of epithelial marker ZO-1 and the mRNA increase of the Mesenchymal marker desmin in response to a toxic medical therapy.
  • Tight junction protein ZO-1 is a protein that in humans is encoded by the TJP1 gene.
  • ZO-1 is a protein located on a cytoplasmic membrane surface of intercellular tight junctions.
  • the encoded protein may be involved in signal transduction at cell-cell junctions.
  • Desmin is a protein that in humans is encoded by the DES gene.
  • Desmin is a type III intermediate filament found near the Z line in sarcomeres.
  • Desmin is a 52kD protein that is a subunit of intermediate filaments in skeletal muscle tissue, smooth muscle tissue, and cardiac muscle tissue.
  • the nitrated lipids ameliorate glomeruloseclerosis, alleviate the accumulation of mesangial matrix, attenuate the prominent tubular dilation, reduce the intraluminal protein casts, improve the narrow Bowman's capsule, and attenuate of albuminuria.
  • pretreatment with nitrated lipids before the administration of a toxic medical therapy ameliorates albuminuria concomitantly with a reduction of plasma
  • TBARS thiobarbituric acid-reactive substances
  • Nitrated lipids include an antioxidant property by suppressing NADPH oxidase expression to account for the renoprotective action in a pretreatment step before administration of a toxic medical therapy.
  • Inflammation is an important component of pathophysiology of toxic medical therapies, such as ADR nephropathy.
  • Tubulointerstitial inflammation with infiltration of T and B lymphocytes and macrophages occurs in response to a toxic medical therapy, such as ADR.
  • Macrophages play a pivotal role in the disease process of ADR nephropathy and other immunosuppressive actions of toxic medical therapies.
  • proinflammatory cytokines Tumor necrosis factor (TNF-a), Interleukin 1 (IL- ⁇ ) and monocyte chemotactic protein- 1 (MCP-1) in the early stages of ADR nephropathy.
  • administration of nitrated lipids significantly inhibits the induction of the proinflammatory cytokines Tumor necrosis factor (TNF-a), Interleukin 1 (IL- ⁇ ⁇ ) and monocyte chemotactic protein- 1 (MCP-1) in response to a toxic medical therapy.
  • Nitrated lipids attenuate the endotoxin-elicited inflammatory response via diverse mechanisms involving activation of mitogen-activated protein kinase phosphatase 1 and nitroalkylation of NF- ⁇ p65 in response to a toxic medical therapy. Moreover, nitrated lipids have anti-inflammatory and renoprotective action in endotoxin-induced endotoxemia in response to a toxic medical therapy as to
  • cytokines i.e., TNF-a and IL-1 ⁇
  • adhesion molecules i.e., ICAM1
  • the effective amount of the nitrated lipids to be administered will vary depending upon a variety of factors, e.g., the condition to be treated, the age, body weight, general health, sex, and diet of the subject, the dose intervals, and the administration route.
  • the effective amount of the nitrated lipid ranges from about 1 ⁇ g per day to about 1 g per day, from about 1 mg per day to about 500 mg per day, from about 1 mg per day to about 100 mg per day, or from about 2 mg per day to about 10 mg per day.
  • any of the nitrated lipids disclosed herein may be administered to the subject alone or in combination with one or more other therapeutic agents.
  • administered in combination it is meant that the nitrated lipids and the therapeutic agents may be administered as a single composition, simultaneously as separate doses, or sequentially.
  • Sequential administration refers to administering the nitrated lipids and at least one therapeutic agent either before or after the other.
  • therapeutic agents may be used, including, but not limited to, those useful in the treatment of the underlying condition, disease, or disorder giving rise to any of the toxic medical therapies disclosed herein.
  • the nitrated lipids may be administered to a subject via any number of pharmaceutical formulations and administration routes.
  • the formulations can take the form of granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. These formulations may further include a variety of well-known pharmaceutically acceptable additives, carriers, and/or excipients as necessary.
  • the formulations may be delivered to the subject by various routes of administration, e.g., by topical administration, transdermal administration, oral administration, by nasal administration, rectal administration, subcutaneous injection, intravenous injection, intramuscular injection, or intraperitoneal injection. Any of the formulations, delivery methods, and pharmaceutically acceptable additives, carriers, and excipients disclosed in U.S. Patent Publication No. 2007/0232579 may also be used with the methods described herein.
  • Another possible route of administration includes incorporating the nitrated lipid into various food products. Food products, include, but are not limited to butter, margarine, vegetable oils, and the like.
  • the subjects of the disclosed methods include any animal that can benefit from the administration of a nitrated lipid.
  • the subject is a mammal, e.g., a human, a primate, a dog, a cat, a horse, a cow, a pig, or a rodent, e.g., a rat or mouse.
  • the mammal is a human.
  • the subject is undergoing or has undergone any of the disclosed toxic medical therapies. Such subjects may or may not actually be experiencing any of the disclosed side effects.
  • the subject has not yet undergone the toxic medical therapy, but is susceptible to any of the disclosed side effects because of an imminent toxic medical therapy.
  • a range includes each individual member.
  • a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1, 2, 3, 4, or 5 atoms, and so forth.
  • mice Male 3-4-month-old B6129SF2/J mice were from Jackson Laboratories (Bar Harbor, Me.). All animals were housed in an air-conditioned room with a 12-hour light/dark cycle. All procedures and protocols were in accordance with guidelines set by the Laboratory Animal Care Committee at the University of Utah.
  • 9-Nitrooleic acid and 10-nitrooleic acid are two regioisomers of nitrooleic acid (OA- N0 2 ), which are formed by nitration of oleic acid in approximately equal proportions in vivo.
  • the two compounds were purchased from Cayman Chemicals (Ann Arbor, Mich.) (9-nitrooleic acid: Cat#10008042; 10-nitrooleic acid: Cat#10008043) and used as an 1 : 1 mixture of the isomers.
  • FIG. 1 A single dose of i.p. injection of cisplatin induced renal dysfunction as indicated by the marked rise in plasma BUN (FIG. 1), accompanied by severe renal histological abnormalities characterized by distortion of the overall renal morphology, dilation of renal tubules, and appearance of protein cast (FIG. 2).
  • FIG. 2 posttreatment with OA-N0 2 markedly attenuated these functional and pathological changes (FIGS. 1-2).
  • kidney thiobarbituric acid-reactive substances (TBARS, index of oxidative stress) (FIG. 5), and activity of caspase (index of apoptosis) (FIG. 6A), all of which were attenuated or completely corrected by OA-NO 2 .
  • TBARS kidney thiobarbituric acid-reactive substances
  • caspase index of apoptosis
  • mice Male BABL/C mice were purchased from the Jackson Laboratories (Bar Harbor, ME, USA). Mice were maintained in a temperature-controlled barrier facility with a 12: 12-h light- dark cycle and were given free access to standard laboratory chow and tap water. Mice were randomized into three groups: 1) control, 2) Adriamycin (ADR), and 3) ADR+ nitro-oleic acid (OA-NO 2 ). In Group 3, OA-N0 2 (dissolved in ethanol) was administered at 5 mg/kg/day via subcutaneously implanted osmotic mini-pump and vehicle (ethanol) was given to the other two groups. This dose was chosen based a previous study (35).
  • mice 2 and 3 received a single tail vein injection of ADR at 10 mg/kg.
  • Group 1 received a single tail vein injection of saline.
  • Twenty four-hour urine was collected with using metabolic cages.
  • Seven days after ADR treatment all mice were killed and kidneys were immediately harvested gene expression or histological analyses. All protocols employing mice were conducted in accordance the principles and guidance of the University of Utah
  • Urine samples were centrifuged for 5 minutes at 10,000 rpm. Blood samples from anesthetized mice were collected by puncturing the vena cava using a 1-ml insulin syringe containing 50 ⁇ of 1 mM EDTA in the absence of protease inhibitors. Urine and plasma albumin was determined using a murine microalbuminuria enzyme-linked immunosorbent assay kit (Cat# 1011, EXOCELL). Plasma triglyceride level was determined using a LabAssay Triglyceride ELISA Kit (Cat#290-63701, WAKO).
  • Urine and plasma levels of urea were measured by Urea Nitrogen Direct kit (Cat# 0580-250, Stanbio Laboratory,), and urine and plasma levels of creatinine were measured by Creatinine Liquicolor kit (Cat#0420-250, Stanbio Laboratory).
  • grade 1 normal appearance
  • grade II involvement of up to 25% of the glomerulus
  • grade II involvement of 25 to 50%> of the glomerulus
  • grade III involvement of 50 to 75%o of the glomerulus
  • grade IV involvement of 75 to 100% of the glomerulus.
  • glomerulosclerosis index was calculated by multiplying the number of glomeruli with a sclerosis score of I by one, the number with a score of II by two, III by three, and IV by four. These values were summed and divided by the number of glomeruli assessed, including those with a sclerosis score of zero.
  • the SI for each kidney specimen was a sum of the points from 30 glomeruli.
  • Tubulointerstitial injury defined as tubular atrophy, dilatation, thickening of the basement membrane, protein cast
  • Anti-WTl antibody was purchased from Dako (Mob437, Dako).
  • the first strand cDNAs served as the template for quantitative PCR performed in Applied Biosystems 7900 Real Time PCR System using SYBR green PCR reagent (Applied Biosystems, Foster City, CA, USA). The amplification was carried out for 40 cycles with conditions of 15-s denaturation at 95°C.
  • oligonucleotides used for qPCR is listed as follows: GAPDH sense: 5'-GTC TTC ACTACCATGGAGAAGG-3 ' and antisense: 5'-TCATGGATGACCTTGGCC AG-3'; Fibronectin (FN) sense: 5'- CGTGGAGC AAGAAGGAC AA-3 ' and antisense: 5 '-GTGAGTCTGCGGTTGGT AAA-3 '; SMAa sense: 5'-CCCTGAAGAGCATCC GACA-3' and antisense: 5'-
  • CTCTCTTCCTCCACCAC-3' and antisense 5 '-ACAGCTTCTTTGGGACACCT-3 '.
  • Collagen type III sense 5 '-AGGCAAC AGTGGTTCTCCTG-3 ' and reverse 5'-GAC
  • the kidney lysates were stored at -80°C until assayed. Protein concentrations were determined using Coomassie reagent. An equal amount of the whole tissue protein was denatured at 100°C for 10 min, separated by SDS-PAGE, and transferred onto nitrocellulose membranes. The blots were blocked overnight with 5% nonfat dry milk in Tris-buffered saline (TBS), followed by incubation for 1 h primary antibody. The blots were washed with TBS followed by incubation with horseradish peroxidase-conjugated secondary antibody. Immune complexes were detected using ECL methods. The immunoreactive bands were quantified using the Gel and Graph Digitizing System (Silk Scientific, Tustin, CA).
  • TBARS thiobarbituric acid-reactive substances
  • OA-NO 2 attenuates albuminuria and renal dysfunction in managing
  • BALB/c mice were administered vehicle, ADR, or ADR in combination of OA-N0 2 ; OA-N0 2 was delivered via osmotic mini-pump 2 days prior to ADR injection. At day 5 after ADR injection, albuminuria was most evident in ADR group (508.89+48.52 ⁇ g/24h) as compared with control group (33.39+3.50 ⁇ g/24h), and was attenuated in ADR+OA-N0 2 group (342.40+33.26ug/24h). These changes were observed at day 3 and maintained at day 7.
  • ADR mice developed severe hyperlipidemia (plasma triglyceride: 396.18+70.94 mg/dl) that was less in ADR+OA-N0 2 group (plasma triglyceride: 212.70+39.22 mg/ dl) (Fig. 3A). Plasma creatinine and BUN were determined to reflect renal function. ADR mice had elevated plasma creatinine and BUN, both of which were significantly attenuated in ADR+OA-NO 2 group, as shown in Figs. 9B-9C.
  • WTl is a pivotal transcription factor that is essential for the maintenance of the differentiated features of adult podocytes.
  • Figs. 11A&11B immunoblotting revealed a marked reduction of WTl after ADR injury compared with controls, OA-N0 2 pretreatment prevented the down-regulation of WTl in the ADR mice (P ⁇ 0.05).
  • the number of podocytes was semi-quantitatively analyzed by immunohistochemical analysis of WT-1. The number of WTl -positive cells was reduced in the ADR group and was partially restored in the ADR+OA-NO 2 group, as shown in Figs.
  • qRT-PCR was performed to examine mRNA expression of Zonula occludens-1 (ZO-1) and desmin. Renal ZO-1 mRNA exhibited a trend of reduction in the ADR group as compared with the control group and a significant elevation in the ADR+OA-NO 2 group, as shown in Fig. HE. Desmin mRNA was up-regulated in the ADR mice, and treatment with OA- NO 2 prevented this increase, as shown in Fig. 11F.
  • Renal fibrosis was examined by determining the expression of a-SMA and fibronectin (FN) and TGF- ⁇ in the kidney.
  • a-SMA and fibronectin (FN) and TGF- ⁇ were examined by determining the expression of a-SMA and fibronectin (FN) and TGF- ⁇ in the kidney.
  • Figs. 12A-12 ADR mice showed marked increases in a-SMA and fibronectin (FN) expression at the mRNA levels relative to the control by realtime PCR (Figs. 12A&12B), and Western blotting revealed marked up-regulation of a-SMA and FN (Figs. 12C&12D). The densitometric values of these two proteins are shown in Figs. 12E&12F.
  • OA-NO 2 treatment prevented the up-regulation of a-SMA and FN in the ADR mice ( ⁇ 0.05).
  • OA-NO 2 hampers renal oxidative stress in managing chemotherapy-related toxicity
  • oxidative stress has emerged as an important pathogenic factor in the development of ADR nephropathy.
  • TBARS thiobarbituric acid reactive substances
  • NAD(P)H oxidase is an important source of ROS generation in various pathological conditions. Renal expression of major subunits of NAD(P)H oxidase was examined. As shown in Figs. 14A&B, renal mRNA expression of p47 phox and gp91 phox was significantly increased in ADR mice as compared with the control group and the increase was less in the ADR+OA-NO 2 group ( ⁇ 0.05). The change in gp91 phox was further confirmed at the protein level ( ⁇ 0.01; Figs. 14C&14D).
  • ADR induces proinflammatory response in the kidney, releasing cytokines and chemokines responsible for subsequent kidney injury.
  • qRT-PCR analysis of TNF-a, IL- ⁇ , and MCP-1 was performed. The renal expression of these proinflammatory mediators was in induce din parallel in ADR mice and the inductions were all suppressed by OA-NO 2 as shown in Figs. 15A-15C.
  • a 50 year old is diagnosed with invasive lung cancer.
  • the cancer is visualized either clinically or radiographically, and the patient undergoes pretreatment or posttreatment with a nitrated lipid and then exposed to chemotherapy or radiation.
  • the chemotherapy may include a chemical agent of at least one of the following: alkylating agents, anti-metabolites, alkaloids and terpenes, topoisomerase inhibitors, antibiotics, monoclonal antibodies, tyrosine kinase inhibitors, nanoparticles, hormones, contrast agents, NSAIDS, COX-2 inhibitors, ACE inhibitors, ARBs, and lithium.
  • patient is exposed to physical agent including at least one of the following: ionizing radiation, proton therapy, electrochemotherapy, or laser radiation.
  • ionizing radiation proton therapy
  • electrochemotherapy or laser radiation.
  • the nitrated lipid lessens a side effect of the chemotherapy or radiation including at least one of: organ system damage, nausea, vomiting, and hair loss.
  • the patient's organ systems including at least one of: the urinary system, the digestive system, the nervous system, the auditory system, the circulatory system, the endocrine system, the excretory system, the skeletal system, the respiratory system, the reproductive system, the muscular system, the lymphatic system, immune system,
  • integumentary system and the integumentary system.
  • the tissues are injected by radiographic guidance or direct visualization during mediastinoscopy or surgery. Following injection, it is noticed that there may be less side effects of the chemotherapy or radiation. Nitrated lipid administration may be repeated in intervals as necessary.
  • Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells and impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules, such as DNA.
  • Nitrated lipids may decrease side effects of alkylating agents by attenuating plasma level of MPO (marker of neutrophil infiltration), attenuating expression of NADPH oxidase subunits p47 phox and gp91 phox (major superoxide generating enzyme), attenuating thiobarbituric acid- reactive substances (TBARS, index of oxidative stress), and attenuating activity of caspase (index of apoptosis).
  • MPO marker of neutrophil infiltration
  • NADPH oxidase subunits p47 phox and gp91 phox major superoxide generating enzyme
  • TBARS index of oxidative stress
  • caspase index of apoptosis
  • Anti-metabolites prevent these substances from becoming incorporated into DNA during the "S" phase (of the cell cycle), stopping normal development and division. Anti-metabolites also affect RNA synthesis and due to their efficiency, Anti-metabolites are the most widely used cytostatics.
  • Nitrated lipids may decrease side effects of alkylating agents by inhibiting NF- ⁇ , preserve expression of WT1 proteins, prevent downregulation of WT1 proteins, reverse the mRNA reduction of epithelial marker ZO-1, inhibit production of proinflammatory cytokines Tumor necrosis factor (TNF-a), Interleukin 1 (IL- ⁇ ) and monocyte chemotactic protein- 1 (MCP-1), attenuate ADR-induced up-regulation of NADPH oxidase subunit gp91 phox and p47 phox at both mRNA and protein levels.
  • TNF-a Tumor necrosis factor
  • IL- ⁇ Interleukin 1
  • MCP-1 monocyte chemotactic protein- 1
  • Alkaloids are derived from plants and block cell division by preventing microtubule function, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules.
  • Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. Nitrated lipids may decrease side effects of alkaloids and
  • topoisomerases by inhibiting NF- ⁇ , preserve expression of WT1 proteins, prevent
  • WT1 proteins reverse the mRNA reduction of epithelial marker ZO-1, inhibit production of proinflammatory cytokines Tumor necrosis factor (TNF-a), Interleukin 1 (IL- ⁇ ), inducible nitric oxide synthase (iNOS), Cyclooxygenase-2 (COX-2), ICAM-l .VCAM- 1, and monocyte chemotactic protein- 1 (MCP-1), attenuate ADR-induced up-regulation of NADPH oxidase subunit gp91 phox and p47 phox at both mRNA and protein levels.
  • TNF-a Tumor necrosis factor
  • IL- ⁇ Interleukin 1
  • iNOS inducible nitric oxide synthase
  • COX-2 Cyclooxygenase-2
  • ICAM-l .VCAM- 1 monocyte chemotactic protein- 1
  • Nitrated lipids may decrease side effects of alkaloids by inhibiting NF- ⁇ , preserve expression of WT1 proteins, prevent downregulation of WT1 proteins, reverse the mRNA reduction of epithelial marker ZO-1, inhibit production of proinflammatory cytokines Tumor necrosis factor (TNF-a), Interleukin 1 (IL- ⁇ ) and monocyte chemotactic protein- 1 (MCP-1), attenuate ADR-induced up-regulation of NADPH oxidase subunit gp91 phox and p47 phox at both mRNA and protein levels.
  • TNF-a Tumor necrosis factor
  • IL- ⁇ Interleukin 1
  • MCP-1 monocyte chemotactic protein- 1

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Abstract

L'invention concerne des méthodes pour traiter les effets secondaires d'une thérapie médicale toxique au moyen de lipides nitrés. En particulier, les méthodes consistent à utiliser des acides gras nitrés ou des esters de ceux-ci pour traiter les effets secondaires, y compris une lésion de l'organisme provoquée par une chimiothérapie, une radiothérapie, et l'administration d'autres agents toxiques.
PCT/US2014/047073 2013-07-17 2014-07-17 Utilisation de lipides nitrés pour le traitement d'effets secondaires de thérapies médicales toxiques WO2015009956A1 (fr)

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