WO2024208828A1 - Radioprotection par inhibition de la superoxyde dismutase 1 - Google Patents

Radioprotection par inhibition de la superoxyde dismutase 1 Download PDF

Info

Publication number
WO2024208828A1
WO2024208828A1 PCT/EP2024/058942 EP2024058942W WO2024208828A1 WO 2024208828 A1 WO2024208828 A1 WO 2024208828A1 EP 2024058942 W EP2024058942 W EP 2024058942W WO 2024208828 A1 WO2024208828 A1 WO 2024208828A1
Authority
WO
WIPO (PCT)
Prior art keywords
sod1
inhibitor
radiation
cancer
radiotherapy
Prior art date
Application number
PCT/EP2024/058942
Other languages
English (en)
Inventor
Francesca PAGLIARI
Jeannette JANSEN
Daniel Garcia
Joao Seco
Original Assignee
Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts filed Critical Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
Publication of WO2024208828A1 publication Critical patent/WO2024208828A1/fr

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/04—Chelating agents

Definitions

  • the present invention relates to an inhibitor of intracellular copper-zinc-superoxide dismutase for use in protecting a subject from injury by a radiation burst.
  • the present invention also relates to a kit comprising an SOD1 inhibitor and a radiosensitizer of cancer cells, to an in vitro use of an SOD1 inhibitor for protecting non-cancer cells from ionizing radiation, and to methods, compositions, and uses related thereto.
  • Ionizing radiation may have, depending on its dose, profound effects on living cells.
  • Direct effects are caused by radiation directly interacting with genetic material, e.g. DNA, or some other cellular component critical to the survival of the cell.
  • genetic material e.g. DNA
  • the probability of radiation interacting with the genetic material is low, however, since genetic material only represents a small fraction of the biological molecules constituting a cell.
  • Indirect effects are mainly caused by interaction of radiation with water, producing radicals such as hydroxyl radicals, superoxide ions, and the like. These radicals cause the breakdown of biological molecules and, depending on intensity of breakdown, cause destruction of the cell and the symptoms of radiation injury known in the art.
  • SOD1 Pfam PF00080
  • SOD2 PFAM PF02777
  • SOD3 which is also a copper-zinc enzyme, is located extracellularly.
  • Inhibitors of SODs were proposed as anti-cancer agents, e.g. tetrathiomolybdate comprising compounds (Donate et al. (2008), Br J Cancer 98:776).
  • Ionizing radiation has long been an important modality in cancer treatment, since high doses of radiation can kill cancer cells; however, simultaneously, toxicity is induced in surrounding non- malignant tissues, which causes adverse events and may affect compliance with recommended protocols by patients.
  • the present invention relates to an inhibitor of intracellular copper-zinc- superoxide dismutase (SOD1 inhibitor) for use in protecting a subject from injury by a radiation burst (radiation burst injury).
  • SOD1 inhibitor intracellular copper-zinc- superoxide dismutase
  • composition defined using the phrase “consisting essentially of’ encompasses any known acceptable additive, excipient, diluent, carrier, and the like.
  • a composition consisting essentially of a set of components will comprise less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1% by weight, most preferably less than 0.1% by weight of non-specified component(s).
  • GAP and BESTFIT are preferably employed to determine their optimal alignment and, thus, the degree of identity.
  • the default values of 5.00 for gap weight and 0.30 for gap weight length are used.
  • the Basic Local Alignment Search Tool (BLAST) implementation is used with default parameter values for alignment.
  • BLAST Basic Local Alignment Search Tool
  • the term "essentially identical" indicates a %identity value of at least 80%, preferably at least 90%, more preferably at least 98%, most preferably at least 99%. As will be understood, the term essentially identical includes 100% identity. The aforesaid applies to the term "essentially complementary” mutatis mutandis.
  • polypeptide refers to a molecule consisting of several, typically at least 20 amino acids that are covalently linked to each other by peptide bonds. Molecules consisting of less than 20 amino acids covalently linked by peptide bonds are usually considered to be "peptides".
  • the polypeptide comprises of from 50 to 1000, more preferably of from 75 to 1000, still more preferably of from 100 to 500, most preferably of from 110 to 400 amino acids.
  • the polypeptide is comprised in a fusion polypeptide and/or a polypeptide complex.
  • SOD1 preferably is a mammalian SOD1, more preferably a human SOD1.
  • Activity of SOD1 can be measured by methods known in the art, e.g. from Vonk et al, (2010), JBC 285(37):2891; corresponding kits are commercially available.
  • the term "inhibitor of copper-zinc-superoxide dismutase”, also referred to as "SOD1 inhibitor” is understood by the skilled person to relate to a chemical compound inhibiting SOD1 activity.
  • the SOD1 inhibitor is a direct SOD1 inhibitor, i.e., preferably, is a compound directly interacting with SOD1 or at least one of its components and, thereby, inhibits SOD1 activity.
  • the SOD1 inhibitor may be an unspecific superoxide dismutase inhibitor, but preferably is a specific superoxide dismutase inhibitor, more preferably is a specific SOD1 inhibitor. Methods for identifying SOD inhibitors, in particular SOD1 inhibitors, are known to the skilled person.
  • an SOD1 inhibitor is a compound inhibiting SOD1 activity in cultured host cells by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50% at a concentration of at most 1 mM, preferably at most 0.1 mM, more preferably at most 0.01 mM, still more preferably at most 0.001 mM.
  • an SOD1 inhibitor is a compound inhibiting SOD1 activity in cultured host cells by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50% at a concentration causing cell death in at most 25%, preferably at most 10%, more preferably at most 5%, still more preferably at most 1%, of said cultured cells.
  • an SOD1 inhibitor is a compound inhibiting SOD1 activity in vivo in a subject by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%, at a dose causing at most Grade 1 (mild) or Grade 2 (moderate) adverse events as specified in the Common Terminology Criteria for Adverse Events v3.0 (CTCAE of 09 August 2006).
  • the SOD1 inhibitor is a low-molecular mass compound, preferably with a molecular mass of at most 1 kDa, more preferably at most 0.5 kDa.
  • the SOD1 inhibitor comprises a copper complexant.
  • the SOD1 inhibitor comprises tetrathiomolybdate ions, 4,5-dihalogeno-2-aryl-pyridazin-3(2H)-one, 2-methoxyestradiol, and/or cyanide ions.
  • the SOD1 inhibitor comprises tetrathiomolybdate ions.
  • tetrathiomolybdate and “tetrathiomolybdate ions” are known to the skilled person.
  • the molecular formula of tetrathiomolybdate is MoS4 2 '(CAS No. 16330-92-0).
  • Tetrathiomolybdate ions may be provided by any compound deemed appropriate by the skilled person, e.g. its acid H2M0S4 or a, preferably pharmaceutically acceptable, salt thereof, e.g. bis-choline tetrathiomolybdate (ATN-224, CAS No.
  • the SOD1 inhibitor is bis-choline tetrathiomolybdate (ATN-224, CAS No. 649749-10-0).
  • the 4,5-dihalogeno-2-aryl-pyridazin-3(2H)-one is 4,5-dichloro-2- (m-tolyl)-pyridazin-3(2H)-one (LCS-1, CAS No. 41931-13-9), 4,5-dibromo-2-(m-tolyl)- pyridazin-3(2H)-one (LCS-1.28, CAS No. 1035450-90-8), or 4,5-dichloro-2(2,4- dichlorophenyl)pyridazin-3(2H)-one (LCS-1.34, CAS No. 24725-65-3).
  • the SOD1 inhibitor is 2-methoxyestradiol ((8R,9S,13S,14S,17S)-2-Methoxy- 13-methyl-6,7,8,9,l l,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol, Cas No. 362-07-2) or a derivative or prodrug thereof.
  • a "prodrug" of 2-methoxyestradiol as the term is used herein, relates to a chemical compound having a chemical structure different from 2- methoxyestradiol, but being metabolized to 2-methoxyestradiol in the body of a subject.
  • a “derivative" of 2-methoxyestradiol is a compound having a similar, but non-identical, structure compared to 2-methoxyestradiol and having the property of being an S0D1 inhibitor.
  • a derivative is a compound obtainable from 2-methoxy estradiol by at most three, preferably at most two, more preferably by one derivatization steps known to the skilled person.
  • alkylation preferably O- alkylation, preferably methylation, ethylation, propylation, or isopropylation
  • esterification preferably of - OSO2NH, -COOH and/
  • the 2- methoxyestradiol derivative or prodrug has a structure according to formula (II) wherein R 10 and R 11 are independently selected from -OSO2NH, -OH, -OSO3,OCH3, -OCH2CH3, -NH2, with the provisio that R 10 and R 11 are not both -OH; preferably wherein R 10 and R 11 are -OSO2NH.
  • the 2-methoxyestradiol derivative preferably is 2-methoxyestradiol disulfamate ([(8R,9S,13S,14S,17S)-2-methoxy-13- methyl-3-sulfamoyloxy-6,7,8,9,l 1,12,14, 15, 16,17-decahydrocyclopenta[a]phenanthren- 17- yl] sulfamate, CAS No.401600-86-0).
  • the SOD1 inhibitor comprises cyanide ions (CAS No. 57-12-5.
  • the SOD1 inhibitor preferably is hydrogen cyanide or any salt thereof deemed appropriate by the skilled person, e.g. sodium cyanide or potassium cyanide.
  • they are preferably used as SOD1 inhibitors in vitro, e.g. on cultured cells, and/or also preferably are not used in vivo in a subject, in particular in case the subject is a human.
  • radiation is radiation interacting with, preferably causing damage to, biological material, in particular cells.
  • radiation comprises, preferably is, particulate radiation, in particular radiation comprising helium ions (alpha radiation), carbon ions, oxygen ions, and/or neutrons; or comprises, preferably is, electron radiation, in particular beta radiation, or comprises, preferably is, photon radiation, in particular gamma radiation.
  • the radiation is a type of radiation used in radiotherapy, in particular radiotherapy of cancer.
  • radiation burst relates to a, preferably foreseeable or predictable, short term increase in radiation, the term “short-term” preferably relating to a time frame of at most 12 hours, preferably at most 6 hours, more preferably at most 2 hours, still more preferably at most 0.5 hours, most preferably at most one minute.
  • radiation bursts are known in the art, e.g. radiation bursts caused by solar flares typically last for several hours, a planned radiation burst experienced by a radiation worker may last for a few minutes or hours, while e.g. a radiotherapy session may be finished within minutes or even less than a minute.
  • the radiation burst is radiotherapy, more preferably is cancer radiotherapy.
  • radiotherapy is understood by the skilled person and preferably relates to the use of ionizing radiation to kill or control an undesirable cell population in a subject, wherein said undesirable cell population preferably comprises cancer cells.
  • radiotherapy includes curative radiotherapy as well as adjunctive radiotherapy.
  • the radiation burst is administered to the subject as a radiotherapy session.
  • the radiation burst may be radiotherapy with a dose rate of at most 10 Gy/s, preferably at most 0.5 Gy/s, even more preferably at most 0.05 Gy/s.
  • radiotherapy preferably is radiotherapy with conventional dose rates.
  • radiotherapy with higher dose rates is administered, e.g. with a dose rate of more than 10 Gy/s, preferably more than 50 Gy/s, even more preferably more than 100 Gy/s.
  • the dose per treatment i.e. dose per session preferably is of from 0.1 Gy to 10 Gy, preferably of from 1 Gy to 5 Gy.
  • radiotherapy is radiotherapy with a dose per treatment of from 10 Gy to 100 Gy, preferably of from 20 Gy to 50 Gy.
  • the aforesaid doses indicated herein in Gy are doses of absorbed radiation energy per kilogram.
  • the aforesaid doses may be body doses or organ or organ system doses.
  • said doses are topical doses at the site of radiotherapy.
  • the SOD1 inhibitor may in particular be for use in protecting a subject from radiation burst injury in treating a subject by radiotherapy, in particular treating and/or preventing cancer by radiotherapy,
  • cancer relates to a disease of an animal, including man, characterized by uncontrolled growth by a group of body cells (cancer cells). This uncontrolled growth may be accompanied by intrusion into and destruction of surrounding tissue (infiltration) and possibly spread of cancer cells to other locations in the body (metastasis).
  • cancer is also included by the term cancer is a recurrence of a cancer (relapse).
  • the cancer is a solid cancer, a metastasis, or a relapse thereof.
  • the cancer is of stage 0 to stage III.
  • the cancer is a cancer of the brain, skin, lung, liver, pancreas, intestines, esophagus, heart, kidney, prostate, breast, head&neck, bone, bone marrow, reproductive organs, and/or spinal cord pedicles, preferably as indicated herein above.
  • treating refers to an amelioration of a disease or disorder referred to herein or the symptoms accompanied therewith to a significant extent; as used herein, the term includes prevention of deterioration of a disease, disorder, or symptoms associated therewith. Said treating as used herein also includes an entire restoration of health with respect to the diseases or disorders referred to herein. It is to be understood that treating, as the term is used herein, may not be effective in all subjects to be treated. However, the term shall require that, preferably, a statistically significant portion of subjects suffering from a disease or disorder referred to herein can be successfully treated.
  • Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student's t-test, Mann- Whitney test etc.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the treatment shall be effective for at least 10%, at least 20% at least 50% at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort or population.
  • treating comprises inhibiting proliferation, more preferably killing, of cancer cells.
  • treating cancer is reducing tumor and/or cancer cell burden in a subject.
  • effectiveness of treatment of e.g. cancer is dependent on a variety of factors including, e.g. cancer stage and cancer type.
  • cancer treatment further comprises at least one of chemotherapy, immunotherapy, surgery, and radiotherapy.
  • treating comprises treating a relapse.
  • treating comprises treating an advanced stage cancer.
  • preventing and prevention refer to retaining health with respect to the diseases or disorders referred to herein for a certain period of time in a subject. It will be understood that said period of time may be dependent on the radiation dose and number of radiation therapy sessions which are administered, as well as individual factors of the subject. It is to be understood that prevention may not be effective in all subjects treated as specified herein. However, the term requires that, preferably, a statistically significant portion of subjects of a cohort or population are effectively prevented from suffering from a disease or disorder referred to herein or its accompanying symptoms. Preferably, a cohort or population of subjects is envisaged in this context which normally, i.e. without preventive measures according to the present invention, would develop a disease or disorder as referred to herein.
  • preventing in particular relates to preventing cancer development, preventing metastasis formation, and/or preventing relapse, preferably relates to preventing metastasis formation and/or preventing relapse.
  • radiotherapy may be accompanied or complemented by other treatment modalities, such as chemotherapy, surgery, and/or immunotherapy.
  • chemotherapy chemotherapy, surgery, and/or immunotherapy.
  • surgery are understood by the skilled person. Appropriate standard treatment protocols are available in the art.
  • immunotherapy relates to the treatment and/or prevention of disease, preferably cancer, by modulation of the immune response of a subject.
  • Said modulation may be inducing, enhancing, or suppressing said immune response, e.g. by administration of at least one immune checkpoint modulator and/or cytokine.
  • the cytokine is an interferon, an interleukin, or a chemokine in such case.
  • the immunotherapy may also comprise administration of T cells, e.g. CAR T cells and/or recombinant T cell receptor T cells, and/or at least one T cell engager, i.e.
  • the term "injury by a radiation burst”, which may also be referred to as “radiation burst injury” is understood by the skilled person in the light of the description herein.
  • the radiation burst injury is at least one disease or disorder or symptom thereof caused by a dose of radiation in a subject or a host cell.
  • the radiation burst injury is an acute radiation injury or a chronic radiation injury; the skilled person is aware that the terms "acute” and “chronic” injury are used in the context of radiation injury as relating to the timing between radiation and injury, not to the duration of radiation.
  • an acute radiation injury is a reaction to irradiation occurring within minutes, hours, or within at most 7 days after irradiation
  • a chronic radiation injury is a reaction to irradiation occurring more than 7 days after irradiation.
  • Typical radiation injuries grouped by the organ system they occur most frequently, are summarized in Table 1 below. Table 1 : Acute and chronic radiation injuries of organs and organ systems.
  • an acute radiation injury is preferably selected from the list consisting of bum, ulceration, delayed fracture healing, reduced blood cell counts, reduced white blood cells, reduced platelets, enteritis, nausea, vomiting, swelling, seizure, dysphagia, ulcerations, inflammation pneumonitis, blood vessel swelling, hepatitis, nephritis, hemorhage, and reduced reproductive capacity.
  • a chronic radiation injury is selected from the list consisting of fibrosis, osteoporosis, osteomalacia, bone mineral loss, bone marrow failure, strictures, fistulae, sinus formation, cognitive deficits, blood vessel damage, heart attack, liver failure, renal failure, and reduced reproductive capacity.
  • radiation injury may be cell death of non-cancer cells, scarring at a treated site, ulceration, moist desquamation, erythema, and/or dry desquamation, all preferably at a treated site.
  • the radiation burst injury is not a mutagenesis-related injury, i.e. preferably is not an injury caused by a direct effect of ionizing radiation on genetic material, in particular DNA.
  • protecting from radiation burst injury is understood by the skilled person in view of the disclosure herein, in particular herein above and the Examples.
  • said protecting is reducing the extent or frequency of at least one symptom of radiation burst injury by at least at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%.
  • at least one radiation burst injury, in particular a chronic radiation burst injury is prevented by at least 75%, more preferably at least 90%.
  • the extent of radiation burst injury is a measure of the intensity at which a given radiation burst injury occurs; thus, the extent of radiation burst injury may be measured in a single individual and compared to a reference of control subjects.
  • the extent of radiation burst injury may, however, also be determined over a multitude of subjects, e.g. by calculating a mean, or a similar statistically relevant parameter.
  • a frequency of radiation burst injury is a measure of how many subjects in a plurality of subjects have a given radiation burst injury after a radiation burst, preferably at a predetermined extent.
  • the extent of radiation burst injury will preliminarily be a measure of severity of radiation burst injury, while the frequency of radiation burst injury will primarily be a measure of how frequently a radiation burst injury occurs in a predetermined population.
  • protecting from radiation burst injury may be reducing the extent of radiation burst injury, may be reducing the frequency of radiation burst injury, or may be both.
  • the radiation burst is radiotherapy and protecting a subject is protecting non-cancer cells from radiotherapy.
  • the SOD1 inhibitor is preferably administered topically, e.g. in the vicinity of an irradiated site.
  • the SOD1 inhibitor may, however, also be administered systemically, in particular in case an intracorporal site is irradiated or in case of large area or whole-body irradiation.
  • the radiation burst is a radiotherapy, in particular a radiotherapy session; also preferably, protecting a subject is protecting non-cancer cells from radiotherapy.
  • the present invention relates to an inhibitor of copper- zinc-superoxide dismutase (SOD1 inhibitor) for use in protecting non-cancer cells from radiotherapy of cancer in a subject.
  • protecting non-cancer cells preferably comprises reduction of non-cancer cell death after radiotherapy by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%; and/or comprises reduction of scarring by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%.
  • protecting non-cancer cells comprises avoiding necrosis and/or blistering at the treated site; and/or comprises avoiding ulceration and/or moist desquamation at the treated site. Further preferably, protecting non-cancer cells comprises at most development of erythema and/or dry desquamation at the treated site as radiation adverse effect(s).
  • the SOD1 inhibitor is for use in protecting a subject from radiation burst injury.
  • the SOD1 inhibitor preferably is for medical use in a subject, preferably for preventing radiation burst injury; in case the radiation burst is radiotherapy e.g. of cancer, the effect of radiotherapy preferably is treatment of cancer, while, also preferably, the effect of SOD1 inhibitor administration is protection of non-cancer cells.
  • radiotherapy in the presence of at least one SOD1 inhibitor in non-cancer cells, cancer cells are killed or inhibited, while non-cancer cells are protected from the effects of radiation.
  • said use comprises administration of said SOD1 inhibitor in a time frame of from 1 min to 12 h, preferably 1 min to 6 h, more preferably 1 min to 3 h, still more preferably 1 min to 2 h, before start of said radiation burst.
  • said use comprises administration of said SOD1 inhibitor in a time frame of from 5 min to 60 min, preferably 5 min to 45 min, more preferably 5 min to 30 min, before start of said radiation burst.
  • SOD1 is inhibited over the whole duration of the radiation burst; thus, in case of extended duration radiation bursts, repeated and/or continuous administration of the SOD1 inhibitor may be envisaged.
  • the dose of the SOD1 inhibitor is adjusted such that SOD1 activity in the areas, tissue, organ, or subject is inhibited by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably by at least 50%, preferably over the whole duration of the radiation burst.
  • higher doses of the SOD1 inhibitor may be envisaged, e.g. to achieve further reduction of radiation burst injury.
  • Appropriate doses of SOD 1 inhibitors are in principle known in the art and can be adjusted by the skilled person by measuring SOD1 activity and/or superoxide ion concentration.
  • the SOD inhibitor is comprised in a pharmaceutical composition, said pharmaceutical composition preferably further comprising a pharmaceutically acceptable carrier.
  • a pharmaceutical composition preferably further comprising a pharmaceutically acceptable carrier.
  • pharmaceutically active compounds can be present in liquid or dry, e.g. lyophilized, form. It will be appreciated that the form and character of the pharmaceutical acceptable excipient, e.g.
  • the SOD1 inhibitor and/or medicament preferably is administered systemically, preferably orally or parenterally, e.g. by intravenous administration, or is administered topically, preferably intra-tumorally; in case of cancer radiotherapy, topical administration may be peritumoral, and/or topical at a site of radiotherapy. Administration may, however, also be into a blood vessel, typically an artery, afferent to an intended site of effect, such as a peritumoral region. However, depending on the nature of the formulation and the desired therapeutic application, the SOD1 inhibitor and/or medicament may be administered by other routes as well.
  • dosages for any one patient may depend upon many factors, including the patient's size, age, the particular formulation of the medicament to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • the medicament referred to herein is, preferably, administered at least once, e.g. as a bolus. However, the medicament may be administered more than one time and, preferably, at least twice, e.g. permanently or periodically after defined time windows. SOD1 inhibition can be monitored by periodic assessment. Dosage recommendations may be indicated in the prescriber or user instructions in order to anticipate dose adjustments depending on the considered recipient.
  • appropriate doses for the pharmaceutically active compounds described herein are known in the art for single use of said compounds. Thus, a dose may be in particular such a dose known in the art.
  • the medicament according to the present invention may comprise further active agents in addition to the aforementioned active agent(s).
  • the pharmaceutically active compounds according to the invention are to be applied together with at least one further drug and, thus, may be formulated together with this at least one further drug as a medicament.
  • said at least one further active agent is a chemotherapeutic agent or an immunotherapeutic agent, such as a T cell or an immune checkpoint modulator, or is a radio sensitizer, all preferably as specified herein above.
  • the formulation of a pharmaceutical composition preferably takes place under GMP standardized conditions or the like in order to ensure quality, pharmaceutical safety, and effectiveness of the medicament.
  • the methods proposed herein enable significant reduction of radiation injury, in particular of non-cancer cells, during exposure of a subject to irradiation, such as e.g. in radiotherapy.
  • the means and methods of the present invention also allow performing high-dose radiotherapy with reduced or at least not increased radiation injury compared to conventional dose therapy.
  • the present invention enables mimicking FLASH radiotherapy while using radiotherapy at conventional dose rates.
  • the present invention also relates to a kit comprising an SOD1 inhibitor and a radiosensitizer of cancer cells, preferably comprised in a common housing.
  • the kit preferably contains instructions for carrying out said methods.
  • the instructions can be provided by a user's manual on paper or in electronic form.
  • the kit is adapted for use in a method of the present invention, more preferably is adapted to comprise all reagents required to perform said method or methods.
  • the kit comprises the compounds as specified in single doses, i.e. comprises the compounds in amounts corresponding to a single dose to be administered to a subject.
  • the compounds in the kit are for separate or for combined administration.
  • Separatate administration relates to an administration wherein at least two of the pharmaceutically active compounds of the present invention are administered via different routes and/or at different parts of the body of a subject.
  • one compound may be administered by enteral administration (e.g. orally), whereas a second compound is administered by parenteral administration (e.g. intravenously).
  • the kit comprises at least two physically separated preparations for separate administration, wherein each preparation contains at least one pharmaceutically active compound; said alternative is preferred e.g. in cases where the pharmaceutically active compounds of the combined preparation have to be administered by different routes, e.g.
  • the compounds in the kit are for simultaneous or for sequential administration.
  • Simultaneous administration relates to an administration wherein the pharmaceutically active compounds of as specified are administered at the same time, i.e., preferably, administration of the pharmaceutically active compounds starts within a time interval of less than 15 minutes, more preferably, within a time interval of less than 5 minutes. Most preferably, administration of the pharmaceutically active compounds starts at the same time, e.g. by swallowing a tablet comprising the pharmaceutically active compounds, or by swallowing a tablet comprising one of the pharmaceutically active compounds and simultaneous injection of the second compound, or by applying an intravenous injection of a solution comprising one pharmaceutically active compound and injecting second compound in different part of the body.
  • sequential administration relates to an administration of the pharmaceutically active compounds such that effective concentrations are present in relevant tissue(s) during at least part of the duration of a radiation burst, but which, preferably, is not a simultaneous administration as specified herein above.
  • sequential administration is an administration wherein administration of the pharmaceutically active compounds, preferably all pharmaceutically active compounds, starts within a time interval of 12 hours, still more preferably within a time interval of 4 hours, even more preferably within a time interval of one hour, most preferably within a time interval of 5 minutes.
  • sequential administration may in particular be envisaged in cases where two pharmaceutically active compounds have significantly different pharmacokinetic properties.
  • the present invention relates to a use of an SOD1 inhibitor for protecting non-cancer cells from ionizing radiation.
  • Said use preferably is an in vitro use.
  • Preferably said use comprises inducing mutations in the genomes of said non-cancer cells.
  • Embodiment 1 An inhibitor of intracellular copper-zinc-superoxide dismutase (SOD1 inhibitor) for use in protecting a subject from injury by a radiation burst (radiation burst injury).
  • SOD1 inhibitor intracellular copper-zinc-superoxide dismutase
  • Embodiment 2 The SOD1 inhibitor for use of embodiment 1, wherein said SOD1 inhibitor comprises a copper complexant.
  • Embodiment 3 The SOD1 inhibitor for use of embodiment 1 or 2, wherein said SOD1 inhibitor comprises tetrathiomolybdate ions, a 4,5-dihalogeno-2-aryl-pyridazin-3(2H)-one, 2- methoxyestradiol or a derivative or prodrug thereof, and/or cyanide ions.
  • Embodiment 4 The SOD1 inhibitor for use of any one of embodiments 1 to 3, wherein said SOD1 inhibitor is bis-choline tetrathiomolybdate (ATN-224, CAS No. 649749-10-0), 4,5- dichloro-2-(m-tolyl)-pyridazin-3(2H)-one (LCS-1, CAS No. 41931-13-9), 4,5-dibromo-2-(m- tolyl)-pyridazin-3(2H)-one (LCS-1.28, CAS No.
  • Embodiment 5 The SOD1 inhibitor for use of any one of embodiments 1 to 4, wherein said subject is a mammal.
  • Embodiment 7 The SOD1 inhibitor for use of any one of embodiments 1 to 6, wherein said SOD1 comprises an amino acid sequence as shown in SEQ ID NO: 1 (Genbank Acc No. AAB05662.1) or a sequence at least 70% identical thereto.
  • Embodiment s The SOD1 inhibitor for use of embodiment 6, wherein said SOD1 comprises an amino acid sequence as shown in SEQ ID NO: 1 or a sequence at least 90% identical thereto.
  • Embodiment 9 The SOD1 inhibitor for use of any one of embodiments 1 to 8, wherein said use comprises administration of said SOD1 inhibitor in a time frame of from 1 min to 12 h, preferably 1 min to 6 h, more preferably 1 min to 3 h, still more preferably 1 min to 2 h, before start of said radiation burst.
  • Embodiment 10 The SOD1 inhibitor for use of any one of embodiments 1 to 9, wherein said use comprises administration of said SOD1 inhibitor in a time frame of from 5 min to 60 min, preferably 5 min to 45 min, more preferably 5 min to 30 min, before start of said radiation burst.
  • Embodiment 11 The SOD1 inhibitor for use of any one of embodiments 1 to 10, wherein said radiation burst causes a radiation dose of from 1 Gy to 100 Gy, preferably of from 2 Gy to 25 Gy.
  • Embodiment 12 The SOD1 inhibitor for use of any one of embodiments 1 to 11, wherein said radiation burst causes said radiation dose within at most 12 hours, preferably at most 6 hours, more preferably within 2 hours, still more preferably within 0.5 hours, most preferably within less than one minute.
  • Embodiment 13 The SOD1 inhibitor for use of any one of embodiments 1 to 12, wherein said dose is a body dose or an organ dose.
  • Embodiment 16 The SOD1 inhibitor for use of any one of embodiments 1 to 15, wherein said radiation burst injury is an acute radiation injury selected from the list consisting of burn, ulceration, delayed fracture healing, reduced blood cell counts, reduced white blood cells, reduced platelets, enteritis, nausea, vomiting, swelling, seizure, dysphagia, ulcerations, inflammation pneumonitis, blood vessel swelling, hepatitis, nephritis, hemorhage, and reduced reproductive capacity.
  • said radiation burst injury is an acute radiation injury selected from the list consisting of burn, ulceration, delayed fracture healing, reduced blood cell counts, reduced white blood cells, reduced platelets, enteritis, nausea, vomiting, swelling, seizure, dysphagia, ulcerations, inflammation pneumonitis, blood vessel swelling, hepatitis, nephritis, hemorhage, and reduced reproductive capacity.
  • Embodiment 18 The SOD1 inhibitor for use of any one of embodiments 1 to 17, wherein said radiation burst injury is not a mutagenesis-related injury.
  • Embodiment 19 The SOD1 inhibitor for use of any one of embodiments 1 to 18, wherein protecting from radiation burst injury is reducing a severity of at least one symptom of at least one radiation burst injury by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%.
  • Embodiment 20 The SOD1 inhibitor for use of any one of embodiments 1 to 19, wherein said radiation burst is radiotherapy.
  • Embodiment 21 The SOD1 inhibitor for use of any one of embodiments 1 to 20, wherein said protecting is protecting non-cancer cells from radiotherapy of cancer.
  • Embodiment 22 The SOD1 inhibitor for use of any one of embodiments 1 to 22, wherein said use comprises topical administration of said SOD1 inhibitor to said non-cancer cells.
  • Embodiment 23 The SOD1 inhibitor for use of any one of embodiments 1 to 22, wherein said radiation is radiotherapy with a dose rate of at most 10 Gy/s, preferably at most 0.5 Gy/s, even more preferably at most 0.05 Gy/s.
  • Embodiment 24 The SOD1 inhibitor for use of any one of embodiments 1 to 23, wherein said radiotherapy is radiotherapy with a dose rate of more than 10 Gy/s, preferably more than 50 Gy/s, even more preferably more than 100 Gy/s.
  • Embodiment 25 The SOD1 inhibitor for use of any one of embodiments 1 to 24, wherein said radiotherapy is radiotherapy with a dose per treatment of from 0.1 Gy to 10 Gy, preferably of from 1 Gy to 5 Gy.
  • Embodiment 26 The SOD1 inhibitor for use of any one of embodiments 1 to 25, wherein said radiotherapy is radiotherapy with a dose per treatment of from 10 Gy to 100 Gy, preferably of from 20 Gy to 50 Gy.
  • Embodiment 27 The SOD1 inhibitor for use of any one of embodiments 1 to 26, wherein said dose is a topical dose at the site of radiotherapy.
  • Embodiment 28 The SOD1 inhibitor for use of any one of embodiments 1 to 27, wherein protecting non-cancer cells comprises reduction of non-cancer cell death after radiotherapy by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%.
  • Embodiment 29 The SOD1 inhibitor for use of any one of embodiments 1 to 28, wherein protecting non-cancer cells comprises reduction of scarring by at least 20%, preferably at least 30%, more preferably at least 40%, still more preferably at least 50%.
  • Embodiment 30 The SOD1 inhibitor for use of any one of embodiments 1 to 29, wherein protecting non-cancer cells comprises avoiding necrosis and/or blistering at the treated site.
  • Embodiment 31 The SOD1 inhibitor for use of any one of embodiments 1 to 30, wherein protecting non-cancer cells comprises avoiding ulceration and/or moist desquamation at the treated site.
  • Embodiment 32 The SOD1 inhibitor for use of any one of embodiments 1 to 31, wherein protecting non-cancer cells comprises at most erythema and/or dry desquamation at the treated site as radiation adverse effect(s).
  • Embodiment 33 The SOD1 inhibitor for use of any one of embodiments 1 to 32, wherein said cancer is a solid cancer.
  • Embodiment 34 The SOD1 inhibitor for use of embodiment 33, wherein said cancer is stage 0 to stage III.
  • Embodiment 35 The SOD1 inhibitor for use of any one of embodiments 1 to 34, wherein said cancer is a cancer of the brain, skin, lung, liver, pancreas, intestines, esophagus, heart, kidney, prostate, breast, head&neck, bone, bone marrow, reproductive organs, and/or spinal cord pedicles.
  • Embodiment 38 An SOD1 inhibitor for use in radiotherapy of cancer, wherein said radiotherapy comprises reducing or avoiding adverse effects of radiotherapy mediated by effects of ionizing radiation on non-cancer cells.
  • Embodiment 39 The SOD inhibitor for of any one of embodiments 36 to 38, further having a feature of any one of embodiments 1 to 35.
  • Embodiment 40 Use of an SOD1 inhibitor for the manufacture of a medicament for protecting non-cancer cells from radiotherapy of cancer and/or for reducing or avoiding adverse effects of radiotherapy mediated by effects of ionizing radiation on non-cancer cells.
  • Embodiment 41 A method for protecting non-cancer cells in radiotherapy of a subject comprising administering a SOD1 inhibitor to said subject before said radiotherapy.
  • Embodiment 43 A kit comprising an SOD1 inhibitor and a radiosensitizer of cancer cells.
  • Embodiment 44 The kit of embodiment 43, wherein said radiosensitizer is not said SOD1 inhibitor.
  • Embodiment 48 The use of embodiment 48, wherein said use is an in vitro use.
  • Embodiment 49 The use of embodiment 47 or 48, wherein said use comprises inducing mutations in the genomes of said non-cancer cells.
  • Embodiment 50 A compound comprising tetrathiomolybdate ions, a 4,5-dihalogeno-2- aryl-pyridazin-3(2H)-one, 2-methoxyestradiol or a derivative or prodrug thereof, and/or cyanide ions.
  • Embodiment 51 A composition comprising a compound selected from the list consisting of bis-choline tetrathiomolybdate (ATN-224, CAS No. 649749-10-0), 4,5-dichloro-2-(m- tolyl)-pyridazin-3(2H)-one (LCS-1, CAS No. 41931-13-9), 4,5-dibromo-2-(m-tolyl)- pyridazin-3(2H)-one (LCS-1.28, CAS No. 1035450-90-8), 4,5-dichloro-2(2,4- dichlorophenyl)pyridazin-3(2H)-one (LCS-1.34, CAS No. 24725-65-3), and N,N'-Bis(2- aminoethyl)-2 ethanediamine (Trientine, CAS No. 112-24-3).
  • ATN-224 CAS No. 649749-10-0
  • LCS-1 CAS No. 41931
  • Embodiment 52 The compound of embodiment 50 or the composition of embodiment 51, wherein said compound is bis-choline tetrathiomolybdate (ATN-224, CAS No. 649749-10-0).
  • Embodiment 53 The compound or composition of any one of embodiments 50 to 52 for use in protecting a subject from injury by a radiation burst (radiation burst injury).
  • Embodiment 54 The compound or composition for use of embodiment 53 further having a feature of any one of embodiments 5 to 35.
  • Embodiment 55 Use of the compound of embodiment 50 or the composition of embodiment 51 for the manufacture of a medicament for protecting non-cancer cells from radiotherapy of cancer and/or for reducing or avoiding adverse effects of radiotherapy mediated by effects of ionizing radiation on non-cancer cells.
  • Embodiment 56 A method for protecting non-cancer cells in radiotherapy of a subject comprising administering the compound of embodiment 50 or the composition of embodiment 51 to said subject before said radiotherapy.
  • Embodiment 57 A method for treating and/or preventing cancer in a subject by radiotherapy, said method comprising
  • Embodiment 58 A kit comprising (i) the compound of embodiment 50 or the composition of embodiment 51 and (ii) a radiosensitizer of cancer cells.
  • Embodiment 59 The kit of embodiment 58, wherein said radiosensitizer is selected from the list consisting of temozolomide, metronidazole, misonidazole, bromodeoxyuridine, motexafin gadolinium and efaproxiral.
  • Embodiment 60 Use of the compound of embodiment 50 or the composition of embodiment 51 for protecting non-cancer cells from ionizing radiation.
  • Embodiment 61 The use of embodiment 60, wherein said use is an in vitro use.
  • Embodiment 62 The use of embodiment 60 or 61, wherein said use comprises inducing mutations in the genomes of said non-cancer cells.
  • Fig. 1 Conventional and FLASH irradiation in the presence or absence of ATN-224 or NaCN, fractions of cells surviving the indicated doses.
  • ATN-224 cells (non-irradiated) in the presence of ATN-224;
  • ATN Conv cells after irradiation at conventional dose rates in the presence of ATN-224;
  • ATN Flash cells after irradiation at high dose rates in the presence of ATN-224;
  • NaCN cells (nonirradiated) in the presence of NaCN; NaCN conv: cells after irradiation at conventional dose rates in the presence ofNaCN; cells after irradiation at high dose rates in the presence of NaCN.
  • Y-axis fraction of surviving cells relative to non-irradiated cells.
  • a clonogenic assay experimental setting was used to study the impact of ATN 224 after radiation treatment with different dose rates.
  • a day before the treatment 400 000 H460 cells were seeded into 35 mm petri dishes (Greiner) and incubated overnight. Cells were treated before irradiation using 60 pM of ATN-224 for 30 minutes; incubation was performed in the same conditions as cell culture. After incubation, cells were irradiated using a MultiRad225 X- ray source (Faxitron Bioptics) with 10 Gy using a conventional dose rate (conv) of 2.15 Gy/s and a high dose rate (HDR) of approximately 10 Gy/s.
  • Conv conventional dose rate
  • HDR high dose rate
  • the petri dishes were placed very close to the source.
  • the dosimetry was performed using EBT XD (Ashland) radiochromic films (RF) only for irradiation using HDR by placing a RF in the bottom of the petri dishes.
  • RF radiochromic films
  • SOD1 activity was measured with the superoxide dismutase assay manufactured by Sigma- Aldrich (order No. CS0009), according to manufacturer's instructions.
  • Table 2 SOD activities after indicated treatments; sd: standard deviation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Toxicology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un inhibiteur de superoxyde dismutase à cuivre-zinc intracellulaire destiné à être utilisé pour protéger un sujet de toute lésion causée par une rafale de rayonnement. La présente invention concerne également un kit comprenant un inhibiteur de SOD1 et un radiosensibilisant de cellules cancéreuses, une utilisation in vitro d'un inhibiteur de SOD1 pour protéger des cellules non cancéreuses contre un rayonnement ionisant, ainsi que des méthodes, des compositions et des utilisations associées.
PCT/EP2024/058942 2023-04-03 2024-04-02 Radioprotection par inhibition de la superoxyde dismutase 1 WO2024208828A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23166353.5 2023-04-03
EP23166353 2023-04-03

Publications (1)

Publication Number Publication Date
WO2024208828A1 true WO2024208828A1 (fr) 2024-10-10

Family

ID=85800787

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/058942 WO2024208828A1 (fr) 2023-04-03 2024-04-02 Radioprotection par inhibition de la superoxyde dismutase 1

Country Status (1)

Country Link
WO (1) WO2024208828A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026791A1 (fr) * 1996-01-26 1997-07-31 The Regents Of The University Of California PROCEDES DE MODULATION DE LA FORMATION DE RADICAUX PAR UTILISATION D'ENZYMES CuZnSOD MUTANTES
WO2008080056A2 (fr) * 2006-12-21 2008-07-03 Sloan-Kettering Institute For Cancer Research Pyridazinones et composés furanniques
US10722526B2 (en) 2015-12-01 2020-07-28 Korea Institute Of Radiological & Medical Sciences Pharmaceutical compositions for radioprotection or radiomitigation and methods for using them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026791A1 (fr) * 1996-01-26 1997-07-31 The Regents Of The University Of California PROCEDES DE MODULATION DE LA FORMATION DE RADICAUX PAR UTILISATION D'ENZYMES CuZnSOD MUTANTES
WO2008080056A2 (fr) * 2006-12-21 2008-07-03 Sloan-Kettering Institute For Cancer Research Pyridazinones et composés furanniques
US10722526B2 (en) 2015-12-01 2020-07-28 Korea Institute Of Radiological & Medical Sciences Pharmaceutical compositions for radioprotection or radiomitigation and methods for using them

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", MACK PUBLISHING COMPANY
CHE ET AL., DRUG DISCOVERY TODAY, vol. 21, no. 1, 2016, pages 143
DONATE ET AL., BR J CANCER, vol. 98, 2008, pages 776
EVANS ET AL., INT J RAD ONCOL BIOL PHYS, vol. 11, no. 6, 1985, pages 1163
EVANS ET AL: "Tumor radiosensitization with concomitant vone marrow radioprotection: A study in mice using diethyldithiocarbamate (DDC) under oxygenated and hypoxic conditions", INTERNATIONAL JOURNAL OF RADIATION: ONCOLOGY BIOLOGY PHYSICS, PERGAMON PRESS, USA, vol. 11, no. 6, 1 June 1985 (1985-06-01), pages 1163 - 1169, XP026842413, ISSN: 0360-3016, [retrieved on 19850601] *
JIANG ET AL., CANCER LETT, vol. 438, 2018, pages 154
LI XIANG ET AL: "Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment", vol. 27, no. 1, 27 December 2021 (2021-12-27), DE, pages 148, XP093081290, ISSN: 1433-1373, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8746559/pdf/molecules-27-00148.pdf> DOI: 10.3390/molecules27010148 *
MASHIBA ET AL., LIFE SCIENCES, vol. 49, 1991, pages 1419
MASHIBA H ET AL: "Enhancement of radiosensitizing effect of the nitroimidazole derivative RK28 on the proliferation of MethA tumor cells in combined use with diethyldithiocarbamate", LIFE SCIENCE, PERGAMON PRESS, OXFORD, GB, vol. 49, no. 19, 1 January 1991 (1991-01-01), pages 1419 - 1425, XP025566691, ISSN: 0024-3205, [retrieved on 19910101], DOI: 10.1016/0024-3205(91)90394-Q *
MILAS ET AL., INT J RAD ONCOL BIOL PHYS, vol. 10, no. 12, 1984, pages 2335
MILAS L ET AL: "In vivo radioprotective activities of diethyldithiocarbamate (DDC)", INTERNATIONAL JOURNAL OF RADIATION: ONCOLOGY BIOLOGY PHYSICS, PERGAMON PRESS, USA, vol. 10, no. 12, 1 December 1984 (1984-12-01), pages 2335 - 2343, XP026842809, ISSN: 0360-3016, [retrieved on 19841201] *
MISRA ET AL., JBC, vol. 254, no. 22, 1979, pages 11623
TRAPP ET AL., MELANOMA RES, vol. 19, no. 6, 2009, pages 350
TRAPP V ET AL: "Redox-related antimelanoma activity of ATN-224", MELANOMA RESEARCH 2009 LIPPINCOTT WILLIAMS AND WILKINS GBR, vol. 19, no. 6, December 2009 (2009-12-01), pages 350 - 360, XP009547631, ISSN: 0960-8931 *
VONK ET AL., JBC, vol. 285, no. 37, 2010, pages 2891
VOZENIN ET AL., NAT REV CLIN ONCOL, vol. 19, 2022, pages 791

Similar Documents

Publication Publication Date Title
Chen et al. Ferroptosis as a potential target for cancer therapy
JP6147799B2 (ja) Ｐａｒｐインヒビターとの組合せ療法
Horsman et al. Combination of nicotinamide and hyperthermia to eliminate radioresistant chronically and acutely hypoxic tumor cells
Gorbunov et al. Brain damage and patterns of neurovascular disorder after ionizing irradiation. Complications in radiotherapy and radiation combined injury
Overgaard Effect of misonidazole and hyperthermia on the radiosensitivity of a C3H mouse mammary carcinoma and its surrounding normal tissue
Clarke et al. Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia
Smith et al. Therapeutic targeting of microglia mediated oxidative stress after neurotrauma
Xiao et al. BMSC-derived exosomal Egr2 ameliorates ischemic stroke by directly upregulating SIRT6 to suppress notch signaling
Taghizadeh-Hesary “Reinforcement” by tumor microenvironment: the seventh “R” of radiobiology
Zhong et al. GLUT-1 siRNA enhances radiosensitization of laryngeal cancer stem cells via enhanced DNA damage, cell cycle redistribution, and promotion of apoptosis in vitro and in vivo
Hockey et al. Dexamethasone for intracranial neurosurgery and anaesthesia
Han et al. Design, synthesis and anticancer activity studies of novel 4-butylaminophenyl hydrazide-hydrazones as apoptotic inducers
KR20150120953A (ko) 방사선과 조합하여 사용하는 방사선 증감제 화합물
Kanemaru et al. Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia
Shi et al. Emerging roles of ferroptosis in glioma
Fan et al. Autophagy activation by rapamycin before hypoxia-reoxygenation reduces endoplasmic reticulum stress in alveolar epithelial cells
US20090197853A1 (en) Methods and compositions of treating cancer
WO2024208828A1 (fr) Radioprotection par inhibition de la superoxyde dismutase 1
Chuai et al. A possible prevention strategy of radiation pneumonitis: combine radiotherapy with aerosol inhalation of hydrogen-rich solution
JP2006505620A (ja) Ｘ−ニトロ化合物、それらの医薬組成物及びそれらの使用
Jiang et al. Topotecan reduces neuron death after spinal cord injury by suppressing caspase-1-dependent pyroptosis
US20180214573A1 (en) Gene therapies for neurodegenerative disorders targeting ganglioside biosynthetic pathways
US9987302B2 (en) Methods of treating DNA damage
Patenaude et al. Injectable Oxygen Microparticles Boost Radiation–Mediated In Situ Vaccination and Systemic Antitumor Immune Responses
EP4122465A1 (fr) Agent thérapeutique contre le cancer du sein