EP1408994A2 - Chemische-stabilizierte chlorit lösungen für das behandeln des krebses - Google Patents

Chemische-stabilizierte chlorit lösungen für das behandeln des krebses

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Publication number
EP1408994A2
EP1408994A2 EP00957529A EP00957529A EP1408994A2 EP 1408994 A2 EP1408994 A2 EP 1408994A2 EP 00957529 A EP00957529 A EP 00957529A EP 00957529 A EP00957529 A EP 00957529A EP 1408994 A2 EP1408994 A2 EP 1408994A2
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EP
European Patent Office
Prior art keywords
cells
carcinoma
stabilized chlorite
macrophages
cell
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Application number
EP00957529A
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English (en)
French (fr)
Inventor
Frederich W. Kuhne
Vitam Kodelja
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Oxo Chemie AG
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Oxo Chemie AG
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Publication of EP1408994A2 publication Critical patent/EP1408994A2/de
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    • 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
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
    • 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
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to stabilized chlorite matrices as immunomodulatory agents and anti-cancer agents.
  • the stabilized chlorite matrix inhibits can affect the activation of macrophages in a manner similar to interferon gamma but without affecting the release of cytokines that cause side effects, such as tumor necrosis alpha.
  • the stabilized chlorite matrix also upregulates the expression of the DCC protein in macrophages, a protein whose expression is related to neoplastic transformation. By activating macrophages, the stabilized chlorite matrix therefore is useful as an immunomodulatory agent and in treating cancer.
  • a feature common to an immune response is the recognition of an antigen (either foreign or self, but perceived as foreign), and subsequent processing by the immune system.
  • antigen is degraded by enzymes in the cytoplasm, endoplasmic reticulum (ER) and lysosomes of cells, (usually macrophages, dendritic cells and other antigen presenting cells (APCs)), or in serum.
  • the degraded antigen is presented on the surface of the APC by MHC class I or II molecules. This presentation of the antigenic epitope by the MHC molecule, and subsequent binding to the T cell receptor (TCR) of a T cell is known as antigen presentation.
  • interferons are type of cytokine that plays a complex and central role in the resistance of mammalian hosts to pathogens and has been found useful in cancer therapy.
  • Type I interferon IFN- ⁇ and IFN- ⁇
  • IFN- ⁇ type II interferon
  • NK cells natural killer cells
  • IFN- ⁇ has an ability to inhibit cell proliferation at much lower concentrations comparing with IFN- ⁇ , and IFN- ⁇ .
  • Rubin, B. Y. et al. (1980): Proc. Natl. Acad. Sci. U.S.A., 77, 5928 and also to activate cells, including natural killer cell, killer T-cell, K-cell and macrophage, which have cancer therapeutic effects J. L. Crane et al., J. Natl. Cancer Inst, 61 , 871- 874, 1978; J. E.
  • U.S. Patent No. 5,268,169 describes the use of IFN- ⁇ for treating ovarian carcinoma.
  • the use of purified recombinant interferon in cancer therapy and in modulating the immune response has been of limited success because of the high costs of producing recombinant material and because IFN- ⁇ causes side effects which occur from the stimulation of inflammatory and shock related cytokines such as TNF- ⁇ .
  • Aqueous solutions of a chemically stabilized chlorite matrix that are capable of intravenous administration are known.
  • Other chlorine-containing solutions also are known to have reported medicinal uses.
  • United States Patent No. 5,019,402 discloses a solution containing chlorine dioxide or a chlorine dioxide-liberating mixture of a chlorite, a weakly acidic buffer and a heat-activated saccharide which can be used for the sterilization of stored blood components with the exception of those which contain red blood corpuscles, i.e., of leukocytes, blood platelets, coagulation factors and globulins.
  • red blood corpuscles i.e., of leukocytes, blood platelets, coagulation factors and globulins.
  • a corresponding disinfecting action does not occur, presumably because the red blood corpuscles are attacked more quickly by the chlorine dioxide than the targeted micro-organisms. Therefore, this agent also is not suitable for a parenteral administration.
  • European Patent EP 0 200 157 and United States Patent No. 4,725,437 further describe solutions of a chemically-stabilized chlorite matrix for intravenous and perioperative administration.
  • the agent has proved to be effective in the treatment of Candida albicans infections.
  • EP 0 200 157 it is known to use such stabilized chlorite matrices for intravenous and/or local administration in cases of infectious conditions brought about by parasites, fungi, bacteria, viruses and/or mycoplasts. The action is explained by a phagocyte stimulation which is achieved by a single effective administration of the chlorite complex shortly after the infection.
  • PCT publication WO 99/17787 which is hereby incorporated by reference in its entirety, discloses chemically-stabilized chrlorite solutions for inhibiting antigen-specific immune responses.
  • a method of treating cancer and other malignancies in a animal comprising administering an effective amount of an aqueous solution comprising a stabilized chlorite matrix.
  • the method activates inter alia macrophages resulting in upregulation of the expression deleted in colon carcinoma (DCC) protein.
  • An effective amount is 5 to 100 mMol of CIO 2 " per liter of solution.
  • the cancers for which the method is used are those cancers characterized by a reduced expression of the DCC protein.
  • the cancer cells to be treated are selected from the group consisting of colon carcinoma, gastric carcinoma, esophageal carcinoma, rectal carcinoma, pancreatic carcinoma, prostate carcinoma, glioma and neuroblastoma.
  • methods of treating cancer or other malignancies in an animal comprising (a) removing macrophages from the mammal; (b) contacting the macrophages with an effective amount of an aqueous solution comprising a stabilized chlorite matrix under conditions sufficient to increase the expression of DCC on the macrophages; and (c) introducing the macrophages from step (b) back into the mammal.
  • An effective amount is 5 to 100 mMol of CIO 2 " per liter of solution.
  • the cancers for which the method is used are those cancers characterized by a reduced expression of the DCC protein.
  • the cancer cells to be treated are selected from the group consisting of colon carcinoma, gastric carcinoma, esophageal carcinoma, rectal carcinoma, pancreatic carcinoma, prostate carcinoma, glioma and neuroblastoma.
  • the chlorite matrix solutions of the present invention can be dosed in vivo corresponding to the body weight, whereby, because of the continuous breakdown of the active material in the blood, the agent must be administered again at regular intervals.
  • Those skilled in the art are capable of varying the concentrations of antigen-presentation-inhibiting solutions depending on available in vitro data and body weight.
  • an effective amount will be known by those skilled in the art to mean an amount of solution which, when administered in vivo to subjects of varying weight, will bring about modulation of the immune response, and consequently, activation of macrophages and other immune cells.
  • an inhibition effective amount of the chlorite matrix solution will vary between about 0.1 ml/kg to about 1.5 ml/kg, preferably, about 0.5 ml/kg of body weight and at a concentration of about 40 to about 80 mMol CI0 2 " per liter, preferably about 60 mMol CI0 2 " per liter, respectively.
  • the chlorite matrix solution of the invention is administered once daily for anywhere from about three to seven days, preferably five days, followed by a period of rest of from 10 to 20 days, preferably from 14-18 days, and more preferably, 16 days, to constitute one cycle of treatment.
  • patients are treated with more than one cycle, more preferably, at least three cycles, and most preferably, at least five cycles.
  • An alternative treatment regimen consists of intravenously administering the chlorite matrix solution of the invention once daily for a period of five days, followed by two days of rest (i.e., over the weekend), followed by five more consecutive days of administration, followed by a period of rest from anywhere between 1 and 4 weeks to constitute one cycle.
  • patients are treated with more than one cycle, more preferably more than three.
  • Skilled artisans are capable of modifying the administration of the stabilized chlorite matrix of the invention depending on the disease treated and the size of the patient, using the guidelines provided herein.
  • a stabilized chlorite matrix solution in conjunction with radiation therapy to aid in repairing damaged irradiated tissue and reducing side effects.
  • the mode of action in treating damaged and/or infected tissue is described as amplifying the "oxidative burst" response of phagocytes in the presence of bioactivators, e.g., heme compounds.
  • Wound healing and treating the reported infections can be effected in general by activating macrophages present in the body which in turn serve to activate fibroblast cells which stimulate the wound healing response.
  • the stabilized chlorite matrix solutions can activate macrophages by complexing with the heme moieties present in the macrophage membrane.
  • the macrophages Upon activation, the macrophages stimulate the fibroblast cells which in turn generate collagen and endothelial cells that are useful in repairing damaged tissue caused by the wound or by the infections. While not intending on being bound by any theory, the present inventors believe that a macrophage is stimulated by the stabilized chlorite matrix solution by the following sequence of events.
  • the formula for the stabilized chlorite matrix can be summarized as (CI0 2 " ) n x 0 2 , where n is between 0.1-0.25, preferably, about 0.21.
  • the stabilized chlorite matrix becomes a secondary oxidant with oxidative properties different from chlorite and hydrogen peroxide.
  • the stabilized chlorite matrix of the invention has shown pharmacological differences when compared to equimolar chlorite solutions. (Ivankovic et al., 1993).
  • Macrophage activation brought about by the chlorite matrix occurs via a mechanism that is different from that of other macrophage-activating agents such as PMA, TNF- ⁇ , etc. Macrophages can be activated by a stabilized chlorite matrix because the matrix acts as an oxidant in a drug- membrane interaction which is believed to cause an electron deficiency (as a result of electron-reduction +3 CIO 2 " + 4e " ->• "1 CI " ) on the surface of the cell.
  • the membrane of the macrophage now has a charged surface. The present inventors believe that this charged surface may have an influence on surrounding particles (e.g., invading bacteria) and/or may trigger a signal sequence into the cell.
  • the activated macrophage then increases the DNA- synthesis of fibroblasts which is believed to contribute to its wound healing and/or parasite, bacteria, etc. infection healing properties.
  • the present inventors believe further that the known wound-healing mechanism via macrophage activation of the chlorite matrix of the invention also stimulates and enhances the phagocytic activity of the macrophage.
  • the activated macrophage is primed to ingest, digest and dispose of foreign antigens.
  • the use of the claimed stabilized chlorite matrix to render macrophage phagocytic also was known and described in EP 0 200 157 to K ⁇ hne.
  • a stabilized chlorite matrix also can inhibit an antigen-specific immune response, while at the same time enhance the activity of phagocytes. While not intending to be bound by any theory, the present inventors believe that the stabilized chlorite matrix, when administered to a mammal in need thereof, partially or completely impedes the antigen presentation of antigen presenting cells (APCs).
  • APCs antigen presenting cells
  • the expression, "antigen presenting cells” denotes a cell that is capable of presenting an antigen and eliciting an immune response.
  • Useful antigen presenting cells include macrophages and dendritic cells. That administration of WF-10 prevents and/or impedes antigen presentation has been confirmed by in vitro data described in the examples, and is consistent with in vivo data also described in the examples.
  • a typical immune response involves stimulating a macrophage, the stimulated macrophages present MHC Class I and II antigens on surface, which, when coupled with the T cell receptor, will stimulate T cells (typically a T cell subset such as CD4 or CD8 cells, and the like) to proliferate and form cytotoxic T-lymphocytes (CTL) cells which in turn kill cells expressing the antigen.
  • T cells typically a T cell subset such as CD4 or CD8 cells, and the like
  • CTL cytotoxic T-lymphocytes
  • the stimulated APC also secretes various cytokines that can aid in the proliferation of CTLs.
  • Cytokines, or growth factors are hormone-like peptides produced by diverse cells and are capable of modulating the proliferation, maturation and functional activation of particular cell types.
  • cytokines refer to a diverse array of growth factors, such as hematopoietic cell growth factors (e.g., erythropoietin, colony stimulating factors and interleukins), nervous system growth factors (e.g., glial growth factor and nerve growth factor), mostly mesenchymal growth factors (e.g., epidermal growth factor), platelet-derived growth factor, and fibroblast growth factor I, II and III, including interferons.
  • hematopoietic cell growth factors e.g., erythropoietin, colony stimulating factors and interleukins
  • nervous system growth factors e.g., glial growth factor and nerve growth factor
  • mesenchymal growth factors e.g., epidermal growth factor
  • platelet-derived growth factor fibroblast growth factor I, II and III, including interferons.
  • cytokines there may be several cytokines that are involved in inducing cell differentiation and maturation, and that cytokines may have other biological functions.
  • IL-1 there may be several forms, such as IL-1-alpha and IL-1-beta, which nevertheless appear to have a similar spectrum of biological activity.
  • Those cytokines that are primarily associated with induction of cell differentiation and maturation of myeloid and possibly other hematopoietic cells include, inter alia, IL-1 , G-CSF, M-CSF, GM-CSF, Multi-CSF (IL-3), and IL-2( T-cell growth factor, TCGF).
  • IL-1 appears to have its effect mostly on myeloid cells
  • IL-2 affects mostly T-cells
  • IL-3 affects multiple precursor
  • G-CSF affects mostly granulocytes and myeloid cells
  • M-CSF affects mostly macrophage cells
  • GM-CSF affects both granulocytes and macrophage.
  • Other growth factors affect immature platelet (thrombocyte) cells, erythroid cells, and the like.
  • An MHC class II molecule will transport one of the smaller antigenic peptides to the surface of the macrophage and present it to a T cell receptor (TCR). Binding with the cell receptor will trigger the release of activating factors and cytokines such as IL-1 , TNF, etc., which restores the self-defense of the macrophage and enhances the intracellular killing of the foreign body. If binding does not occur, the activating factors will not be released and the macrophage will not know to digest or break the foreign matter down into smaller peptides.
  • the expression "antigen presentation” therefore denotes the process of presentation of an MHC Class II the surface of an APC followed by subsequent binding with a TCR.
  • the present inventors believe that binding of the T-cell to the presented antigen is effected not only by recognition of the antigenic peptide that is presented, but also by the presence of the CD28 antigen on the surface of the T cell and its binding with B7. Binding of B7 to CD28 is believed to costimulate T cell proliferation, cytokine stimulation, cytokine production and proliferation of cytotoxic T cells (CTL).
  • CTL cytotoxic T cells
  • the present inventors believe that an anergic response will ensue.
  • the APC presents the MHC Class II antigen
  • the T cell will not proliferate, nor will the APC release cytokines and other activating factors, even though the TCR on the T cell recognizes the antigen.
  • the present inventors believe that administration of an aqueous solution of a stabilized chlorite matrix results in an increase in concentration of CD28 " T cell subsets and/or a decrease in B7 presentation in APCs. As a consequence, there is no B7-CD28 interaction between the APC and the TCR, and therefore no T cell proliferation or cytokine release.
  • Previously known therapies for preventing T cell proliferation typically acted on cytotoxic T-cells after cytokine stimulation.
  • cyclosporin A is believed to act on the cytotoxic T-Lymphocyte to prevent T- cell proliferation.
  • the APC already has released cytokines that might assist CTL proliferation. Accordingly, a significant amount of these drugs must be administered to prevent the CTL proliferation.
  • There are no known methods for impeding an immune response however, where the APC or TCR are affected in a manner that partially or completely interrupts the antigen presentation interaction between the APC and the T cell.
  • autoimmune diseases and diseases caused by inappropriate immune response such as myasthenia gravis, systemic lupus erythematosis, serum disease, type I diabetes, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, Sj ⁇ rgen syndrome, systemic sclerosis, spondylarthropathies, Lyme disease, sarcoidosis, autoimmune hemolysis, autoimmune hepatitis, autoimmune neutropenia, autoimmune polyglandular disease, autoimmune thyroid disease, multiple sclerosis, inflammatory bowel disease, colitis, Crohn's disease, chronic fatigue syndrome, and the like, do so because the immune response is inappropriate.
  • autoimmune diseases and diseases caused by inappropriate immune response such as myasthenia gravis, systemic lupus erythematosis, serum disease, type I diabetes, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, Sj ⁇ rgen syndrome, systemic
  • transplant or graft patients an inappropriate immune response occurs because the immune system recognizes the transplanted organ or graft's antigens as foreign, and hence, destroys them.
  • transplant and graft patients can develop a graft vs. host response where the transplanted organ or graft's immune system recognizes the host's antigen as foreign and destroys them. This results in other inappropriate immune responses include excess inflammation, allergic asthma, allergic rhinitis and atopic dermatitis.
  • cytotoxic agents particularly those that affect the lymphoid system (and therein particularly the T-lymphocytes), to depress host immunity in certain autoimmune diseases, e.g., systemic lupus erythematosis, and in patients receiving organ transplants.
  • cytotoxic drugs are similar to those often used in cancer chemotherapy, with the attendant myeloid and other hematopoietic side effects.
  • specific antibodies against these lymphoid cells e.g., the anti-Tac monoclonal antibody of Uchiyama et al., J. Immunol.
  • T-cell antibody which specifically binds to the human IL-2 receptor of activated T-cells, can be conjugated to cytotoxic agents, such as drugs, toxins or radioisotopes, to effect a relatively select killing of these cells involved in organ rejection.
  • cytotoxic agents such as drugs, toxins or radioisotopes
  • a T-cell antibody can be conjugated with a beta- or alpha-emitting radioisotope, and this can be administered to the patient prior to undertaking organ transplantation and, if needed, also thereafter.
  • the treatment using the aqueous solution containing a stabilized chlorite matrix can be used instead of, or in conjunction with any of the aforementioned agents.
  • Administering an aqueous solution containing a stabilized chlorite matrix to a mammal can therefore inhibit antigen-specific immune responses, while at the same time not compromise the immune system entirely because the solution also is effective in enhancing phagocytic activity.
  • the invention encompasses methods of treating autoimmune diseases, preventing transplant organ or graft rejection and septic shock as a result thereof, and reducing inappropriate immune responses such as excessive inflammation and allergic reaction. Because there are other methods already known to treat these disorders, skilled artisans are capable of modifying the known techniques by administering an inhibition effective amount of an aqueous solution containing a stabilized chlorite matrix, using the guidelines provided herein. For example, skilled artisans are capable of designing a treatment regimen to treat any of the aforementioned disorders using the stabilized chlorite matrix of the invention by varying the dosage amount, frequency of administration, or mode of administration.
  • a preferred embodiment of the treatment of this invention entails administration to a mammal in need thereof, an aqueous solution of a product that has become known as "tetrachlorodecaoxygen anion complex," commonly abbreviated as 'TCDO," which is a product of Example 1 of U.S. Patent No. 4,507,285.
  • the product is a water clear liquid, miscible with alcohols, having a melting point of -3°C.
  • the Raman spectrum shows bands of 403, 802 (chlorite) and 1562 cm “1 (activated oxygen).
  • the DCC (deleted in colon carcinoma) gene, which contains more than one million base pairs, is a cell surface molecule receptor that is considered to function in tumor suppression.
  • DCC Reduction in the expression of the DCC gene has been observed in Stage 2 and stage 3 carcinomas, indicating relationship between loss of expression and survival.
  • DCC is related to the neural cell adhesion molecule. Reduced expression in the level of DCC has been implicated in poor prognosis in gastrointestinal cancers by Saito et al., Oncology 56(2): 134-41 (1999).
  • the present invention provides a method of treating cancer in a mammal comprising administering an aqueous solution comprising a stabilized chlorite matrix.
  • This method involves activation of macrophages in a manner similar to that of IFN- ⁇ , but with release of lower amounts of inflammatory and shock cytokines such as TNF- ⁇ .
  • the administration of the stabilized chlorite matrix results in increased expression of the DCC protein on macrophages.
  • the method of treating cancer with stabilized chlorite matrix is useful in cancers that are characterized by a reduced expression of the DCC protein.
  • Such cancers include, for example, colon carcinoma, gastric carcinoma, esophageal carcinoma, rectal carcinoma, pancreatic carcinoma, prostate carcinoma, glioma and neuroblastoma.
  • the present invention also provides a method of treating cancer in a mammal comprising: (a) removing macrophages from the mammal; (b) contacting the macrophages with an effective amount of an aqueous solution comprising a stabilized chlorite matrix under conditions sufficient to increase the expression of DCC on the macrophages; and (c) introducing the macrophages from step (b) back into the mammal.
  • the treated macrophages exhibit and activated by the stabilized chlorite matrix and increase the expression of the DCC antigen on the macrophages.
  • Administration of such activated macrophages is useful for treating cancers characterized by a reduced expression of the DCC protein.
  • Example 1 In this example, and the following examples 2-4, details regarding the methods used in performing these examples can be found in Fagnoni, F.F., et al., "Role of B70/B7-CD28 in CD4 + T-Cell Immune Response Induced by Dendritic Cells," Immunology, : 467-74 (1995), the disclosure of which is incorporated herein by reference in its entirety.
  • This example together with the following examples 2-4, elucidate the role of WF10 in inducing anergy by preventing dendritic cell-mediated costimulation at the B7/B70-CD28 interface.
  • Dendritic cells, T cells and monocytes were obtained in the manner described in Fagnoni et al.
  • CD4 + -T cells were activated with allogeneic MLR in the presence or absence of WF10 to DC.
  • Purified resting CD4 + T cells (5-10 ⁇ 10 4 /well) were cultured with irradiated (25 Gy) allogeneic DC in U-bottomed 96-well plates containing 200 ⁇ l of complete medium. The cultures were carried out at 37°, 8% C0 2 in humidified air for 5 days.
  • WF10/number denotes that dilution of WF10 and designates the amount of WF10 per ml of solution.
  • WF10/1600 denotes a diluted solution of WF10 containing 1 ml of WF10 per 1600 ml of solution.
  • Example 1 was repeated with the exception that Adherent monocytes, obtained in accordance Fagnoni et al. were used instead of DC.
  • Administration of WF10 was effective in inhibiting proliferation of CD4 + T- cells from monocyte stimulated MLR. Indeed, with administration of WF1/1600, the stabilized chlorite matrix was effective in completely inhibiting proliferation of CD4 + T-cells from monocytes stimulated with allogeneic MLR, despite increased concentration of monocytes per well.
  • the results of examples 1 and 2 therefore show that WF10 is effective in inhibiting proliferation of CD4 + T cells from DC or monocytes stimulated with allogeneic MLR.
  • Examples 3 and 4 were carried out to determine the effect of WF10 on the inhibition of antigen-induced proliferation of T cells using various antigens.
  • purified resting CD4 + T cells (5-10 ⁇ 10 4 /well) were cultured with irradiated (25 Gy) autologous DC in U-bottomed 96-well plates containing 200 ⁇ l of complete medium. The cultures were carried out at 37°, 8% C0 2 in humidified air for 6 days. Cultures were pulsed with 1 ⁇ Ci [ 3 H]thymidine (6-7 Ci/mm, New England Nuclear, Boston MA) 19 hour before harvest. The [ 3 H]thymidine incorporation by proliferating cells was measured in a ⁇ -scintillation counter.
  • Soluble keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) were added to autologous DC. Measurements were taken for no addition of WF10, addition of WF10/200 and WF10/800 (representing administration of WF10 to the culture medium at time 0 of 0, 1 ml/200 ml of solution and 1 ml/800 ml of solution, respectively) to determine the proliferation of CD4 + T cells when no antigen, TT, KLH25 (25 ⁇ g/ml) and KLH50 (50 ⁇ g/ml) were presented by DC.
  • Example 3 was repeated except that monocytes were used instead of DC for antigen presentation.
  • WF10 was administered in the following increments WF10/200, WF10/400, WF10/800 and WF10/1600. The results show tha there was significant proliferation of CD4 + T cells when monocytes presented the soluble antigens KLH and TT. Administration of WF10, however, almost completely inhibited the proliferation of CD4 + T cells when either KLH or TT were presented by monocytes.
  • WF10 has shown a consistent down regulation of CD147DR + cells achieving statistical significance.
  • WF10 administration in vivo has shown overall reduction of CD37CD87CD28 * cells, and significant increased levels of CD37CD87CD28' cells of long-term duration. These cells are believed by the inventors to be responsible for antigen specific immune tolerance by producing clonal anergy.
  • the in vitro data above also shows that WF10 is effective in inhibiting and/or preventing antigen presentation and producing clonal anergy. This reduced antigen presentation may be critical in B-cell lymphoma and thus, WF10 therapy may be of benefit.
  • One case history with B-cell lymphoma responded to WF10 therapy with a notable reduction of tumor size with no reoccurrence to date.
  • Screening criteria include the following: male or female patients greater than 18 years of age; histologically confirmed follicular lymphoma; measurable disease defined as having lymph nodes > 1 cm in diameter as measured by CT; adequate renal function documented by a serum creatinine ⁇ 2 times in institution's ULN; adequate liver function documented by a serum billrubin less than or equal to 1.5 mg/dl and SGOT (AST) or SGPT (ALT) ⁇ 5 times the institutional upper limit of normal; written informed consent to participate in this study and a willingness to comply with all procedures and scheduled visits; hemoglobin > 9.0 g/dl for woman and > 10.0 g/dl for men; platelet count > 75,000/mm 2 ; and absolute neutrophil count > 750/mm 2 .
  • WF10 will be applied at a dose of 0.5 ml per kg of body weight diluted into 250 to 500 ml normal saline administered by intravenous infusion of 1 hour duration.
  • CT measurements will be taken to determine tumor size at week 0, on day 15, day 30 and day 45.
  • follow-up period will last for a duration of 3 months with final CT measurements on day 90.
  • CT measurements will reveal that administration of WF10 results in a reduction of lymph node size. Patients also will exhibit an increase in CD37CD87CD28 " , an increase in CD147DR + and an increase in CD40 T cell subsets.

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EP00957529A 1999-08-18 2000-08-18 Chemische-stabilizierte chlorit lösungen für das behandeln des krebses Withdrawn EP1408994A2 (de)

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ATE451326T1 (de) 2003-11-21 2009-12-15 Cytotools Ag Reaktive chlorverbindungen, deren derivate, anionen und salze sowie verfahren zu deren herstellung und verwendung
ES2384267T3 (es) * 2005-07-21 2012-07-03 Nuvo Research Ag Soluciones de clorito estabilizadas en combinación con fluoropirimidinas para el tratamiento del cáncer
CN104125826A (zh) 2011-12-22 2014-10-29 努沃研究有限责任公司 亚氯酸盐或氯酸盐脂质体组合物
CN112386606A (zh) * 2019-08-19 2021-02-23 卢序 一种有第二信使作用增加积极氧化压力的氧化剂的用途
EP4147703A4 (de) * 2020-05-21 2023-11-08 Osaka University Therapeutisches mittel gegen epithelkrebs

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WO2001012205A3 (en) 2001-09-13
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