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CN-122005526-A - Application of ammonia-oxyacetic acid combined chemotherapy medicine in enhancing tumor immunotherapy

CN122005526ACN 122005526 ACN122005526 ACN 122005526ACN-122005526-A

Abstract

The application discloses application of an ammonia-oxygen acetic acid combined chemotherapy drug in enhancing tumor immunotherapy knots. Experiments prove that the combination of the aminoxyacetic acid and oxaliplatin can obviously inhibit the growth of tumors and prolong the survival time of tumor-bearing mice in a subcutaneous transplantation tumor mouse model established by colorectal cancer cell line MC38 for the first time. In vivo experiments prove that the tumor volume is obviously reduced compared with a control group after the treatment of the combined oxaliplatin, the median survival time of tumor-bearing mice is obviously prolonged, and further experiments show that the combined oxaliplatin can activate tumor immune microenvironment, particularly more CD8 + T cell tumor microenvironment infiltration is shown, and the CD8 + T cell has stronger functional effect.

Inventors

  • YANG HUI
  • YE DAN
  • MAO YING
  • Liao Yuheng
  • WANG HANZE
  • LIU HANGXIN
  • CHEN XI

Assignees

  • 复旦大学附属华山医院

Dates

Publication Date
20260512
Application Date
20260410

Claims (10)

  1. 1. An active ingredient combination, characterized in that the active ingredient combination comprises: (i) A first active ingredient which is glycine or a pharmaceutically acceptable salt thereof, and (Ii) And a second active ingredient, the second active ingredient being a chemotherapeutic agent.
  2. 2. The active ingredient combination according to claim 1, wherein the chemotherapeutic agent is oxaliplatin.
  3. 3. Use of a combination of active ingredients according to claim 1 for the preparation of a formulation or pharmaceutical composition for: (1) Up-regulating the interferon gene; (2) Up-regulating the interferon stimulating gene; (3) Activating tumor immune microenvironment; (4) Preventing and/or treating tumors; (5) Inhibit tumor growth.
  4. 4. The use according to claim 3, wherein in the active ingredient combination, the chemotherapeutic agent is oxaliplatin.
  5. 5. The method according to claim 3, wherein the tumor is selected from the group consisting of colorectal cancer and melanoma.
  6. 6. The use according to claim 3, wherein the tumour is colorectal cancer and the chemotherapeutic agent in the active ingredient combination is oxaliplatin.
  7. 7. A pharmaceutical composition comprising (a) a safe and effective amount of the active ingredient combination of claim 1, and (B) a pharmaceutically acceptable carrier and/or adjuvant.
  8. 8. Use of a pharmaceutical composition according to claim 7 for the preparation of a formulation for: (1) Up-regulating the interferon gene; (2) Up-regulating the interferon stimulating gene; (3) Activating tumor immune microenvironment; (4) Preventing and/or treating tumors; (5) Inhibit tumor growth.
  9. 9. A medicine box is characterized in that, the kit comprises: (C1) A first formulation within a first container, the first formulation comprising a first active ingredient which is glycine or a pharmaceutically acceptable salt thereof; (C2) A second formulation in a second container, the second formulation comprising a second active ingredient, the second active ingredient being a chemotherapeutic agent, and (C3) Instructions for use of the kit for preventing and/or treating a tumor.
  10. 10. Use of ammoxyacetic acid or a pharmaceutically acceptable salt thereof for (i) preparing a formulation or a kit for enhancing the therapeutic effect of a chemotherapeutic agent on a subject having a tumor, or (ii) preparing an agonist for enhancing the anti-tumor effect of a chemotherapeutic agent.

Description

Application of ammonia-oxyacetic acid combined chemotherapy medicine in enhancing tumor immunotherapy Technical Field The application relates to the technical field of biological medicines, in particular to application of an ammonia-oxyacetic acid combined chemotherapeutic drug in enhancing tumor immunotherapy. Background Colorectal cancer (colorectal cancer, CRC) is one of the digestive system malignancies with leading morbidity and mortality worldwide, severely threatening human health and bringing a heavy social and economic burden. Currently available clinical interventions such as surgical excision, radiotherapy, chemotherapy, and molecular targeted therapies, although having achieved certain effects, some patients benefit therefrom, have significant limitations. On the one hand, some patients are already at middle and late stage at the time of diagnosis, the tumor is locally aggressive or is accompanied by distant metastasis, and complete excision is difficult to realize, on the other hand, even if normalized treatment is carried out, a considerable proportion of patients have tumor recurrence and metastasis. Therefore, the overall curative effect of colorectal cancer is not ideal, and development of a new treatment strategy is urgently needed. Therefore, the molecular mechanism of colorectal cancer occurrence and development is deeply analyzed, new treatment targets are mined, and more effective combined treatment strategies are explored, so that the method has important significance for improving the overall treatment effect and prolonging the survival of patients, and also forms one of the key directions in the current tumor research field. Classical chemotherapeutic drug oxaliplatin (Oxaliplatin) is a classical platinum chemotherapeutic drug and is widely applied to first-line treatment of solid tumors such as colorectal cancer. It induces DNA cross-linking and replication blocking, mainly by forming adducts with DNA, thereby initiating DNA damage and leading to tumor cell apoptosis. Oxaliplatin, in addition to its direct cytotoxic effect, is also thought to induce immunogenic cell death, promoting tumor antigen release and dendritic cell activation. On the basis, DNA damage and cytoplasmic DNA accumulation caused by the damage can further activate a cGAS-STING channel, and induce the expression of I-type interferon and related interferon stimulation genes, so that the anti-tumor immune response is enhanced to a certain extent. However, the immune activating effect is generally relatively limited, and it is still necessary to further amplify its immune modulating effect by a combination therapeutic strategy. Aminooxyacetic acid (aminooxyacetic acid, AOA) is a small molecule metabolic regulation compound known to act as a transaminase inhibitor, inhibiting the enzymatic activity of pyridoxal phosphate-dependent enzymes such as glutamic oxaloacetic transaminase (glutamic-oxalacetic transaminase, GOT) and glutamic pyruvic transaminase (glutamate-pyruvate transaminase, GPT), and thus interfering with intracellular amino acid metabolic processes. The existing research mainly focuses on the role of the ammonia oxyacetic acid in the aspects of tumor metabolism reprogramming and cell proliferation regulation, and the potential application of the ammonia oxyacetic acid in tumor immunity regulation and further enhancing oxaliplatin-mediated anti-tumor curative effect has not been reported yet. Therefore, how to overcome the problem of limited curative effect of oxaliplatin as a chemotherapeutic drug in colorectal cancer treatment, develop a combined treatment strategy capable of enhancing the anti-tumor immune effect of oxaliplatin, and become a technical problem to be solved in the field. It should be noted that the information disclosed in the above background section is only for enhancing understanding of the background of the application and thus may include information that does not form the prior art that is already known to those of ordinary skill in the art. Disclosure of Invention The application aims to provide a new scheme for solving the technical problem that the treatment effect is limited due to the fact that a chemotherapeutic drug (such as oxaliplatin) is difficult to induce continuous and effective anti-tumor immune response for treating tumors (such as colorectal cancer and melanoma). In a first aspect of the application, there is provided an active ingredient combination comprising: (i) A first active ingredient which is glycine or a pharmaceutically acceptable salt thereof, and (Ii) And a second active ingredient, the second active ingredient being a chemotherapeutic agent. In another preferred embodiment, at least one of the active ingredients in the active ingredient combination is independent. In another preferred embodiment, the weight ratio of the glycine or pharmaceutically acceptable salt thereof to the chemotherapeutic agent is 1-50:0.5-15, preferably 1-30:0.5-10, more preferabl