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WO2025113347A1 - Utilisation d'une composition pharmaceutique comprenant de l'acide rétinoïque dans la préparation d'un médicament pour le traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale - Google Patents

Utilisation d'une composition pharmaceutique comprenant de l'acide rétinoïque dans la préparation d'un médicament pour le traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale Download PDF

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Publication number
WO2025113347A1
WO2025113347A1 PCT/CN2024/133880 CN2024133880W WO2025113347A1 WO 2025113347 A1 WO2025113347 A1 WO 2025113347A1 CN 2024133880 W CN2024133880 W CN 2024133880W WO 2025113347 A1 WO2025113347 A1 WO 2025113347A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
retinoic acid
hepatocellular carcinoma
chemotherapy regimen
folfox4
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Pending
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PCT/CN2024/133880
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English (en)
Chinese (zh)
Inventor
石洁
程树群
孙居仙
刘畅
毛菲菲
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Third Affiliated Hospital Of Pla Naval Medical University
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Third Affiliated Hospital Of Pla Naval Medical University
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the field of medicine, and in particular relates to use of a pharmaceutical composition containing retinoic acid in preparing a medicine for treating hepatocellular carcinoma with abdominal metastasis.
  • HCC Hepatocellular carcinoma
  • liver cancer stem cells play an important role in the recurrence and metastasis of liver cancer.
  • Systemic treatments for HCC such as immunotherapy, targeted therapy, or intravenous chemotherapy, generally have unsatisfactory effects and obvious toxic and side effects.
  • Sorafenib tosylate (Nexavar from Bayer; a multikinase inhibitor that exerts antiproliferative (RAF1, BRAF, and KIT), antiangiogenic (vascular endothelial growth factor receptor [VEGFR] and platelet-derived growth factor receptor” [PDGFRB]), and proapoptotic effects) and lenvatinib mesylate (Lenvima from Merck; a multikinase inhibitor of VEGFR 1-3, fibroblast growth factor receptor (FGFR) 1-4, RET, KIT, and PDGFRa) are the only drugs approved for first-line systemic treatment of advanced HCC that cannot be surgically resected.
  • Second-line therapies include multikinase inhibitors such as regorafenib and cabozantinib, anti-VEGFR2 mAbs, ramucirumab, and Immune checkpoint inhibitors (anti-PD-1mAb), nivolumab and pembrolizumab.
  • multikinase inhibitors such as regorafenib and cabozantinib
  • anti-VEGFR2 mAbs anti-VEGFR2 mAbs
  • ramucirumab ramucirumab
  • Immune checkpoint inhibitors anti-PD-1mAb
  • nivolumab and pembrolizumab Immune checkpoint inhibitors
  • Retinoic acid also known as all-trans-Retinoic acid (ATRA), retinoic acid, retinoic acid, etc.
  • ATRA all-trans-Retinoic acid
  • retinoic acid has a chemical name of (13E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexenyl)-2,4,6,8-nonatetraenoic acid, and a molecular formula of C 20 H 28 O 2 . It is mainly a derivative of vitamin A acid, an intermediate metabolite of vitamin A in the body, and an indispensable substance for maintaining growth and development. It has a strong effect of inducing cell differentiation and immunomodulation.
  • APL acute promyelocytic leukemia
  • myelodysplasia myelodysplasia
  • other blood malignancies in China. It also has good applications in other clinical fields such as skin diseases, solid tumors and vascular-related diseases.
  • retinoic acid As a differentiation inducing agent, retinoic acid is clinically used in the treatment of advanced liver cancer with certain effects. Previous studies have shown that retinoic acid can induce differentiation of CD133+ liver cancer stem cells, improve the sensitivity of liver cancer cells to cytotoxic drugs, and thus enhance the therapeutic effect. However, the main problem causing poor prognosis and survival rate of HCC patients is the abdominal metastasis and distal metastasis caused by HCC, and there has been no research on whether retinoic acid combined with other drugs can significantly reduce the abdominal metastasis of hepatocellular carcinoma.
  • retinoic acid combined with intravenous FOLFOX4 oxaliplatin/pentafluorouracil/leucovorin
  • FOLFOX4 oxaliplatin/pentafluorouracil/leucovorin
  • the inventors provide a new use of a pharmaceutical composition containing retinoic acid, which is highly effective, low-toxic, inexpensive and not prone to drug resistance, for treating hepatocellular carcinoma with abdominal metastasis.
  • the purpose of the present invention is to provide a pharmaceutical composition for treating hepatocellular carcinoma with abdominal metastasis, which is highly effective, low-toxic, low-cost and not prone to drug resistance, and contains retinoic acid, so as to provide a new idea for the safe, effective, convenient and economical clinical treatment of hepatocellular carcinoma with abdominal metastasis.
  • the present invention is realized through the following technical solutions:
  • the present invention provides a pharmaceutical composition for treating hepatocellular carcinoma with abdominal metastasis, the pharmaceutical composition comprising FOLFOX4 chemotherapy regimen and retinoic acid, the FOLFOX4 chemotherapy regimen being the main active ingredient for treating hepatocellular carcinoma with abdominal metastasis, and the retinoic acid being an auxiliary ingredient for enhancing the FOLFOX4 chemotherapy regimen for treating hepatocellular carcinoma with abdominal metastasis.
  • the usage ratio of the FOLFOX4 chemotherapy regimen to the retinoic acid is 1-10:7 by weight.
  • the usage ratio of the FOLFOX4 chemotherapy regimen to the retinoic acid is 4-6:7 by weight.
  • the usage ratio of the FOLFOX4 chemotherapy regimen to the retinoic acid is 5:7 by weight.
  • the FOLFOX4 chemotherapy regimen consists of oxaliplatin, 5-fluorouracil and calcium folinate.
  • the pharmaceutical composition further comprises other drugs having liver-protecting effects.
  • the other drugs having liver-protecting effects are one or more of Schisandra chinensis, puerarin, silymarin, reduced glutathione, glutamine or vitamin D.
  • the present invention provides use of the pharmaceutical composition described in the first aspect in the preparation of a medicament for treating hepatocellular carcinoma with abdominal metastasis.
  • the present invention has the following beneficial effects:
  • the present invention combines the applicant's advantages in researching and developing retinoic acid, screens out a pharmaceutical composition with synergistic effects in treating liver cancer with abdominal metastasis, significantly enhances the effect of FOLFOX4 chemotherapy regimen in treating hepatocellular carcinoma with abdominal metastasis, and significantly increases the safety of using such drugs and the medication compliance of patients.
  • Figure 1 Photos of tumors removed from each group of mice at the end of the experiment in Example 1.
  • Figure 2 Average tumor weight of mice in each group at the end of the experiment in Example 1.
  • Figure 3 In vivo imaging monitoring of mice in each group during the study period and at the end of the experiment in Example 2.
  • Figure 4 Imaging results before and after treatment of a representative patient case of hepatocellular carcinoma with abdominal metastasis.
  • the inventors in their in-depth study of the mechanism of retinoic acid in treating advanced liver cancer, have found through extensive screening that the combined use of FOLFOX4 chemotherapy with retinoic acid can significantly enhance the effect of FOLFOX4 chemotherapy in treating hepatocellular carcinoma with abdominal metastasis. Based on this, the present invention was completed.
  • liver cancer with abdominal metastasis refers to advanced hepatocellular carcinoma with abdominal metastasis.
  • auxiliary ingredients generally refer to substances that have no or almost no target pharmacological activity but can enhance the target pharmacological activity of the main active ingredient.
  • the target pharmacological activity of the present invention is mainly the effect of treating hepatocellular carcinoma with abdominal metastasis.
  • the retinoic acid and the FOLFOX4 chemotherapy regimen in the pharmaceutical composition of the present invention are administered in different pharmaceutical preparations.
  • the dosage forms of retinoic acid and the FOLOX4 chemotherapy regimen are different, and retinoic acid and the FOLOX4 chemotherapy regimen can be administered simultaneously or sequentially.
  • the administration time, number of administrations and frequency of administration of "retinoic acid” and “FOLFOX4 chemotherapy regimen” need to be determined according to the specific diagnosis results of the disease, which is within the technical scope mastered by technicians in this field.
  • the effective doses of all drugs for humans can be converted by the effective doses of the drugs for mice or rats, which is also easy to achieve for ordinary technicians in this field.
  • Example 1 Inhibitory effect of FOLOX4 combined with retinoic acid on the growth of Hub7 subcutaneous transplanted tumors
  • a subcutaneous transplant tumor model was constructed using the liver cancer cell line Huh7 (purchased from ATCC) to detect the inhibitory effect of FOLOX4 combined with retinoic acid on the growth of Hub7 subcutaneous transplant tumors.
  • Huh7 liver cancer cells were injected subcutaneously into the right groin of 3-4 week-old NSG mice.
  • the mice were randomly divided into 4 groups: model group, retinoic acid group, FOLOX4 group and combination group, with 5 mice in each group.
  • the dosing schedule is as follows:
  • Model group 5% glucose was intraperitoneally injected once a week and normal saline was gavaged once a day;
  • Retinoic acid group 20 mg/kg retinoic acid was given by gavage once a day;
  • FOLOX4 group FOLOX4 regimen was given by intraperitoneal injection once a week, including oxaliplatin 10 mg/kg, 5-Fu 65 mg/kg, and folinic acid 25 mg/kg;
  • Retinoic acid (20 mg/kg) was administered by oral gavage once a day, and FOLOX4 regimen was administered by intraperitoneal injection once a week, including oxaliplatin (10 mg/kg), 5-Fu (65 mg/kg), and folinic acid (25 mg/kg).
  • the above regimen was administered continuously for 6 weeks.
  • mice The weight of mice was monitored every three days and the size of the tumor was measured with a caliper.
  • the trend of tumor changes can be monitored by plotting a tumor volume curve.
  • mice were euthanized and the tumors were removed and photographed.
  • the experimental data were statistically analyzed using Graphpad Prism 8.0 software.
  • the experimental data results were expressed as mean ⁇ SD.
  • Data statistics involved t-test or one-way analysis of variance (ANOVA) statistical methods. p ⁇ 0.05 indicated that the data difference was statistically significant.
  • the photos of the tumors of mice in each group peeled off at the end of the experiment are shown in Figure 1.
  • the average tumor weight of mice in each group is shown in Figure 2.
  • the experimental results show that compared with the model group, both the retinoic acid group and the FOLFOX4 group can significantly reduce the tumor weight of the experimental animals, and the FOLFOX4 regimen has a better inhibitory effect on tumors than retinoic acid.
  • the FOLFOX4 regimen is combined with retinoic acid, the inhibitory effect of the combination group on the tumors of experimental animals will become more significant, and the tumor weight of the animals in the combination group is significantly different from that of the FOLFOX4 regimen group (p ⁇ 0.001).
  • the above results suggest that the combination of the FOLFOX4 regimen and retinoic acid has a synergistic inhibitory effect on the growth of Hub7 subcutaneous transplanted tumors.
  • Example 2 Inhibitory effect of FOLOX4 combined with retinoic acid on Hub7 abdominal metastasis
  • an abdominal metastasis model was constructed by using Huh7 cells expressing luciferase to observe the inhibitory effect of FOLOX4 combined with retinoic acid on the growth of abdominal metastasis of liver cancer.
  • 1 ⁇ 10 6 Huh7 liver cancer cells were intraperitoneally injected into NSG mice on day 0, and the abdominal tumor model was successfully constructed by small animal live imaging (BLI) on day 14. Then, the experimental animals were randomly divided into 4 groups: model group, retinoic acid group, FOLOX4 group and combination group, with 5 animals in each group.
  • the dosing schedule is as follows:
  • Model group 5% glucose was intraperitoneally injected once a week and normal saline was gavaged once a day;
  • Retinoic acid group 20 mg/kg retinoic acid was given by gavage once a day;
  • FOLOX4 group FOLOX4 regimen was given by intraperitoneal injection once a week, including oxaliplatin 10 mg/kg, 5-Fu 65 mg/kg, and folinic acid 25 mg/kg;
  • Retinoic acid (20 mg/kg) was administered by oral gavage once a day, and FOLOX4 regimen was administered by intraperitoneal injection once a week, including oxaliplatin (10 mg/kg), 5-Fu (65 mg/kg), and folinic acid (25 mg/kg).
  • the above regimen was administered continuously for 7 weeks.
  • mice were monitored by in vivo imaging at regular intervals during the study and at the end of the experiment.
  • the experimental data were statistically analyzed using Graphpad Prism 8.0 software.
  • the experimental data results were expressed as mean ⁇ SD.
  • Data statistics involved t-test or one-way analysis of variance (ANOVA) statistical methods. p ⁇ 0.05 indicated that the data difference was statistically significant.
  • Example 3 Representative case of hepatocellular carcinoma with abdominal metastasis
  • the combination therapy regimen is as follows:

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

Utilisation d'une composition pharmaceutique d'acide rétinoïque dans la préparation d'un médicament pour le traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale. La composition pharmaceutique comprend un protocole de chimiothérapie FOLFOX4 et de l'acide rétinoïque. Le protocole de chimiothérapie FOLFOX4 est un principe actif primaire pour traiter un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale. L'acide rétinoïque est un composant secondaire utilisé pour améliorer le protocole de chimiothérapie FOLFOX4 dans le traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale. Le protocole de chimiothérapie FOLFOX4 est constitué par l'oxaliplatine, le 5-fluorouracile et le folinate de calcium. Dans l'aspect du traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale, la composition pharmaceutique de la présente invention présente une efficacité significativement supérieure par rapport à des doses équivalentes du protocole de chimiothérapie FOLFOX4 seul et de l'acide rétinoïque seul, ce qui indique que l'utilisation combinée des deux a un effet synergique significatif.
PCT/CN2024/133880 2023-11-27 2024-11-22 Utilisation d'une composition pharmaceutique comprenant de l'acide rétinoïque dans la préparation d'un médicament pour le traitement d'un carcinome hépatocellulaire accompagné d'une métastase dans la cavité abdominale Pending WO2025113347A1 (fr)

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CN202311591773.7A CN117357534A (zh) 2023-11-27 2023-11-27 包含维甲酸的药物组合物在制备治疗肝细胞癌伴腹腔转移的药物中的用途
CN202311591773.7 2023-11-27

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Publication number Priority date Publication date Assignee Title
CN117357534A (zh) * 2023-11-27 2024-01-09 中国人民解放军海军军医大学第三附属医院 包含维甲酸的药物组合物在制备治疗肝细胞癌伴腹腔转移的药物中的用途

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