CN117357534A - Application of pharmaceutical composition containing retinoic acid in preparation of medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis - Google Patents

Application of pharmaceutical composition containing retinoic acid in preparation of medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis Download PDF

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Publication number
CN117357534A
CN117357534A CN202311591773.7A CN202311591773A CN117357534A CN 117357534 A CN117357534 A CN 117357534A CN 202311591773 A CN202311591773 A CN 202311591773A CN 117357534 A CN117357534 A CN 117357534A
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pharmaceutical composition
hepatocellular carcinoma
peritoneal metastasis
retinoic acid
treating hepatocellular
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石洁
程树群
孙居仙
刘畅
毛菲菲
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Third Affiliated Hospital Of Chinese People's Liberation Army Naval Medical University
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Third Affiliated Hospital Of Chinese People's Liberation Army Naval Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—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

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention belongs to the field of medicines, and in particular relates to application of a pharmaceutical composition containing retinoic acid in preparing a medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis. The pharmaceutical composition comprises a FOLFOX4 chemotherapy regimen, which is the primary active ingredient for treating hepatocellular carcinoma with peritoneal metastasis, and tretinoin, which is an adjunct ingredient for enhancing the FOLFOX4 chemotherapy regimen for treating hepatocellular carcinoma with peritoneal metastasis. The FOLFOX4 chemotherapy regimen consisted of oxaliplatin, 5-fluorouracil and calcium folinate. The medicine composition has obviously better effect than the FOLFOX4 chemotherapy scheme and retinoic acid with the same dosage in terms of treating hepatocellular carcinoma accompanied with peritoneal metastasis, which shows that the medicine composition has obvious synergistic effect after the two are combined, and has good clinical application prospect.

Description

Application of pharmaceutical composition containing retinoic acid in preparation of medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis
Technical Field
The invention belongs to the field of medicines, and in particular relates to application of a pharmaceutical composition containing retinoic acid in preparing a medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis.
Background
Hepatocellular carcinoma (hepatocellular carcinoma, HCC) has in recent years stabilized in our country in cancer incidence and mortality. About 80% of patients with hidden onset of the disease are diagnosed as middle and late stages and lose the opportunity of radical treatment. Although surgical resection is the treatment of choice, only about 15% of HCC patients meet the criteria for such intervention, while about 70% of those experience relapse within 5 years and median survival is only 3-6 months once portal cancer plugs (portal vein tumor thrombus, PVTT) or distant metastases (extrahepatic metastasis, EHM) are pooled.
Currently, there are very limited drug therapies for treating HCC, and previous studies have shown that liver cancer stem cells play an important role in the recurrent metastasis of liver cancer. Systemic treatment regimens for HCC, such as immunotherapy, targeted therapy or intravenous chemotherapy, have problems of unsatisfactory efficacy as a whole, obvious toxic and side effects of treatment, and the like. Sorafenib tosylate (Nexavar from Bayer; a multi-kinase inhibitor that exerts antiproliferative effects (RAF 1, BRAF and KIT), antiangiogenic effects (vascular endothelial growth factor receptor [ VEGFR ] and platelet derived growth factor receptor "[ PDGFRB ]) and pro-apoptotic effects) and lenvatinib mesylate (Lenvima from Merck; multi-kinase inhibitors of VEGFR 1-3, fibroblast Growth Factor Receptor (FGFR) 1-4, RET, KIT and PDGFRa) are the only drugs approved for advanced HCC first line system treatment that cannot be resected by surgery. Second line therapies include multi-kinase inhibitors such as regorafenib (regorafenib) and cabozantinib (cabozantinib), anti-VEGFR 2 mAb, ramucirumab (ramucirumab) and immune checkpoint inhibitors (anti-PD-1 mAb), nivolumab (nivolumab) and pembrolizumab (pembrolizumab). Although immunotherapy and targeted therapy may show significant effectiveness against HCC to some extent, clinically indicated resistance and the problem of high price are all problems that patients have to face during the course of administration. In addition, there is no specific chemotherapy for HCC in clinic, a general chemotherapy for digestive system tumor is usually adopted, and the chemotherapy generally has the problems of poor curative effect and high systemic toxicity, and in the clinical application process, the problem that the patient cannot complete the complete periodic treatment due to adverse reaction of chemotherapy cannot be born often occurs. Thus, there is an urgent and unmet clinical need to find a therapeutic regimen or pharmaceutical composition for the treatment of HCC that is efficient, low-toxic, inexpensive, and not prone to developing drug resistance.
Retinoic Acid (ATRA), tretinoin acid, etc. with chemical name of (13E) -3, 7-dimethyl-9- (2, 6-trimethylcyclohexenyl) -2,4,6, 8-nonyltetraenoic acid, molecular formula of C 20 H 28 O 2 The vitamin A acid derivative is mainly an intermediate metabolite of vitamin A in the body and is an essential substance for maintaining growth and development. The preparation has strong effects of inducing cell differentiation and regulating immunity, is the first clinical medicine for treating acute promyelocytic leukemia (acute promyelocytic leukemia, APL), myelodysplastic and other blood malignant diseases in China, and has better application in other clinical fields such as skin diseases, solid tumors, vascular related diseases and the like.
Retinoic acid is used as an induced differentiation agent, and has a certain effect when being clinically used for treating advanced liver cancer. Previous studies have shown that retinoic acid can induce differentiation of CD133 + Liver cancer stem cells, which can improve the sensitivity of liver cancer cells to cytotoxic drugs, thereby enhancing the curative effect of the treatment. However, the major causes of poor prognosis and survival in HCC patientsThe problem is peritoneal metastasis and distal metastasis due to HCC, and no study has been made heretofore as to whether retinoic acid in combination with other drugs can significantly reduce hepatocellular carcinoma with peritoneal metastasis. In the process of developing clinical researches, the inventor surprisingly finds that retinoic acid combined with intravenous FOLFOX4 (oxaliplatin/pentafluoroeturacil/calcium folinate) chemotherapy has good effect on patients with liver cancer accompanied by peritoneal metastasis.
Based on the findings, the inventor provides a novel application of a high-efficiency, low-toxicity, low-cost and drug-resistant pharmaceutical composition containing retinoic acid for treating hepatocellular carcinoma accompanied by peritoneal metastasis.
Disclosure of Invention
The invention aims to provide a high-efficiency, low-toxicity and low-cost drug-resistant pharmaceutical composition for treating hepatocellular carcinoma with peritoneal metastasis, which comprises retinoic acid, for patients with hepatocellular carcinoma with peritoneal metastasis, and provides a new thought for safely, effectively, conveniently and economically treating hepatocellular carcinoma with peritoneal metastasis in clinic.
Specifically, the invention is realized through the following technical schemes:
in a first aspect, the present invention provides a pharmaceutical composition for treating hepatocellular carcinoma with peritoneal metastasis, the pharmaceutical composition comprising a FOLFOX4 chemotherapy regimen, which is the primary active ingredient for treating hepatocellular carcinoma with peritoneal metastasis, and retinoic acid, which is an adjunct ingredient for enhancing the FOLFOX4 chemotherapy regimen for treating hepatocellular carcinoma with peritoneal metastasis.
Alternatively, in the above pharmaceutical composition, the ratio of the dosage of the FOLFOX4 chemotherapeutic regimen to the retinoic acid is 1-10 in weight ratio: 7.
alternatively, in the above pharmaceutical composition, the ratio of the dosage of the FOLFOX4 chemotherapeutic regimen to the retinoic acid is 4-6 in weight ratio: 7.
alternatively, in the above pharmaceutical composition, the ratio of the dosage of FOLFOX4 chemotherapy regimen to the retinoic acid is 5, on a weight basis: 7.
alternatively, in the above pharmaceutical composition, the FOLFOX4 chemotherapy regimen consists of oxaliplatin, 5-fluorouracil and calcium folinate.
Alternatively, in the above pharmaceutical composition, oxaliplatin is present in a weight ratio: 5-fluorouracil: calcium folinate = 1:1-10:1-10.
Alternatively, in the above pharmaceutical composition, oxaliplatin is present in a weight ratio: 5-fluorouracil: calcium folinate = 1:5-10:1-5.
Alternatively, in the above pharmaceutical composition, oxaliplatin is present in a weight ratio: 5-fluorouracil: calcium folinate = 1:6.5:2.5.
alternatively, in the above pharmaceutical composition, the pharmaceutical composition further comprises other drugs having liver protecting effect.
Preferably, the other medicine with liver protecting effect is one or more of schisandra fruit, puerarin, silymarin, reduced glutathione, glutamine or vitamin D.
Alternatively, in the above pharmaceutical composition, by combining various active ingredients in the pharmaceutical composition, the pharmaceutical composition has a remarkable synergistic effect in treating hepatocellular carcinoma accompanied by peritoneal metastasis.
In a second aspect, the present invention provides the use of a pharmaceutical composition according to the first aspect above for the manufacture of a medicament for the treatment of hepatocellular carcinoma accompanied by peritoneal metastasis.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Is limited to a space and will not be described in detail herein.
Compared with the prior art, the invention has the following beneficial effects:
the invention combines the advantages of the applicant in researching and developing retinoic acid, screens out a pharmaceutical composition with a synergistic effect in treating liver cancer accompanied with peritoneal metastasis, remarkably enhances the effect of the FOLFOX4 chemotherapy scheme in treating hepatocellular carcinoma accompanied with peritoneal metastasis, and remarkably increases the safety of using the pharmaceutical composition and the medication compliance of patients.
Drawings
Fig. 1: photographs of tumors from groups of mice stripped at the end of the experiment in example 1.
Fig. 2: average tumor weight of mice of each group at the end of the experiment in example 1.
Fig. 3: in vivo imaging monitoring of mice in each group during the study and at the end of the experiment in example 2.
Fig. 4: imaging examination results before and after treatment of representative patient cases with hepatocellular carcinoma accompanied by peritoneal metastasis.
Detailed Description
In the intensive study of the mechanism of tretinoin for treating advanced liver cancer, the inventor discovers that the effect of the FOLFOX4 chemotherapy scheme for treating hepatocellular carcinoma with peritoneal metastasis can be remarkably increased by combining the FOLFOX4 chemotherapy scheme with tretinoin for the first time through a large number of screening. The present invention has been completed on the basis of this finding.
As used herein, "liver cancer with peritoneal metastasis" refers to advanced hepatocellular carcinoma with peritoneal metastasis.
As used herein, "adjunct ingredient" generally refers to a substance that has no or little target pharmacological activity, but is capable of enhancing the target pharmacological activity of the primary active ingredient. The target pharmacological activity of the invention is mainly the effect of treating hepatocellular carcinoma accompanied with peritoneal metastasis.
As used herein, tretinoin and FOLFOX4 chemotherapy regimens in the pharmaceutical compositions of the present invention are administered in different pharmaceutical formulations. The dosage forms of retinoic acid and FOLOX4 chemotherapy regimens are different, and retinoic acid and FOLOX4 chemotherapy regimens may be administered simultaneously or sequentially.
In the above-described medical uses, the administration time, the administration frequency, and the administration frequency of "retinoic acid" and "FOLFOX4 chemotherapy regimen", etc., need to be determined according to the specific diagnosis result of the condition, which is within the technical scope of the person skilled in the art.
For example, applying a therapeutic regimen to a mouse or rat to a human, the effective dose of all drugs to the human can be scaled by the effective dose of the drug to the mouse or rat, as would be readily accomplished by one of ordinary skill in the art.
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Unless otherwise indicated, the percentages and parts referred to in the present invention are weight percentages and parts.
Example 1: inhibition of Hub7 subcutaneous engraftment tumor growth by FOLOX4 in combination with retinoic acid
1.1 Experimental materials and methods
The inhibition of Hub7 subcutaneous engraftment growth by FOLOX4 in combination with retinoic acid was examined by constructing a subcutaneous engraftment tumor model from hepatoma cell line Huh7 (purchased from ATCC).
Will be 2X 10 6 The Huh7 liver cancer cells were injected subcutaneously into the right inguinal region of 3-4-week-old NSG mice until the subcutaneous tumor grew to about 200mm 3 At this time, mice were randomly divided into 4 groups: model group, retinoic acid group, FOLOX4 group and combination group, 5 each.
The dosing regimen is as follows:
(1) Model group: 5% glucose is injected intraperitoneally once a week, and physiological saline is administrated by lavage once a day;
(2) Tretinoin group: retinoic acid, 20mg/kg, was administered by intragastric administration once daily;
(3) FOLOX4 group: FOLOX4 regimen is administered once weekly by intraperitoneal injection, wherein oxaliplatin is 10mg/kg, 5-Fu is 65mg/kg, and folinic acid is 25mg/kg;
(4) Combination group: retinoic acid was administered by intragastric administration once daily, 20mg/kg, and the FOLOX4 regimen was administered by intraperitoneal injection once weekly, with oxaliplatin 10mg/kg, 5-Fu 65mg/kg, and folinic acid 25mg/kg.
The above regimen was continued for 6 weeks.
The body weight of the mice was monitored every three days and the tumor size was measured with calipers, the tumor volume was calculated with the formula v= (square of length x width)/2, the length and width being the maximum longitudinal and transverse diameters, respectively, and the tumor trend could be monitored by plotting the tumor volume curve.
At the end of the experiment after 6 weeks of dosing, mice were euthanized and tumors of the mice were dissected for photography.
Experimental data were statistically analyzed by Graphpad Prism 8.0 software, experimental data results were expressed as mean ± SD, data statistics involved t-test or one-way analysis of variance (ANOVA) statistical methods, and p <0.05 was statistically significant for differences in data.
1.2 experimental results
Photographs of tumors from each group of mice stripped at the end of the experiment are shown in figure 1. The average tumor weights of the mice in each group are shown in fig. 2. Experimental results show that compared with the model group, the retinoic acid group and the FOLFOX4 group can obviously reduce the tumor weight of experimental animals, and the inhibition effect of the FOLFOX4 scheme on tumors is superior to that of retinoic acid. When the FOLFOX4 regimen was combined with tretinoin, the inhibition of tumor in the experimental animals became more pronounced in the combination group, and there was a significant difference in tumor weight in the combination group (p < 0.001) compared to the FOLFOX4 regimen group. The above results suggest that the FOLFOX4 regimen in combination with retinoic acid produces a synergistic inhibition of Hub7 subcutaneous engraftment tumor growth.
Example 2: inhibition of Hub7 peritoneal metastasis by FOLOX4 in combination with retinoic acid
2.1 Experimental materials and methods
In the study, a peritoneal metastasis model is constructed by using Huh7 cells expressing luciferase, and the inhibition effect of FOLOX4 combined with retinoic acid on the growth of liver cancer peritoneal metastasis is observed. In this study, 1X 10 will be at day 0 6 The Huh7 hepatoma cells were intraperitoneally injected into NSG mice, and the success of the intraperitoneal tumor model construction was shown by a small animal in vivo imager (BLI) on day 14. The experimental animals were then randomly divided into 4 groups, 5 in each of the model group, retinoic acid group, FOLOX4 group and combination group.
The dosing regimen is as follows:
(1) Model group: 5% glucose is injected intraperitoneally once a week, and physiological saline is administrated by lavage once a day;
(2) Tretinoin group: retinoic acid, 20mg/kg, was administered by intragastric administration once daily;
(3) FOLOX4 group: FOLOX4 regimen is administered once weekly by intraperitoneal injection, wherein oxaliplatin is 10mg/kg, 5-Fu is 65mg/kg, and folinic acid is 25mg/kg;
(4) Combination group: retinoic acid was administered by intragastric administration once daily, 20mg/kg, and the FOLOX4 regimen was administered by intraperitoneal injection once weekly, with oxaliplatin 10mg/kg, 5-Fu 65mg/kg, and folinic acid 25mg/kg.
The above regimen was continued for 7 weeks.
Mice were monitored in vivo by imaging periodically during the study and at the end of the experiment.
Experimental data were statistically analyzed by Graphpad Prism 8.0 software, experimental data results were expressed as mean ± SD, data statistics involved t-test or one-way analysis of variance (ANOVA) statistical methods, and p <0.05 was statistically significant for differences in data.
2.2 experimental results
The in vivo imaging monitoring of each group of mice during the study and at the end of the experiment is shown in figure 3. At the end of the study, the fluorescence ROI values for each group of mice are shown in table 1. Experimental results show that FOLFOX4 scheme has weak inhibition effect on Hub7 peritoneal metastasis when used alone, and has certain inhibition effect (p < 0.01) on Hub7 peritoneal metastasis when retinoic acid is used alone, compared with model group. However, when the FOLFOX4 regimen was combined with tretinoin, the combination group was able to significantly inhibit Hub7 peritoneal metastasis. The experimental results of the combination group were significantly different from the model group and the retinoic acid single group (p <0.001 and p <0.001, respectively). The above results suggest that the FOLFOX4 regimen in combination with retinoic acid produces a synergistic inhibition of Hub7 peritoneal metastatic growth.
Table 1: fluorescence ROI values (mean ± SD) for each group of mice at the end of the study
Note that: in comparison with the set of models, ** p<0.01， *** p<0.001; in comparison with the group of retinoic acids, ## p<0.01。
example 3: representative examples of hepatocellular carcinoma accompanied by peritoneal metastasis
Patients (liver surgery in the eastern hepatobiliary surgery hospital in Shanghai, a clinical laboratory collaborative research and development unit), men, 67 years old, and postoperative abdominal multiple metastasis were found. The peritoneal metastases disappeared 6 times using the atra+folfox4 protocol. The results of imaging examination of representative cases of hepatocellular carcinoma with peritoneal metastasis before and after treatment are shown in FIG. 1.
The combination treatment regimen is as follows:
chemotherapy regimen:
oxaliplatin 85mg/m 2 (first day), calcium folinate 200mg/m 2 (first day), 5-FU 400mg/m 2 (first day), 5-FU 600mg/m 2 (for 40 hours).
Tretinoin usage:
20mg is orally administered 3 times/day, and is administered 3 days before chemotherapy for 5 days.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (10)

1. A pharmaceutical composition for treating hepatocellular carcinoma with peritoneal metastasis, characterized in that: the pharmaceutical composition comprises a FOLFOX4 chemotherapy regimen, which is the primary active ingredient for treating hepatocellular carcinoma with peritoneal metastasis, and tretinoin, which is an adjunct ingredient for enhancing the FOLFOX4 chemotherapy regimen for treating hepatocellular carcinoma with peritoneal metastasis.
2. The pharmaceutical composition according to claim 1, wherein: the ratio of the FOLFOX4 chemotherapy regimen to the retinoic acid is 1-10 by weight: 7.
3. the pharmaceutical composition according to claim 2, wherein: the ratio of the dosage of the FOLFOX4 chemotherapy regimen to the retinoic acid is 4-6, on a weight ratio basis: 7.
4. the pharmaceutical composition according to claim 1, wherein: the FOLFOX4 chemotherapy regimen consisted of oxaliplatin, 5-fluorouracil and calcium folinate.
5. The pharmaceutical composition according to claim 4, wherein: oxaliplatin: 5-fluorouracil: calcium folinate = 1:1-10:1-10.
6. The pharmaceutical composition according to claim 5, wherein: oxaliplatin: 5-fluorouracil: calcium folinate = 1:5-10:1-5.
7. The pharmaceutical composition according to claim 1, wherein: the pharmaceutical composition also comprises other drugs with liver protection effect.
8. The pharmaceutical composition according to claim 7, wherein: the other medicine with liver protecting effect is one or more of fructus Schisandrae chinensis, puerarin, silymarin, reduced glutathione, glutamine or vitamin D.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein: the pharmaceutical composition has remarkable synergistic effect in treating hepatocellular carcinoma accompanied with peritoneal metastasis by combining various active ingredients in the pharmaceutical composition.
10. Use of a pharmaceutical composition according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of hepatocellular carcinoma accompanied by peritoneal metastasis.
CN202311591773.7A 2023-11-27 2023-11-27 Application of pharmaceutical composition containing retinoic acid in preparation of medicine for treating hepatocellular carcinoma accompanied by peritoneal metastasis Pending CN117357534A (en)

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