RU2134589C1 - Method of treatment of patients with primary liver cancer and set for treatment of patients with primary liver cancer - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: method of treatment of patients with primary liver cancer involves firstly administration of alpha-fetoprotein in physiological solution in hepatic artery followed by administration of an anticancer substance preliminary dissolved in 96% ethyl alcohol where lipiodol ultrafluid is added additionally. An antitumor substance is doxorubicin at the dose 30-40 mg dissolved in 1 ml of 96% ethyl alcohol in 10 ml lipiodol ultrafluid and alpha-fetoprotein is administrated at the dose 2 mg/10 ml of physiological solution. The set for treatment of patients with primary liver cancer has an antitumor agent, 96% ethyl alcohol, lipiodol ultrafluid, alpha-fetoprotein, sterile physiological solution (15 ml in ampoule) where doxorubicin is added as an antitumor agent at amount 30-40 mg in 3-4 flasks (volume is 10 ml), sterile lipiodol ultrafluid (5 ml in 2 ampoules), sterile human preparation of lyophilized alpha-fetoprotein at amount 2 mg in flasks (volume is 1 ml in ampoule). EFFECT: enhanced effectiveness of method, decreased toxicity. 3 cl, 1 tbl, 3 ex

Description

 The invention relates to medicine, in particular to oncology. Can be used for chemotherapy of cancer patients suffering from various forms of cancer, such as primary and metastatic liver cancer, breast cancer, leukemia, etc.

 According to statistics, primary and metastatic liver cancer is often the cause of death of patients, firstly, because of the difficulty to diagnose the disease in time and to perform surgical removal of the tumor, and secondly, because of the inability to conduct effective conservative chemotherapy due to the risk of irreversible toxic damage to the liver and kidneys (cirrhosis, massive thrombosis, renal and hepatic insufficiency, etc.) in the treatment of anti-cancer antibiotics. In addition, primary liver cancer is a chemotherapy-resistant disease. The effectiveness of systemic chemotherapy with fluorouracil is extremely low, some improvements in treatment results have been observed with systemic chemotherapy with doxorubicin. However, a large number of cases of general toxic reactions, often incompatible with life, were simultaneously observed.

 It is known to use regional chemotherapy, in which doxorubicin was introduced into the area of the tumor lesion using a catheter through the hepatic artery, which dramatically increased the effectiveness of chemotherapy and at the same time reduced the non-specific toxicity of treatment. Simultaneous embolization of the blood vessels of the liver with the help of lipiodol ultrafluid made it possible to limit the distribution zone of doxorubicin with the simultaneous angiostatic effect of the drug, which made it possible to limit the blood supply to the tumor and suppress its growth. However, high doses of the drug administered left nonspecific toxicity at a fairly high level (up to 40%), which did not significantly increase the average life span of patients. If, with an inoperable form of primary and metastatic liver cancer, the average life expectancy of patients after diagnosis did not exceed 2-5 months, with regional therapy with doxorubicin and lipiodol ultrafluid, the average life expectancy increased to 9-12 months (see, for example, Konno T. et al - in Eur. J. Cancer, 1992, N 28, p. 40-40-40).

 This article proposes the use of a hydrophobic compound of lipiodol ultrafluid, which is a poppy seed oil with substituted ethyl ether on glycerol ether with the addition of 0.38% iodine, for the regional introduction of anti-cancer drugs into the area of the tumor lesion. With the introduction of a suspension of lipiodol ultrafluid, blockage of small blood vessels that feed the tumor occurs. The area of local embolism does not resolve until 2 weeks. With the simultaneous introduction of the antitumor drug, doxorubicin, into this area, the area of active exposure of the drug to the embolization zone is limited, i.e. doxorubicin, as a rule, very slowly went beyond the border of the embolization zone, which sharply reduced its toxic side effects while increasing the effectiveness of treatment.

 It is also known that the oncoembryonic marker alpha-fetoprotein (AFP) is selectively absorbed by cancerous but not normal cells and has the ability to bind various antibiotics and purposefully transport them to cancerous but not normal cells (see, for example, Deutsch HF - in J. Tumor Marker Oncology, 1994, N 9, p. 1-14).

 In addition, the recently established ability of AFPs to cause program death or apoptosis of cancerous but not normal cells, as well as modulate apoptotic signals induced by other factors, has allowed the use of complex anticancer drugs based on ACE for canned cancer treatment (Dudich EI et al - Tumor Biol ., 1998, 19, 30-40).

 Closest to the claimed is a method of treating primary liver cancer, comprising first introducing alpha-fetoprotein into the hepatic artery in physiological saline, and then an antitumor substance previously dissolved in 96% ethanol, to which lipiodol ultrafluid is additionally added (see, for example , patent RU N 2065307, MKI A 61 K 38/17, 1994).

 The disadvantage of this method is the difficulty of manufacturing an antitumor substance - doxorubicin - estrone and a sufficiently high dose used in the treatment, which did not allow minimizing the likelihood of nonspecific toxicity.

 The proposed method allows to reduce therapeutic doses of the drugs used and to reduce the likelihood of toxic side effects while enhancing the anti-cancer therapeutic effect.

 This object is achieved in that in the proposed method for the treatment of primary liver cancer, comprising first introducing alpha-fetoprotein into the hepatic artery in saline and then an antitumor substance previously dissolved in 96% ethanol, to which lipiodol ultrafluid is additionally added, as the antitumor substance uses doxorubicin in a dose of 30-40 mg dissolved in 1 ml of 96% ethanol per 10 ml of lipiodol ultrafluid, alpha-fetoprotein is administered in a dose of 2 mg 10 ml of saline.

 The positive effect of the proposed treatment method when using doxorubicin and AFP is achieved by reducing the concentration of free antibiotic in the tissues and increasing the proportion of the antibiotic associated with AFP, which carries out targeted transfer of the cytotoxic agent to cancer cells, bypassing healthy ones. This proposal uses the ability of AFPs to specifically and specifically enhance cytotoxic effects against cancer cells of low doses of anti-cancer antibiotics, such as doxorubicin, and at the same time significantly limit the non-specific toxicity of anti-cancer antibiotics to normal tissues, which significantly reduces therapeutic doses and reduces the likelihood of toxic side effects. effects. In addition, the claimed method of treatment allows its use in patients with contraindications to the use of steroid hormones, while in the known method - the prototype - the use of the complex doxorubicin - estrone is possible only in a certain category of patients with hormone-independent tumors.

Implementation of the proposed method is as follows:
in the treatment of cancer using the proposed complex chemotherapy with doxorubicin and AFP, a mixture of 30-40 mg of doxorubicin and 2 mg of purified human AFP obtained from umbilical cord serum is used. The drug is administered to the patient intravenously or regionally in the tumor zone using the method of transcatheter regional chemotherapy using lipiodol ultrafluid. The use of regional chemotherapy using the proposed method is more preferable in the presence of primary or metastatic tumors in the liver. In the case of non-determinate dissemination of the tumor throughout the body, systemic intravenous administration of the proposed drugs is indicated.

 During regional chemotherapy, 30-40 mg of doxorubicin is previously dissolved in 1 ml of 96% ethanol, then 10 ml of the sterile preparation of lipiodol ultrafluid is added and shaken vigorously until a fine suspension is formed. AFP - 2 mg is sterilely dissolved in 10 ml of isotonic saline and introduced dropwise through a catheter into the tumor zone through the hepatic artery, then a solution of doxorubicin in lipiodol ultrafluid is introduced in the same way.

 The treatment is repeated after 4-5 weeks in the presence of positive dynamics.

 With systemic chemotherapy, 30-40 mg of doxorubicin is previously dissolved in 1 ml of 96% ethanol, then 10 ml of sterile isotonic saline is added and mixed with sterile AFP solution (2 mg in 100 ml of saline). Then the drug is administered intravenously through a dropper for 2-3 hours. As an AFP, it is also possible to use human AFP obtained from the AFP culture medium - secreting cultured in vitro human hepatoma cell lines, for example, HepG2 or recombinant human AFP expressed in bacterial cells of Echerichia Coli .

 In total, the proposed method was used to treat 6 patients aged 15 to 64 years. The conditions for the preliminary selection of patients were the absence of jaundice and ascites, inoperability, and the absence of severe concomitant diseases. Assessment of toxicity and effectiveness was carried out according to WHO criteria. The following parameters were studied after treatment: the duration of remission, the time from the start of treatment to the progression of the process when evaluating treatment: "stabilization", "minimal", "partial", "full effect", as well as the life expectancy of patients, which was calculated from the start of treatment . In the course of treatment, the patients were prescribed the following types of examinations: coagulogram, ECG, clinical blood and urine tests, laparoscopy, determination of alpha-fetoprotein in the blood, angiography, computed tomography, and ultrasound tomography.

 The main results of the study are presented in the table.

 Example 1. An extract from the medical history from 12/12/96. Patient M.G., husband., Age 64 years.

 Based on the data of ultrasound and tomography and radiopaque angiography, a liver carcinoma was diagnosed. Due to the large size of the tumor (diameter of about 7 cm), surgical removal is not recommended. The patient was given 3 consecutive injections of the drug AFP - doxorubicin - lipiodol. Directed using a catheter through the hepatic artery, a suspension was injected from a solution of 2 mg of AFP in 5 ml of saline and 35 ml of doxorubicin suspended in 10 ml of lipiodol. Repeated and subsequent injections were made after 4 weeks. A tomographic examination of the patient’s liver, performed 4 weeks after the first injection, showed a significant decrease in tumor size (more than 50%). Subsequent injections led to stabilization of the process, and upon observation of the patient within a year after the start of therapy showed a significant improvement in his condition and the absence of any manifestations of nonspecific toxicity typical of doxorubicin chemotherapy.

 Example 2. Extract from the medical history of 126.10.96. Patient A.Ya., female, age 54 years. Diagnosis: metastatic liver damage after surgical removal of breast cancer (right). One year after the operation to remove the mammary gland and excise the axillary lymph nodes, the patient revealed multiple metastatic neoplasms in the liver with a diameter of 1 cm during a tomographic examination. Two injections of the AFP preparation, doxorubicin and lipiodol ultrafluid, were made. A suspension of a solution of 2 mg of AFP in 5 ml of saline and 40 ml of doxorubicin suspended in 10 ml of lipiodol ultrafluid was injected through the hepatic artery using a catheter. 4 weeks after the first injection of the drug, a tomographic and angiographic diagnostic study of the liver was performed, in which no tumor was detected. At the next visit after a month, the patient was re-injection of the drug. During the observation period (8 months), the patient was not found new tumor formations in the liver. The remission process was not complicated by the toxic reaction to doxorubicin chemotherapy.

 Example 3. Extract from the medical history of 112.05.96. Patient A.D., male., Age 19 years. Diagnosis: disseminated rhabdosarcoma of the intestine with multiple metastases in the pelvic organs and peritoneum. Three times surgical removal of the intestinal tract affected by the tumor process was performed. Tumor processes rapidly progressed. The patient was given an intravenous injection of the AFP preparation (3 mg in 100 ml of saline) and then doxorubicin (40 mg in 100 saline) was administered dropwise for 3 hours. Observation of the patient within a week after the injection showed a significant improvement in general condition and tone with almost complete the absence of toxic effects typical of doxorubicin therapy. With further observation of the patient, stabilization of the process and the absence of further progression of tumor growth were noted. Repeated injection of the drug in the same way was done after 3 weeks. The patient was observed for 3 months after the start of AF-doxorubicin therapy. The stabilization of the process was observed with low non-specific toxicity.

 The applicant also offers a kit for the treatment of patients with primary liver cancer.

 The prototype is a kit for the treatment of primary liver cancer (see, for example, patent RU N 2065307, MKI A 61 K 38/17, 1994).

 This kit includes a sterile lyophilized preparation of human AFP in an amount of 1-10 mg in vials with a capacity of 10 ml, a sterile preparation of doxorubicin-estrone in an amount of 20-60 mg in vials with a capacity of 15 ml, sterile saline solution with a volume of 15 ml in an ampoule, ethyl alcohol with a volume of 5 ml in an ampoule, sterile lipiodol ultrafluid with a volume of 20 ml in two 10 ml ampoules.

 The proposed kit for the treatment of primary liver cancer includes doxorubicin in the amount of 30-40 mg, in 3-4 bottles of 10 ml, sterile lipiodol ultrafluid in two ampoules of 5 ml and a sterile lyophilized preparation of human AFP in the amount of 2 mg per dose of 10 ml bottles. In addition, the kit includes ampoules with sterile saline solution (15 ml of 0.9% sodium chloride in distilled pyrogen-free water) and with 96% ethyl alcohol (1 ml). The kit is implemented as follows: during regional chemotherapy, 30-40 mg of doxorubicin is previously dissolved in 1 ml of 96% ethanol, then 10 ml of the sterile preparation lipiodol ultrafluid is added and shaken vigorously until a fine suspension is formed. 2 mg of AFP is sterilely dissolved in 10 ml of isotonic saline and introduced dropwise through a catheter into the tumor zone through the hepatic artery, then a solution of doxorubicin in lipiodol prepared as described above is administered in the same manner. The treatment is repeated after 4-5 weeks with a positive trend.

 With systemic chemotherapy, 30-40 mg of doxorubicin is previously dissolved in 1 ml of 96% ethanol, then 10 ml of sterile isotonic saline solution is added and mixed with a sterile AFP solution (2 mg in 100 ml of saline). The drug is administered intravenously through a dropper for 2-3 hours.

Claims (2)

 1. A method of treating primary liver cancer, comprising first introducing alpha-fetoprotein into the hepatic artery in saline and then an antitumor substance previously dissolved in 96% ethanol, to which lipiodol ultrafluid is additionally added, characterized in that it is an antitumor substance doxorubicin is used in a dose of 30-40 mg, dissolved in 1 ml of 96% ethanol, per 10 ml of lipiodol ultrafluid, alpha-fetoprotein is administered at a dose of 2 mg in 10 ml of saline.  2. A kit for the treatment of primary liver cancer containing an antitumor substance, 96% ethyl alcohol, lipiodol, ultrafluid, alpha-fetoprotein, sterile saline solution with a volume of 15 ml in an ampoule, characterized in that it contains doxorubicin in quantity 30 as an antitumor substance -40 mg in 3-4 bottles with a volume of 10 ml, sterile lipiodol ultrafluid in 2 ampoules of 5 ml, a sterile lyophilized preparation of human alpha-fetoprotein in an amount of 2 mg in vials with a capacity of 10 ml and 96% ethyl alcohol with a volume of 1 ml in an ampoule .

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