A method of treating breast cancer

 

(57) Abstract:

The invention relates to medicine, namely to Oncology. The aim of the invention is to increase the effectiveness of chemotherapy for breast cancer. This goal is achieved by introducing into the surrounding tumor tissue using a needleless injector emulsion drugs. The emulsion comprises an aqueous solution of the cytostatic agent, an oil solution of vitamins, surfactants, and are prepared under the effect of ultrasound frequency 44 kHz for 15 min to 1 h. p. F.-ly.

The invention relates to medicine, namely to Oncology. Currently, chemotherapy in cancer treatment is widely used. Treatment of locally common forms of breast cancer and "aggressive" forms of morphological and clinical data requires the use of chemotherapy as a mandatory component in the combined treatment of this pathology (N.And.Perevozchikova. 1993. "Anti-tumor chemotherapy"). However, despite the emergence of new chemotherapeutic drugs, the use of this type of treatment in traditional forms is still not effective enough. However, increasing the dose of drugs overanxiously dominated by reactions actively proliferating tissues: bone marrow, the mucosa of the gastrointestinal tract, hair follicles (A. J. Bialik, N. And.Evdokimova, N. A. Agarunov, C. U. Savenok. 1993. "Manual of practical Oncology"). Some tumors are composed of cells with the phenotype of drug resistance. This is due to the presence of the transmembrane protein P-glycoprotein. It is almost impossible to create a high, long-lasting concentration of drugs in tumor tissue and in the ways of regional lymph flow due to the inevitable "reset" part of administered drugs through arterio-venous shunts. To overcome these shortcomings should satisfy the cytostatic to malignant neoplasm (Gupta P. K. "Drug Fargeting in Cancer Chemotherapy: Aclin: Cal Rerspective/j." Pharm. Sci. 1990, 79, N11, S. 949-962).

The aim of the invention is to increase the effectiveness of chemotherapy.

This goal is achieved by the use for the treatment of mestnorasprostranenny breast cancer indirect endolymphatic chemotherapy modified cytostatics. In the treatment of this method to patients in the surrounding tumor tissue using a needleless injector JGB 50 was introduced emulsion of cyclophosphamide, 5-fluorouracil, methotrexate. The emulsion comprises an aqueous solution of platinum and is in As well, E, K (Aaqol). Emulsion of cyclophosphamide was administered daily for 8 days at the rate of 200 mg/m2the square body of the patient, the emulsion of 5-fluorouracil was administered at 1 and 8 days at the rate of 600 mg/m2the emulsion methotrexate was administered at 1 and 8 days at the rate of 40 mg/m2. The components of the indirect effect of endolymphatic chemotherapy are presented as follows. Chemotherapy, long-term deponeerimise in the lymph channel, combine with proteins in the lymph and then enter the blood already in the new as being a genotype to a tumor on the one hand and less toxic on the other. Removing the mechanical and chemical unit with lymph nodes, chemotherapy drugs are nonspecific irritants lymphoid tissue. The latter fact helps to increase the production of lymphocytes. The result of the combined action of chemotherapeutic agents increases lymph flow, increases the production of lymph, qualitatively improves its composition (Y. N. Sidorenko. 1985. "Endolymphatic chemotherapy of malignant neoplasms"). therapeutic effect of endolymphatic chemotherapy and implemented through immunological mechanisms. As a result, there cytotoxic interaction between all immunocompetent EEOC with another (Y. N. Borduchkov.1990."New aspects of endolymphatic therapy"). For realization of the effect of endolymphatic therapy by stimulating resorption of tissue in the lymph possible use of needleless injector, which was administered a drug in the form of a spray jet (Y. M. Levin.1987. "Endolymphatic therapy"). Emulsion form of cytostatics consists of surfactant tween-40, oil solution of vitamins A, E, K (Ecol), an aqueous solution of cytotoxic agents: cyclophosphamide, 5-fluorouracil, methotrexate. Surfactant tween-40 was used as the emulsion stabilizer. It was also noted that the introduction of chemotherapeutic agents with surfactant type twin concentration of the cytostatic agent in the blood plasma is higher in comparison with the use of the same drug in aqueous solution (Hellstens. Axelsson B. Eksdorg S. Lindkvis C. "Organ distribution or adriamycin After"; ntravesical instillation with or with out Tween-80 in the rat"/Clrol.Res-1988-16 N4-C 325-327).

The surfactant improves the bioavailability of drugs (Boer A. G. de, Hoogdalem E. J. VAN, Brcimer D. D. "Improvement of drug absorption Througn. Enhancers"/ Eur.J.Drug.Metab.And Pharmacokinet. 1990, 15, N2, S. 155-157).

Oil solution of vitamins a And E, was used as a lipid delivery system of the drug in the tumor. The use of lipids as carriers of drugs contributes to the change in the pharmacokinetics, including intracellular. Lipid visioli, stormily delivery and controlled release of drugs, the advantages of lipid delivery systems is their good biological compatibility, the ability to complete assasinate in vivo, the absence of antigenic properties. (Jiro Harada, Hibino Hidehiko "Lipid systems for delivery of drugs". (KAGAKU= J. Japan O:L CHen. Soc. 1988, 37, N10, S. 864-871.) Emulsion form of the drugs were prepared immediately before use in sterile conditions. Part of the emulsion was mixed and exposed to ultrasound with a frequency of 44 kHz for 15 minutes, the Ratio of the component parts of the emulsion is as follows: oil solution of vitamins: water solution of cytostatic as 3:7, number of twin 40 not less than 10% of the total volume of the emulsion. These ratios are optimal, they manage to get in the tumor maximum concentration of the cytostatic agent, a long and gradual decline of its maximum inhibition of tumor growth (C. N. Lanin, N. Century Romanov, V. I. Borisov, I. G. Rusakov, L. A. Nikoulichev. 1992. "Monitoring the effectiveness of anticancer triethylenethiophosphoramide using high-performance liquid chromatogram"). During the 30-day observation emulsion breaking is not reached. When chromatographic study determined that after ultrasonic otopleniya using a needleless injector IKB-50 into the surrounding tumor tissue, away from palpable tumour edge of 0.5-1 cm, injection of 1 ml mode intramuscular injection. The treatment lasted 8 days. The dose of the drugs was calculated individually, taking into account the area of the patients body on the nomogram. The drugs were administered according to the scheme CMF: cyclophosphamide 200 mg/m21 to 8 days, 5-forall 600 mg/m21 and 8 days, methotrexate 40 mg / m21 and 8 days. On the first day of treatment was administered emulsion of cyclophosphamide, 5-fluorouracil, methotrexate. In 2,3,4,5,6,7 days was injected emulsion of platinum. At day 8 was injected emulsion of cyclophosphamide, 5-fluorouracil, methotrexate. Before the introduction of the skin of the breast, double-processed 96% alcohol.

Example. Patient Dvorakova Century. And. 1939 R. history 459693, appealed to the regional Oncology center, Voronezh 29.01.93, When surveyed in the upper-outer quadrant of the left breast revealed dense neoplasm without clear boundaries, bad shift, rounded up to 4 cm in diameter, localized in the upper-outer quadrant of cancer. In the left axillary region is palpated lymph node up to 1.5 cm in diameter. When ultrasound examination diagnosed a tumor of the left breast with localization in the upper-outer kwanyi punctate from the tumor from 1.02.93, detected breast cancer cells with degeneration of cells. The patient was diagnosed with breast cancer T2 N1 MO. The patient identified the following treatment plan:

1. Preoperative indirect endolymphatic polychemotherapy modified cytostatics scheme CMF.

2. 2 weeks after the end of chemotherapy radical mastectomy on Pati.

3. In the postoperative period chemohormonal indicated.

Modified drugs were administered using a needleless injector JGB-50. The introduction of drugs produced in the tumor-surrounding tissue by injection of 1 ml mode intramuscular injection. 1 and 8 days entered: modified cyclophosphamide 400 mg modified 5-fluorouracil 750 mg modified methotrexate 40 mg In 2,3,4,5,6,7 days was administered 400 mg of the modified platinum. Local and systemic complications during treatment were observed. Blood tests without pathological changes.

The results of the treatment were determined by ultrasound. 2 weeks after the end of chemotherapy dimensions neoplasms: 15 x 11 x 15 mm, axillary lymph nodes 5 mm in diameter. 16.03.93 g is but the next. Histological examination from 25.03.93, N 12050-65 mammary gland with the minor pectoral muscle and subcutaneous fat. Tumor site consists of extensive necrosis. Lymph nodes partially replaced by fatty tissue, small, soft. In the clippings nodules widespread necrosis of adipose tissue, in which the field of lipophages. Next in the tissue of the gland cysts formed eosinophilic epithelium, diffuse dilated ducts. Dairy slices reduced, in the study of 6 lymph node metastases were not found. Conclusion: the status after chemotherapy treatment for breast cancer. Necrosis of adipose tissue with cellular resorption, cancer metastasis was not found. Sick surveyed in December 1993, made the bone scintigraphy of the skeleton, liver ultrasound, right breast, radiography of the chest. Signs of recurrence and metastases no.

By the above method were treated 6 patients. In 2 of them showed complete regression of the tumor. In 4 patients experienced tumor shrinkage of more than 50%

1. A method of treating breast cancer, which consists in the introduction of needleless injector drugs for 8 days under the scheme CMF, otlichayushiesya-active substances, injected into the surrounding tumor tissue, reached 0.5 to 1.0 cm from the palpable edge of the tumor, injection of 1 ml mode intramuscular injection.

2. The method according to p. 1, characterized in that the emulsion is produced under the action of ultrasound with a frequency of 44 kHz for 15 minutes

 

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