RU2310460C2 - Sodium arsenite-containing pharmaceutical composition for treatment of malignant tumor - Google Patents

Abstract

FIELD: medicine, oncology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment of solid tumors, for example, large intestine tumor, stomach tumor, breast tumor, ovary tumor, prostate tumor and kidney tumor, and these tumors are sensitive to effect of sodium meta-arsenite. Proposed composition comprises meta-arsenite (AsO₂ ^-) salt taken in the pharmaceutically effective dose and pharmaceutically acceptable accessory agent. Also, invention relates to using this composition in treatment of solid tumors in a patient, and to a method for treatment of solid tumor showing sensitivity to effect of sodium meta-arsenite. Invention provides enhancing effectiveness in treatment of solid tumors.

EFFECT: valuable medicinal property of pharmaceutical composition, enhanced effectiveness of treatment.

13 cl, 1 tbl

Description

The present invention relates to a pharmaceutical composition for treating a malignant tumor comprising arsenic.

Arsenic containing pharmaceutical compositions are known in the treatment of cancer. For example, a review by S.Waxman et al. In The Oncologist 6 (suppl.2), 2001, pp. 3-10, describes the use of arsenic disulfide, arsenic trisulfide and arsenic trioxide in said composition comprising a meta-arsenite salt (AsO ₂ ^- ) and a pharmaceutically acceptable adjuvant.

Due to their inherent toxicity and the emergence of good alternatives, interest in arsenic compounds has remained low so far.

The basis of the invention was the task to offer a pharmaceutical composition for the treatment of malignant tumors, which allows you to treat solid tumors. The pharmaceutical composition can be used to treat such solid tumors for which there is no generally accepted treatment, or as an alternative or additional treatment for such solid tumors.

In connection with the latter circumstance, the pharmaceutical composition of the present invention is characterized in that it is a pharmaceutical composition for treating a solid malignant tumor selected from the group represented by a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor; this composition includes a meta-arsenite salt (AsO ₂ ^- ) and a pharmaceutically acceptable adjuvant.

It was found that certain types of tumors are unusually sensitive to meta-arsenite salt. Moreover, in the salt, the counter-ion meta-arsenite can be any pharmaceutically acceptable counter-ion.

The Waxman article cited G.S. Tarnowski et al. In Cancer Research, 26, 1966, cc. 181-206, where the effect of 14 different antitumor chemical compounds against 8 types of tumors was investigated. Potassium arsenite had an effect only on the growth of Ehrlich ascites tumor. Regarding a tumor of this type, it is noted that it is more sensitive in ascites form than in solid form. This emphasizes the surprising discovery of the present invention.

In a preferred embodiment of the present invention, an alkali or alkaline earth metal salt is used. In a more preferred embodiment of the present invention, the salt is a sodium salt.

Such salts dissolve easily and quickly show their antitumor effect.

The invention also relates to the use of a meta-arsenite salt (AsO ₂ ^- ) to create a pharmaceutical composition for treating a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a tumor the kidneys.

Solid forms of such tumors have been found to belong to the group consisting of a colon tumor, a breast tumor, a prostate tumor, and a kidney tumor.

The present invention also relates to a method for treating a person suffering from a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor, a pharmaceutically effective dose of meta-arsenite salt ( AsO ₂ ^- ).

For a better understanding of the invention, an example is provided that illustrates but does not limit the described invention.

Example

Various human tumor cells were grown at 37 ° C in a humidified atmosphere (95% air, 5% CO ₂ ) in monolayer cultures on RPMI 1640 medium with phenol red (Life Technologies, Karlsruhe, Germany) and with the addition of fetal calf serum. Cells were trypsinized and plated weekly.

Cytotoxicity study

To study the antiproliferative activity of the studied compounds, a modified method was used using propidium iodide (based on the method of WADengler and others in Anti-Cancer Drugs, 6, 1995, cc.552-532. In summary, the method is as follows. Cells were collected in exponential the growth phase of the culture on RPMI 1640 medium supplemented with 10% fetal calf serum, was trypsinized, counted and placed in 96-well microtiter plates with flat-bottomed wells (140 μl cell suspension, 8 × 10 cells / ml). After 24 hours incubation to achieve exponential growth by cells, 10 μl of culture medium (6 control wells per plate) or culture medium containing the test drug was added to the wells. Each concentration of the drug was tested in triplicate. After 4 days of incubation, the culture medium was replaced with an aqueous solution of propidium iodide ( 6 μg / ml) Microtiter plates were kept at -18 ° C for 24 hours, resulting in total cell death. After thawing the plates, fluorescence was measured using a Millipore Cytofluor 2350 microplate reader (530 nm excitation, 620 nm emission) in order to determine the total number of cells. The analysis included untreated and positive controls (5-FU and vindesine).

Growth inhibition was expressed by the experience / control × 100 ratio (or O / K%). The values of IR ₅₀ and IR _{70 were} calculated by comparing the concentration of the substance with respect to the number of cells. The average values of IC ₅₀ and IC _{70 were} calculated by the formula:

where x = a specific line of tumor cells and n = the total number of studied cell lines. If IR ₅₀ and IR ₇₀ cannot be established within the studied dose range, the lowest or highest studied concentration was used for calculation.

Tests were considered significant only if a positive control (5-FU) led to inhibition of tumor growth O / K <30% and solvent-treated control cells had a fluorescence intensity> 500 units.

results

The results are summarized in a table which shows that, in particular, tumor cell lines of a type such as a stomach tumor, an ovarian tumor, and in particular a prostate tumor, a breast tumor, a kidney and colon tumor were sensitive to meta-arsenite compounds. In comparison, promyelocytic leukemia, which is known to respond to arsenic trioxide, showed an IC ₇₀ value of 6.82 μg / ml. Therefore, the tumor cells to which the present invention relates are almost 2-20 times more sensitive to meta-arsenite compound.

Tumor Cell line IR ₇₀ (μg / ml) Colon DLD1 0.48 The stomach Gxf251l 3.08 Mammary gland MXAF401NL 0.32 Ovary Ovcar3 3.02 Prostate PC3 0.85 Kidney RXF486L 0.63

Claims (13)

1. A pharmaceutical composition for treating a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor, including meta-arsenite (AsO ₂ ^- ) sodium and a pharmaceutically acceptable adjuvant substance. 2. The use of meta-arsenite (AsO ₂ ^- ) sodium to obtain a pharmaceutical composition for the treatment of a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor. 3. A method of treating a person suffering from a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor, using a pharmaceutically effective dose of sodium meta arsenite (AsO ₂ ^- ) . 4. The method according to claim 3, in which the tumor is a tumor of the colon. 5. The method according to claim 3, in which the tumor is a tumor of the stomach. 6. The method according to claim 3, in which the tumor is a breast tumor. 7. The method according to claim 3, in which the tumor is a tumor of the ovaries. 8. The method according to claim 3, in which the tumor is a tumor of the prostate. 9. The method according to claim 3, in which the tumor is a kidney tumor. 10. A pharmaceutical composition for treating a solid cancer, wherein said composition comprises sodium meta arsenite (AsO ₂ ^- ) and a pharmaceutically acceptable excipient. 11. A method of treating a patient suffering from a solid malignant tumor, comprising administering to the patient a pharmaceutically effective dose of a composition comprising meta arsenite (AsO ₂ ^- ) sodium. 12. A pharmaceutical composition for treating a solid malignant tumor selected from the group consisting of a colon tumor, a stomach tumor, a breast tumor, an ovarian tumor, a prostate tumor and a kidney tumor, wherein said composition essentially comprises meta arsenite (AsO ₂ ^- ) sodium and a pharmaceutically acceptable excipient. 13. A method of treating a patient suffering from a solid malignant tumor, comprising administering to the patient a pharmaceutically effective dose of a composition essentially containing meta arsenite (AsO ₂ ^- ) sodium.