JPS6318567B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an adjuvant used in neutron capture therapy for skin cancer. In recent years, there has been a strong call for the eradication of cancer, but even though malignant melanoma (so-called skin cancer) has extremely remarkable invasive and destructive properties and metastatic potential, anticancer drugs and radiation have little effect on it, and new treatments are needed. coveted. In general, when treating cancer, it is important not only to kill the tumor but also to preserve the normal functions of the patient's body. Tissue damage is unavoidable and has become a major drawback. Boron neutron capture therapy has been investigated as a method to solve the above problems, and has achieved some success in treating brain tumors. The principle of boron neutron capture therapy is that a special boron compound is injected into the affected area ^, then thermal neutrons are irradiated to the affected area, and ^the reaction between boron ^{( 10} B isotope) and neutrons produces alpha particles ( ⁴ He ) and Li atomic nuclei, and these particles are used to destroy tumor cells. Unlike ordinary ionizing radiation, the thermal neutrons used here have no biological effect due to their low energy and therefore there is no risk of damaging normal cells.
Furthermore, since the particles produced by the reaction are heavy particles, they have a large destructive force but a short range. That is, if this nuclear reaction occurs within a tumor cell, adjacent normal tumors will not be affected at all. The success of this therapy therefore depends on the ability to develop boron compounds that selectively concentrate on tumor cells. Fortunately, in the case of brain tumor treatment mentioned earlier, the phenomenon of the "blood-brain barrier" (water-soluble substances in the blood have difficulty entering healthy brain tissue, while brain tumor tissue easily takes in water-soluble substances) It can be used to attract water-soluble boron compounds to cancer cells. More than 200 boron compounds have been screened so far and are currently considered promising compounds.
Na ₂ B ₁₂ H ₁₁ SH has been selected and used for treatment. On the other hand, in the case of malignant melanoma, no boron compound has yet been found that selectively concentrates on cancer cells. In recent years, boron derivatives of compounds that have an affinity for melanin have been investigated, based on the fact that malignant melanoma is a malignant change of melanin.
-Since dihydroxyphenylalanine is one of the precursors of melanin, it is mixed with boric acid in a 1:1 ratio.
Complex compounds were investigated. However, this complex compound does not provide sufficient selectivity, and cancer cells repopulate. In addition, due to the fact that chlorpromazine forms a complex with the indole nucleus of melanin, boron derivatives of chlorpromazine, such as were also considered, but they were still insufficient in selectivity. However, the present inventors focused on boronophenylalanine, which is considered to be an antagonist of tyrosine, which is one of the melanin precursors, and found that this compound was surprisingly effective against malignant melanoma. The present invention was completed by discovering that the enzyme concentrates in cancer cells. The present invention is based on the general formula (In the formula, R represents hydrogen or an acetyl group, and B
represents the element boron, at least 50% of which is
This is an adjuvant for skin cancer neutron capture therapy, characterized by containing a boronophenylalanine derivative represented by ¹⁰ B) or a pharmacologically acceptable salt thereof as an active ingredient. The boronophenylalanine derivatives represented above include O,m,P-boronophenylalanine, N-acetyl-O-boronophenylalanine, N-acetyl-m-boronophenylalanine, and N-acetyl-p-boronophenylalanine. etc. In addition, examples of these pharmacologically acceptable salts include hydrochloride, sodium salt, and the like. In order to enhance the therapeutic effect of boron in the compound of the present invention, it is desirable that the isotopic ratio of ¹⁰ B is 50% or more (the naturally occurring ratio of ¹⁰ B is 19.8%). The inventors used a special anion exchange resin to
We obtained highly concentrated boric acid containing 91% of ^10B , and using this as a starting material, we were able to synthesize boronophenylalanine ( ⁹¹ % of 10B) containing 91% of ^10B for the first time.
As a result, we were able to enhance the therapeutic effect on malignant melanoma. (In order to obtain the desired therapeutic effect, it is necessary to increase the absolute amount of ¹⁰ B in cancer cells in addition to the selectivity mentioned above.) The present invention uses the above-mentioned boronophenylalanine derivative, usually in an aqueous solution or It is a mixed solution of water and ethanol, containing 0.1 to 0.5% by weight of a boronophenylalanine derivative as an active ingredient, preferably 1% by weight.
It contains ~20% by weight. When the compound of the present invention is used for treatment, it is administered as an aqueous solution as described above by subcutaneous injection near the affected area. The dosage depends on the size of the tumor, but is usually 1 mg to 200 mg of the active ingredient. The toxicity of p-boronophenylalanine hydrochloride, which is a representative compound of the present invention, is low with LD ₅₀ =840 mg/Kg mouse (intravenous injection). Next, examples of the present invention and test examples of effectiveness will be described, but these examples do not limit the content of the present invention. Example 1 10mg of p-boronophenylalanine in 1ml of distilled water
to make a 1% by weight solution. Example 2 200mg of p-boronophenylalanine in 1 part distilled water
ml to make a 20% by weight solution. Test Example 1 (In vitro test) 10% FCS containing 10 μg/ml of the compound of the present invention
(Fetal Calf Serum) added MEM (miniwal
Mouse-derived B- in culture solution (essential medium)
16 Incubate melanoma for approximately 18 hours.
(The compound of the present invention is incorporated into the B-16 melanoma.) Thereafter, this culture solution was replaced with a MEM culture solution containing 10% FCS that does not contain the compound of the present invention, and after culturing for an additional 7 hours, the cells were irradiated with thermal neutrons. The lethal effect of the compound of the present invention was expressed as the survival fraction of B-16 melanoma versus irradiation dose using the colony method, and the results are shown in Figure 1. Example 2 (Selectivity evaluation) One of the compounds of the present invention was administered to hamsters (2 animals) 9 days after transplantation of mouse-derived B-16 melanoma.
% aqueous solution was administered by subcutaneous injection. Two days after the injection, the tumor and liver were removed, freeze-dried, and crushed, and the content of ¹⁰ B was determined. The results are shown in Table-1. (Control ¹⁰ B ₁₂ - Chlorpromazine was administered at 5 mg/ml each)

【table】

[Table] Example 3 30 mg of p-boronophenylalanine hydrochloride was subcutaneously injected into the tumor in the butt of a pig (weight 60 kg) with malignant melanoma that had spontaneously occurred in two places, the back and the butt.
(0.3 ml of 10% by weight aqueous solution) was administered. Thirty minutes later, neutron capture therapy was performed under remote anesthesia (using a medical nuclear reactor at Musashi Institute of Technology). After about 3 months, the treated tumor was completely cured, but the untreated tumor was not cured.

[Brief explanation of the drawing]

In Figure 1, 〓 is when only neutrons are irradiated, and O is p-boronophenylalanine ( ¹⁰ B20
%), and p-boronophenylalanine (
¹⁰ B50%), △ indicates N-acetyl-p-boronophenylalanine ( ¹⁰ B91%), and X indicates p-boronophenylalanine ( ¹⁰ B91%) as neutron capture aids when irradiated with neutrons. .

Claims (1)

[Claims] 1. General formula (In the formula, R represents hydrogen or an acetyl group, and B
represents the element boron, of which at least 50% is ¹⁰ B
1. A auxiliary agent for neutron capture therapy for skin cancer, characterized in that it contains a boronophenylalanine derivative represented by the following formula or a pharmacologically acceptable salt thereof as an active ingredient.