JPS60224619A - Radiation sensitizer - Google Patents

Abstract

PURPOSE:The titled sensitizer, containing a halonitrobenzoic acid derivative as an active constituent, and capable of remarkably increasing the sensitivity of intractable hypoxic cells present in malignant tumors to radiation and increasing excellent effect on radiotherapy. CONSTITUTION:A radiation sensitizer containing a halonitrobenzoic acid derivative of the formula [m and n are 1 or 2; X is halogen; R is OM1/a, OR1 or N(R2)R3; M is metal of Group I a or IIa; a is 1 or 2; R1, R2 and R3 are H, alkyl, hydroxyalkyl or alkyl having ether bond, etc., or R2 and R3 together may link to form alkylene or oxadialkylene, etc.] as an active constituent. Monodichlorodinitrobenzoic acid derivatives are particularly preferred in the above-mentioned active constituent of the formula. The administration form is not particularly limited. The daily dose thereof is generally 20-3,000mg for an oral agent and 0.5-500mg for an injection.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a radiosensitizer containing a specific halonitrobenzoic acid derivative as an active ingredient, which can be used to treat refractory hypoxic cells present in malignant tumors by radiation irradiation. This invention relates to a radiosensitizer that promotes inactivation.

Traditionally, surgical treatment, radiation therapy, chemotherapy, immunotherapy, etc. have been used as cancer treatments, and radiation therapy is an effective treatment method that has been used for many years. .

However, there are problems in that the tumor may not be cured even with radiation therapy, and that the tumor may recur even after being cured.

Reasons for this include the cancer tissue's own radioresistance and the presence of oxygen-deficient radioresistant cells in the tumor. In fact, in radiation irradiation experiments, cells in an oxygen-free atmosphere have a
It is known to be ~3 times more resistant to radiation.

Given this current situation, hypoxic cell sensitizers, which are drugs that increase the sensitivity of hypoxic cells to radiation, are considered to be an extremely effective means of improving the effectiveness of radiotherapy.
Its development is strongly desired.

From this point of view, several hypoxic cell sensitizers have been developed, and nitroimidazole derivatives are known as representative ones. (G. Adams et al., Deation Research, Vol. 67, p. 9, 1976) However, misonidazole, one of the representative compounds of nitroimidazole derivatives, has a sensitizing effect that is approximately twice as high as that without additives in animal transplantation tumor experiments. However, it is difficult to administer large amounts because of its neurotoxicity, and no sensitizing effect has been observed in the human body at doses that are clinically applicable.

As a result of intensive studies to obtain a radiosensitizer that exhibits a higher sensitizing effect at low concentrations, the present inventors found that a specific halonitrobenzoic acid derivative significantly increases the sensitivity of hypoxic cells to radiation. It has been found that the effectiveness of treatment can be increased.

That is, the present invention provides a radiosensitizer containing a halonitrobenzoic acid derivative represented by the following general formula (1) as an active ingredient.

(N 02)t+ [m and n each represent 1 or 2, X represents a halogen atom, R is 0M4. Indicates OR or N (Rz) R3. M represents Group Ia or Group Ila metal, ^ is 1 or 2
shows. I? ,, R2 and R3 each represent a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkyl group having an ether bond, or an alkyl group having a hydroxy group and an ether bond, and R2 and R3 are bonded to each other to form an alkylene group, an oxa It may also represent a dialkylene group or an iminodialkylene group. ] The compound represented by the above general formula (1) used as the active ingredient of the drug of the present invention will be described in detail.

Examples of the halogen atom represented by X include chlorine, bromine, and iodine.

Group Ia metals represented by M include lithium, potassium, and sodium, and Group Ila metals include calcium, magnesium, and strontium.

Examples of the alkyl group represented by R, R, and R1 include methyl, ethyl, propyl, isopropyl, butyl, octyl, etc., and examples of the hydroxyalkyl group include hydroxyethyl, hydroxypropyl, etc. Examples of the alkyl group having the hydroxy Examples of the group and the alkyl group having an ether bond include hydroxyethoxyethyl, hydroxyethoxyethoxyethyl,
Examples include hydroxyethoxypolyethoxyethyl,
Further, examples of the alkylene group formed by R2 and R3 bonding with each other include tetramethylene, pentamethylene, etc., examples of the oxadialkylene group include oxadiethylene, etc., and examples of the iminodialkylene group include iminodiethylene, etc. can be given.

Furthermore, when R in the above compound represents a hydrogen atom, it may be an addition salt of its amines.

Examples of such amines include ammonia, methylamine, ethylamine, diethylamine, triethylamine, butylamine, octylamine, dodecylamine,
Examples include ethanolamine, jetanolamine, triethanolamine, piperidine, piperazine, and morpholine.

The above general formula (I) used as the active ingredient of the drug of the present invention
) Examples of the compound represented by the formula include the following.

2-chloro-315-dinitrobenzoic M, 4-chloro-
3,5-dinitrobenzoic acid, 4-chloro-3-nitrobenzoic acid, 2-chloro-3-nitrobenzoic acid, 2,4-dichloro-3,5-dinitrobenzoic acid, 2-promol 3,
Octalonitrobenzoic acid such as 5-dinitrobenzoic acid: Sodium, potassium, lithium or calcium salt of the above halonitrobenzoic acid: Amide of the above halonitrobenzoic acid with ammonia, ethanolamine, morpholine, piperazine, piperidine, diethylamine and the above halonitrobenzoic acid. Acid and methanol, ethanol, propatool, butanol, octatool, nonanol, hydroxyethanol, hydroxypropateol, butoxyethoxyethanol, ethoxypolyethoxyethanol, nonylphenoxypolyethoxyethanol, sugars (glucose,
Examples include esters with sucrose, maltose, etc.

Among these compounds, monochlorodinitrobenzoic acid derivatives are particularly preferred.

The dosage of the sensitizer of the present invention is sufficient to be 115° or less of misonidazole, which is known as a typical sensitizer, and almost no toxicity is observed by administering this amount.

There are no particular restrictions on the dosage form of the sensitizer of the present invention, and carriers commonly used in the pharmaceutical field can be used, and the sensitizer is prepared according to methods commonly used in this field.

In addition, the daily dosage varies depending on the active ingredient and the type of Mugo, but in general, for oral preparations, the dosage is 20 to 3000.
mg, 0.5 to soo mg for injections, 20 mg for suppositories
~200 mg is desirable, and the optimal dose is determined based on the doctor's judgment according to the symptoms, the type of radiation, the irradiation dose, the degree of irradiation fractionation, etc.

When administering the drug of the present invention, a compound containing the compound represented by general formula (1) as an active ingredient can be administered alone, but depending on the purpose, misonidazole, diethyl maleate, phthionine sulfoximine, etc. It can also be used in combination with other sensitizers, glutathione inhibitors, etc. in the same or separate dosage form.

The reasons why the compounds used in the present invention increase the radiosensitivity of hypoxic cells are currently not clear, but they include uptake into cells, interaction with DNA, and radiation-induced base hydroxylation reactions. DN of
This is thought to be due to promotion of chemical interaction with A.

Next, the present invention will be explained in more detail using specific examples regarding the radiosensitizing effect of the drug of the present invention.

Example ■-79 In order to examine the radiosensitizing effect on Chinese hamster cells, 100,000 ■-79 cells were cultured in a monolayer in a glass petri dish, and the logarithmic phase ■-79 cells were cleaved.

A medium solution of a test compound at a predetermined concentration is added to a Petri dish and left at 37° C. for 60 minutes.

This was placed in a sealed container at room temperature, nitrogen gas was passed through it for 10 minutes to eliminate oxygen, and X-rays were irradiated at a dose rate of 1.6 Gy/min.

After irradiation, wash with phosphate buffer, make single cells with tryptocin, put the specified amount into a culture dish, and add 5 ml of medium.
was added and cultured at 37°C for 7 days, washed with water after staining, and the resulting colonies were measured.

For comparison, tests were also conducted in which only a medium solution containing no compound was added and irradiated under nitrogen and in the presence of air.

By calculating the cell survival rate from these values and plotting the logarithm of the survival rate against the irradiation dose, a linear relationship is obtained.

The intersection of this straight line and the horizontal straight line where the survival rate is 1.0 is the induction period dose: Dq (Gy), and the slope of the straight line is the irradiation dose required to reduce the survival rate to 1/10: Dl.

I met (Gy).

In addition, considering the irradiation dose (D6.I"/, -D Q + 3 DIO) required to inactivate 99.9% of cells,
Ratio (N%/D) to the value of irradiation in air (Dp, '(7,)
I+, /^) and the value of irradiation under a nitrogen stream < o5.
, / D, , , , >, respectively, the air reference sensitization ratio (
SARA number) and nitrogen reference sensitization ratio (N + reference 5ARA number).

The results obtained are shown in Table 1.

Continuation of page 1 ■Int, CI,' identification symbol CD9　K　3/DO 11C07G? 9/46 0 Inventor: Mr. Sakano Internal office reference number

Claims (1)

[Scope of Claims] A radiosensitizer comprising a halonitrobenzoic acid derivative represented by the following general formula (I) as an active ingredient. [m and n each represent 1 or 2, X represents a halogen atom, and R represents OM! t, OR+ or N (R,) R
, 0M indicates Group Ia or Ma group metal, 9 indicates l or 2 * R1+ R2 and R each represent a hydrogen atom,
It represents an alkyl group, a hydroxyalkyl group, an alkyl group having an ether bond, or an alkyl group having a hydroxy group and an ether bond, and R2 and R1 are bonded to each other to represent an alkylene group, an oxadialkylene group, or an iminodialkylene group. 〕