JP2016216404A - Sensitizer for proton beam therapy and method of proton beam therapy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide means that can conserve a biological dose (RBE) under a uniform physical dose in a proton beam therapy.SOLUTION: In a malignant tumor therapy by irradiation of a uniform physical dose of proton beam within the superposition of plural Bragg peaks (SOBP) of irradiated proton beam, a sensitizer for proton beam therapy containing an RNA synthesis inhibitor as an active ingredient used for adjusting a biological dose (RBE) within SOBP is provided. The invention also provides a method of proton beam therapy comprising radiating a uniform physical dose of proton beam within SOBP to the affected area to which a sensitizer containing an RNA synthesis inhibitor as an active ingredient is administered.SELECTED DRAWING: Figure 7

Description

  The present invention relates to a proton beam treatment sensitizer and a proton beam treatment method.

  Proton therapy is radiation therapy in which an accelerated “proton” is applied to a lesion from outside the body. "Protons" are hydrogen nuclei, and protons are accelerated by bundled protons. In addition to proton beams, radiation used for radiation therapy includes X-rays, electron beams, gamma rays, and carbon beams. The treatment with proton beam and carbon beam is sometimes referred to as “particle beam therapy”.

  X-rays currently commonly used for radiation therapy have the property that energy is maximized at a certain depth from the body surface (see FIG. 1). Thereafter, the X-rays gradually decrease, but due to this property, a certain amount of radiation is also applied to the normal tissue behind the lesion. In contrast, protons have a physical feature called “Bragg peak” that emits most of the energy near the end of the depth of reach. Proton rays release most of the energy near the lesion, so if the irradiation position is adjusted appropriately, treatment can be performed without hitting the proton beam behind the lesion. This is a major feature and advantage of proton therapy.

  Radiation therapy has been developed with the aim of appropriately controlling the amount of radiation hitting the lesion site and normal tissue, and at the same time reducing side effects. The proton beam treatment can be performed by using the superior property of stopping at the lesion site by the Bragg peak, which is the characteristic of the proton beam described above, so that the radiotherapy limited to the lesion site is possible. Therefore, proton therapy is an ideal radiotherapy that is expected to achieve both improvement in the control rate of lesions and reduction in side effects.

Y Matsumoto, T Matsuura, M Wada, Y Egashira, T Nishio, and Y Furusawa, Enhanced radiobiological effects at the distal end of a clinical proton beam: in vitro study.J Radiat Res. 2014; 55: 816-22.

  As mentioned earlier, protons have a physical feature called the “Bragg peak” that releases most of the energy near the end of the depth of reach, so that the dose to the surrounding normal tissue is high while irradiating the tumor with a high dose. Reduction is possible. However, the actual treatment is performed by superimposing the Bragg peaks of a plurality of energies and selectively irradiating only the tumor. The superposition of multiple peaks (spread-out Bragg-peak (SOBP)) is set so as to have a constant physical dose at the tumor position (FIG. 2 (A)).

  Conventionally, the biological effect (biological dose (RBE)) was considered to be constant in SOBP with a constant physical dose (Fig. 2 (B)). It has been reported that the actual biological effect of the proton beam set to (referred to as biological dose (RBE)) is not constant in SOBP, and that RBE increases with depth in SOBO (Figure 3). Non-patent document 1).

  Even if the physical dose is uniform within the SOBP, the RBE may not be constant, so that a uniform therapeutic effect may not be achieved.

  Accordingly, an object of the present invention is to provide a means capable of making the biological dose (RBE) constant under a uniform physical dose.

  The present inventors have made various studies to achieve the above object. As a result, the present inventors have found that the biological dose (RBE) can be made constant under a uniform physical dose by allowing an RNA synthesis inhibitor to be present in the affected area that is irradiated with proton beams.

The present invention is as follows.
[1]
Adjust the biological dose (RBE) in SOBP in the treatment of malignant tumors by irradiating proton beam with uniform physical dose within the superposition of multiple Bragg peaks of irradiated proton beam (hereinafter referred to as SOBP) A sensitizer for proton beam therapy containing an RNA synthesis inhibitor as an active ingredient.
[2]
The sensitizer according to [1], wherein the RNA synthesis inhibitor is a cell homologous recombination repair inhibitor for DNA double-strand breaks.
[3]
The sensitizer according to [1] or [2], wherein the RNA synthesis inhibitor is a 3′-substituted nucleoside derivative represented by the following general formula.
(In the formula, B represents a nucleobase which may have a substituent, and Z represents an ethynyl group which may be substituted with a trialkylsilyl group.)
[4]
The sensitizer according to [3], wherein the 3′-substituted nucleoside derivative is at least one compound selected from the group consisting of the following compounds.
1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorocytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
3- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorouracil,
9- (3-C-ethynyl-β-D-ribofuranosyl) adenine,
9- (3-C-ethynyl-β-D-ribofuranosyl) guanine.
[5]
The sensitizer according to [3], wherein the 3′-substituted nucleoside derivative is 1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine represented by the following formula.
[6]
A proton beam treatment method comprising irradiating an affected area to which a sensitizer comprising an RNA synthesis inhibitor as an active ingredient is administered with a uniform physical dose of proton beam in SOBP.
[7]
The method according to [6], wherein the RNA synthesis inhibitor is a cell homologous recombination repair inhibitor for DNA double-strand breaks.
[8]
The method according to [6] or [7], wherein the RNA synthesis inhibitor is a 3′-substituted nucleoside derivative represented by the following general formula.
(In the formula, B represents a nucleobase which may have a substituent, and Z represents an ethynyl group which may be substituted with a trialkylsilyl group.)
[9]
The method according to [8], wherein the 3′-substituted nucleoside derivative is at least one compound selected from the group consisting of the following compounds.
1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorocytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
3- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorouracil,
9- (3-C-ethynyl-β-D-ribofuranosyl) adenine,
9- (3-C-ethynyl-β-D-ribofuranosyl) guanine.
[10]
The method according to [8], wherein the 3′-substituted nucleoside derivative is 1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine represented by the following formula.
[11]
The method according to any one of [6] to [10], wherein the physical dose of the proton beam is 95% or less when the sensitizer is not used.
[12]
The method according to any one of [6] to [11], wherein the dose of the sensitizer to the affected area is in the range of 2.0 mg / m ^{2 to} 6.85 mg / m ² .
[13]
SOBP is the method in any one of [6]-[12] which is the range of 50-300 mm from an epidermis.
[14]
The method according to any one of [6] to [13], wherein the affected area is a malignant tumor.

  ADVANTAGE OF THE INVENTION According to this invention, the treatment method by proton beam irradiation which can make a biological dose (RBE) constant under uniform physical dose can be provided. Furthermore, according to this method, the biological dose (RBE) under a predetermined physical dose can be increased as compared with the case where no RNA synthesis inhibitor is present, so that a desired treatment can be performed with a smaller proton beam dose. There is a possibility that an effect can be obtained.

The relative absorbed dose in the depth direction from the surface of the body of X-rays and proton rays used for radiation therapy is shown. (A) The state of the uniform physical dose provided in the superposition (SOBP) of a plurality of Bragg peaks of irradiated proton beams is shown. (B) The SOBP and biological effects (relation between biological dose (RBE) (difference from actual biological effects (biological dose)) that was assumed in the past are shown. Shows the actual biological effect (referred to as biological dose (RBE)) of a proton beam set to a constant physical dose at the tumor location. The irradiation point of a proton beam in an Example is shown. The survival curve obtained from the colony formation method in an Example is shown. The situation of the improvement of dose distribution by combined use of ECyd obtained in the examples is shown. The situation of the improvement of the dose ratio with respect to the plateau position in the SOBP center by the combined use of ECyd obtained in the examples is shown.

<Sensitizer for proton therapy>
The present invention relates to a sensitizer used for proton beam therapy (sensitizer for proton beam therapy).
The sensitizer for proton beam treatment of the present invention is used in the treatment of malignant tumors by irradiating a proton beam with a uniform physical dose within a superposition of a plurality of Bragg peaks of irradiated proton beams (SOBP). Used to adjust biological dose (RBE). The active ingredient is an RNA synthesis inhibitor. Proton therapy and adjustment of RBE within SOBP will be described later.

  The RNA synthesis inhibitor used as an active ingredient in the sensitizer for proton beam therapy of the present invention is a substance having an action of inhibiting RNA synthesis by RNA polymerase in cells. Any substance that has an action of inhibiting RNA synthesis by RNA polymerase in a cell can be used without particular limitation as an RNA synthesis inhibitor in the present invention.

  The RNA synthesis inhibitor can be, for example, a cell homologous recombination repair ability inhibitor against DNA double-strand breaks. As a homologous recombination repair ability inhibitor, for example, 3′-substituted nucleoside derivatives are known (see WO96 / 18636, WO97 / 43295, and JP2000-154197). In the present invention, the 3′-substituted nucleoside derivatives described in these publications can be used as an RNA synthesis inhibitor, and the 3′-substituted nucleoside derivatives are, for example, compounds represented by the following general formula.

In the formula, B represents a nucleobase which may have a substituent, and Z represents an ethynyl group which may be substituted with a trialkylsilyl group. Examples of the nucleobase include pyrimidine bases such as cytosine, thymine and uracil, and purine bases such as adenine and guanine. The substituent that the nucleobase B can have is a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a lower alkyl group having 1 to 6 carbon atoms, an acyl group, or a lower one having 1 to 6 carbon atoms. Examples thereof include an alkoxycarbonyl group, a lower alkenyloxycarbonyl group having 1 to 6 carbon atoms, and an aralkyloxycarbonyl group. The alkyl group of the trialkylsilyl group represented by Z is a lower alkyl group having 1 to 6 carbon atoms.

Specific examples of 3′-substituted nucleoside derivatives include
1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorocytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
3- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorouracil,
9- (3-C-ethynyl-β-D-ribofuranosyl) adenine,
9- (3-C-ethynyl-β-D-ribofuranosyl) guanine,
Can be mentioned.

1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine whose nucleobase is cytosine is represented by the following formula and may be abbreviated as ECyd hereinafter.

  Methods for producing these 3′-substituted nucleoside derivatives are described in WO96 / 18636, WO97 / 43295, and JP2000-154197.

<Proton therapy>
The present invention includes a proton beam treatment method using the therapeutic sensitizer of the present invention, which comprises an RNA synthesis inhibitor as an active ingredient. The proton beam treatment method of the present invention includes irradiating an affected area to which a therapeutic sensitizer containing the RNA synthesis inhibitor as an active ingredient is administered with a uniform physical dose of proton beam in SOBP.

  The method itself of irradiating a uniform physical dose of proton beams in SOBP is a known method. In the present invention, the affected area of the proton beam treatment target is a malignant tumor. Cancer is the main proton therapy target.

Administration of the therapeutic sensitizer to the affected area can be performed, for example, by administering ECyd intravenously over 24 hours. Dosage, blood, urine and physical periodically observe the neurological examination, can outliers decides to have none detected, a range of 1.0 to 10.0 mg / m ^2, preferably 2.0 mg It is appropriate that the range is from / m ^{2 to} 6.85 mg / m ² .

  Depending on the location of the affected area, SOBP can be, for example, in the range of about 20 to 400 mm from the epidermis, more preferably about 50 to 300 mm.

  When the therapeutic sensitizer of the present invention is used, as shown in FIG. 6 (result of RBE × physical dose in the presence of ECyd), the effect of adjusting RBE in SOBP, more specifically, RBE in SOBP It has the effect of making it more constant and the effect of increasing RBE on the side close to the epidermis in SOBP. The effect of increasing the RBE on the side close to the epidermis in SOBP varies depending on the type of therapeutic sensitizer, the dosage, the condition of SOBP, etc., but considering the effect of increasing this RBE, in the method of the present invention, The physical dose of proton beam can be 95% or less, preferably 90% or less when no therapeutic sensitizer is used. By reducing the physical dose of the proton beam, it is possible to reduce the damage caused by the proton beam to the important organ existing around the affected area.

  Hereinafter, the present invention will be described in more detail based on examples. However, the examples are illustrative of the present invention, and the present invention is not intended to be limited to the examples.

<Cell line>
Chinese hamster lung fibroblasts (V79) were used as the cells. V79 has been used in many studies so far to evaluate the biological effects of proton beams. The cells were cultured in an α-MEM (Life Technologies, Carlsbad, Calif.) Medium supplemented with 10% fetal bovine serum (BioWest, Nuaille, France) at 37 ° C. and 5% CO ₂ .

<Irradiation>
Six hours before irradiation, 1.6 × 10 ⁶ cells were seeded in a chamber slide flask (Lab-Tek ^™ Slide Flask 170920, Thermo Scientific / Nunc, Penfield, NY). One hour before irradiation, the flask was filled with medium or medium containing 0.4 μM ECyd.

Proton irradiation was performed using ProBeat RT of the Hokkaido University Proton Therapy Center. The spread out Bragg peak (SOBP) width was 6 cm, and the irradiation field was 10 × 10 cm ² . Irradiation point is (1) Position A: 5mm deep from the incident point, (2) Position B: 95% position on the proximal side compared to SOBP dose, (3) Position C: SOBP center, (4) Position D: 4 locations at 95% position on the distal side compared to the dose of SOBP (see Fig. 4).

Colony formation method Immediately after irradiation, cells were collected from the slide flask by trypsinization. The number of cells was counted, and an appropriate number was seeded to form about 100 colonies on a 6 cm dish. After 7 days of incubation, colonies (more than 50 cell groups) were counted.

Survival at each dose was calculated using the control's plating efficiency that was not irradiated and plotted on each physical dose. The survival curve obtained from the colony formation method is shown in FIG. The survival curve SF = EXP (-αD-βD ² ) (SF is the survival rate, D is the physical dose) was fitted to a linear quadratic (LQ) model. The relative biological effectiveness (RBE) and sensitizer effective ratio (SER) values were evaluated at D ₁₀ (dose required to reduce survival to 10%, respectively). Each experiment was performed in triplicate. SER is shown in Table 1, and RBE is shown in Table 2. As can be seen from the SER results shown in Table 1, a remarkable increase in proton beam was obtained at point C compared to point D. As can be seen from the RBE results shown in Table 2, the RBE at the C point showed a significant increase, while the RBE at the D point showed little change.

* D _10: Comparison at a dose that the survival rate is reduced to 10%

* D _10: the D ₁₀ of the X-ray as a comparison reference at doses viability decreased to 10% 8.91Gy

Fig. 6 shows the improvement of dose distribution by using ECyd together.
Due to the effect of ECyd, the biological dose (RBE x physical dose) in the target becomes flat, and a uniform treatment effect is expected. The dose ratio to the plateau position at the center of the SOBP increases while maintaining the characteristics of the physical dose distribution of the proton beam, so it is considered possible to concentrate the dose on the target.

  Fig. 7 shows the improvement of the dose ratio with respect to the plateau position in the SOBP center by using ECyd together. The dose ratio is improved, and it is possible to protect normal tissues in front of and behind the tumor while concentrating a high dose on the tumor.

  The present invention is useful in fields related to proton therapy.

Claims (14)

Adjust the biological dose (RBE) in SOBP in the treatment of malignant tumors by irradiating proton beam with uniform physical dose within the superposition of multiple Bragg peaks of irradiated proton beam (hereinafter referred to as SOBP) A sensitizer for proton beam therapy containing an RNA synthesis inhibitor as an active ingredient. The sensitizer according to claim 1, wherein the RNA synthesis inhibitor is a cell homologous recombination repair inhibitor for DNA double-strand breaks. The sensitizer according to claim 1 or 2, wherein the RNA synthesis inhibitor is a 3'-substituted nucleoside derivative represented by the following general formula.
(In the formula, B represents a nucleobase which may have a substituent, and Z represents an ethynyl group which may be substituted with a trialkylsilyl group.) The sensitizer according to claim 3, wherein the 3'-substituted nucleoside derivative is at least one compound selected from the group consisting of the following compounds.
1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorocytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
3- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorouracil,
9- (3-C-ethynyl-β-D-ribofuranosyl) adenine,
9- (3-C-ethynyl-β-D-ribofuranosyl) guanine. The sensitizer according to claim 3, wherein the 3'-substituted nucleoside derivative is 1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine represented by the following formula.
A proton beam treatment method comprising irradiating an affected area to which a sensitizer comprising an RNA synthesis inhibitor as an active ingredient is administered with a uniform physical dose of proton beam in SOBP. The method according to claim 6, wherein the RNA synthesis inhibitor is a cell homologous recombination repair inhibitor for DNA double-strand breaks. The method according to claim 6 or 7, wherein the RNA synthesis inhibitor is a 3'-substituted nucleoside derivative represented by the following general formula.
(In the formula, B represents a nucleobase which may have a substituent, and Z represents an ethynyl group which may be substituted with a trialkylsilyl group.) The method according to claim 8, wherein the 3'-substituted nucleoside derivative is at least one compound selected from the group consisting of the following compounds.
1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorocytosine,
1- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
3- (3-C-ethynyl-β-D-ribofuranosyl) uracil,
1- (3-C-ethynyl-β-D-ribofuranosyl) -5-fluorouracil,
9- (3-C-ethynyl-β-D-ribofuranosyl) adenine,
9- (3-C-ethynyl-β-D-ribofuranosyl) guanine. The method according to claim 8, wherein the 3'-substituted nucleoside derivative is 1- (3-C-ethynyl-β-D-ribofuranosyl) cytosine represented by the following formula.
The method according to any one of claims 6 to 10, wherein a physical dose of proton beam is 95% or less when the sensitizer is not used. Dosage for the affected area of the sensitizer A method according to any one of claims 6 to 11 in the range of ^{2.0 mg / m 2 ~6.85 mg /} m 2. The method according to any one of claims 6 to 12, wherein the SOBP is in the range of 50 to 300 mm from the epidermis. The method according to any one of claims 6 to 13, wherein the affected area is a malignant tumor.