CN101524341B - Use of isoliquiritigenin in preparation of auxiliary therapeutic medicine for tumor radiation therapy - Google Patents
Use of isoliquiritigenin in preparation of auxiliary therapeutic medicine for tumor radiation therapy Download PDFInfo
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Abstract
The invention belongs to the technical field of medicine and in particular relates to a new use of isoliquiritigenin that is an isoflavone compound extracted from glycyrrhiza plants, in particular to the use in the preparation of an auxiliary therapeutic medicine for tumor radiation therapy. The isoliquiritigenin is used for the preparation of a medicine for alleviating untoward effects of malignant tumor radiation therapy and enhancing the treatment effect of the malignant tumor radiation therapy, thereby providing a new optional auxiliary therapeutic medicine for the malignant tumor radiation therapy.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of isoflavonoid that from glycyrrhiza genus, extracts---the new purposes of isoliquiritigenin, particularly it is as the application in the preparation auxiliary therapeutic medicine for tumor radiation therapy.
Background technology
Malignant tumor has become the first deadly disease of global population.Progress along with science, it is existing that the treating malignant tumor mode---operation, chemotherapy and radiotherapy etc. have been obtained rapid progress, and patient's survival rate progressively improves, but most of malignant tumor, especially malignant solid tumor still can't thoroughly be cured, and becomes the high main cause of mortality of malignant tumors.
Radiotherapy is one of basic means of oncotherapy, and its applicating history has exceeded a century.In all healing tumor patients, the relative contribution of operation is 49%, radiotherapy and be that the contribution degree of main Comprehensive Treatment is 40% with radiotherapy, chemotherapy and be that the contribution degree of main Comprehensive Treatment is 11% with chemotherapy.The same with chemotherapy, radiotherapy still is important palliative treatment means.According to the strict estimation of the data of evidence-based medicine EBM, 52% tumor patient can be accepted at least radiotherapy in its tumor therapeutic procedure.Conventional external exposure is inequality to office's control rate of all kinds of entity tumors, and the effective percentage of same histological type tumor radiotherapy is also inconsistent.Clinically it is mainly quickened factors such as propagation, overall tumor load and oxygenation status again owing to tumor cell after the inherent radioresistant of tumor cell, the radiation.
According to statistics, have 70% need accept radiotherapy in the malignant tumor patient approximately in the different phase of its treatment.The present conventional radiotherapy radiographic source that adopts roughly has three classes, and a class is for discharging α, β and gamma-ray various radiosiotope 60Co, the ray of radioactive sources such as 192Ir, 226Ra by decaying and producing; Second class is equipment such as the sigmatron that produces of normal pressure roentgenotherapia machine and all kinds of medical accelerator and high-power electron beam; The 3rd class is for producing the accelerator of HIB.The high-energy ray that wherein preceding two class radiographic sources produce energy line density (the linerar energy transfer that pass at the low that belong to more, LET) ray, the relative simple cheap of its equipment, technology maturation, existing long clinical practice history, and the HIB of the high LET ray of the 3rd class, the equipment that needs large-scale costliness, at present only be in the clinical research stage, but existing clinical research result shows that high LET HIB has clear superiority aspect the treatment tumor in country few in number.
In order better to overcome these intractable tumors, since nineteen eighty just there is the scholar to attempt, and obtained certain success chemotherapy and radiotherapy combined.Because the mechanism of action difference of chemicotherapy, thus have always two kinds of different theories in explanationization, put the obtained success of Comprehensive Treatment.First kind of theory is " space is collaborative ", i.e. radiotherapy acts on the part, and chemotherapy reduces metastasis.Second kind of theory is " radiation sensitization ", i.e. interaction between the chemoradiotherapy has produced collaborative Graft Versus Tumor, finally improved the office's control after the radiotherapy.By the research of nearly more than two decades, find that these two kinds of theories all have clinical research result's support, can find that their actual scope of application separately has distinct feature but anatomize.If tumor is to chemotherapy sensitivity (as lymphoma) especially, perhaps very good (is 90% as early-stage breast cancer lump excision+postoperation radiotherapy office control rate) controlled in office, and the effect of so sequential chemicotherapy can be very good, that is " space is collaborative " is the main cause of Comprehensive Treatment success.For most of other tumors, it but is the determiner that curative effect improves that the radiotherapy office control that " radiation sensitization " of chemotherapy effect brings improves, in the multiple treatment of solid tumors such as glioblastoma, tumor of head and neck, pulmonary carcinoma, the esophageal carcinoma, gastric cancer, colorectal cancer and anus cancer the same period chemicotherapy to compare the shown survival advantage of sequential chemicotherapy promptly be clear proof.
The survival advantage that the Comprehensive Treatment of radiotherapy and chemotherapy obtains is undisputed, but researcher is found curative effect that improves and the side reaction that obviously increases simultaneously and is arrived together: be example with the injury of lung, previously the probability of happening of conventional radiotheraphy only 0～20%, and present use along with the high-intensity therapeutic scheme, incidence rate can reach 45%～60%, and has the part patient therefore dead.Normal tissue injury has become the dose limitation factor, and has reduced adjusted survival rate of quality of life.The main cause that damage produces is that traditional chemotherapy and radiation all lacks the treatment specificity, has also killed the quick splitted normal cell of part when killing tumor cell.In view of this, searching out a kind of " efficient, low toxicity " malignant tumor radiotherapy adjuvant therapy medicaments becomes clinical urgent needs, so far, does not also occur alleviating the untoward reaction of radiotherapy clinically, strengthens the ideal medicament of radiotherapeutic effect simultaneously.
Isoliquiritigenin (2,4,4-trihydroxychalcone, isoliquiritigenin) be from glycyrrhiza genus (Glycyrrhiza) separate, the isoflavonoid of purification, it can pass through macroporous adsorbent resin technology and column chromatography technology separation and purification [Fu Yujie, Liu Xiaona, Hou Chunlian, etc. the research of macroporous adsorbent resin separation and purification isoliquiritigenin. ion exchange and absorption the 3rd phase of .2006]; Also can synthesize by total man's construction method [Southern Yangtze University. a kind of synthetic method of isoliquiritigenin. the patent No.: CN200410065383.7; Yang Li, Shen Fengjia. synthesizing of glycyrrhizin and isoliquiritigenin. Acta Pharmaceutica Sinica, 1994 11 phases].Plant research department, institute of materia medica, Chinese Academy of Sciences Shanghai is to the chemical constitution and the existing detailed narration [flavonoids compound identification handbook [M], Beijing: Science Press, 1981] of physicochemical property of isoliquiritigenin.The molecular formula of isoliquiritigenin is C15H1204, and structural formula is as follows:
Isoliquiritigenin
Studies show that, isoliquiritigenin has very strong pharmacologically active, to cerebral ischemia-reperfusion injury have protective effect [isoliquiritigenin is to the protective effect of mouse brain ischemia reperfusion injury. Wuhan University's journal (medicine) the 3rd phase of .2005], to cervical cancer cell [isoliquiritigenin is to the effect of human cervical carcinoma cell inhibition of proliferation. the 6th phase of Chinese J Pharmacol Toxicol .2005] and prostate gland cancer cell [isoliquiritigenin is to the inhibitory action of Human Prostate Cancer Cells in-vitro multiplication. clinical magazine of urology surgery .2007 o. 11th) propagation inhibited, induce stomach cancer cell [Apoptosis induced byisoliquiritigenin in human gastric cancer MGC-803 cells.Planta Med, 2001,67 (8): 754-757.] apoptosis, make cell cycle arrest in G2/M phase [Isoliquiritigenin inhibits the growth of prostate cancer.Eur Urol, 2003,43 (5): 580-586; Induction of cell cycle arrest and p21 (CIP1/WAF1) expression in human lung cancer cells by isoliquiritigenin.CancerLett; 2004; 207 (1): 27-35.], have arrhythmia [isoliquiritigenin antiarrhythmic effect research. the 5th phase of Pharmacology and Clinics of Chinese Materia Medica .1996], protect the liver [isoliquiritigenin is to the protective effect of rat acute chemical liver injury. the 7th phase of Chinese Hospitals pharmaceutical journal .2008] etc. effect.
Although isoliquiritigenin can suppress tumor cell proliferation, inducing apoptosis of tumour cell, itself antitumor activity is not as good as existing clinical antitumor drug, as paclitaxel, cisplatin etc., so isoliquiritigenin difficulty become clinical antitumor drug.We find, isoliquiritigenin is when the following concentration of 10 μ g/ml, and fail the kill tumor cell, but the inducing tumor cell reverse is the normal function cell, forfeiture continuation multiplication capacity [patent: isoliquiritigenin is as the application of cancer cell differentiation inducer. application number: 200810072917.7] and, certain tumor cell targeting is arranged.Isoliquiritigenin does not have report so far to the influence of tumour radiotherapy.
Summary of the invention
The objective of the invention is to avoid the deficiencies in the prior art that a kind of new purposes of isoliquiritigenin is provided, be that isoliquiritigenin alleviates the untoward reaction of malignant tumor radiotherapy as preparation, strengthen the application of the medicine of malignant tumor the effect of radiation therapy, thereby provide a kind of new alternative adjuvant therapy medicaments for the malignant tumor radiotherapy.
For achieving the above object, the technical scheme taked of the present invention is: provide isoliquiritigenin as the application in the medicine of the auxiliary x-ray bombardment treatment of preparation malignant tumor attenuation synergistic.
The present invention relates to isoliquiritigenin as the application in the medicine of the auxiliary radiation gamma treatment of preparation malignant tumor attenuation synergistic.
The invention still further relates to isoliquiritigenin as the application in the medicine of the auxiliary heavy ion irradiation treatment malignant tumor attenuation synergistic of preparation.
Pharmaceutical composition provided by the invention is according to clinical needs, add corresponding adjuvant, exist with dosage forms such as tablet, pill, granule, capsule, suspension, solution, syrup, injection, cream, ointment, gel, spray, chewing agent or patches.
Malignant tumor of the present invention (malignant tumours) is also referred to as cancer (Cancer), or vegetation (neoplasms), is the general name that a class can betide about more than 100 kinds of diseases at each position of body.World Health Organization (WHO) is defined as the undesired cell that can surpass its normal boundary growth rapidly with it, these cells can be attacked and be adjoined normal position and send out other organ---and this process is called transfer (metastasis), and transfer is the main cause [http://www.who.int] of cancer mortality.
Isoliquiritigenin of the present invention be from the Chinese medicine Radix Glycyrrhizae extraction separation obtain or manual type synthetic, can adopt any open source literature or patented method to extract preparation.
The invention has the beneficial effects as follows: isoliquiritigenin of the present invention adopts any suitable mode, with the radiotherapy use in conjunction in the patient, can alleviate because of local normal tissue injury symptom due to the radiotherapy, as tissue edema, inflammation, pain, hemopoietic function unusual (as leucocytes reduction), gland dysfunction, carcinogenic or the like multiple typical adverse effects symptom; And can obviously strengthen radiotherapy to the killing and wounding or inhibitory action of tumor, thus prolong patient's the disease free survival phase, improve patients ' life quality.
The specific embodiment
Below principle of the present invention and feature are described, institute gives an actual example and only is used to explain the present invention, is not to be used to limit scope of the present invention.
Embodiment 1 isoliquiritigenin is to the synergism and attenuation of x-ray bombardment tumor
1.1 experiment material
Isoliquiritigenin is available from Jiangxi book on Chinese herbal medicine work of nature Science and Technology Ltd., purity 99.8% (HPLC method mensuration).The Lewis lung cancer cell strain available from China typical culture collection center (Wuhan University preservation center), is inoculated in the subcutaneous preservation of going down to posterity of the right armpit of C57BL/6 mice.
1.2 experimental technique
Get the lotus tumor Mus of going down to posterity and take off cervical vertebra and put to death, be fixed on the plate.With iodine tincture and alcohol disinfecting animal skin, cut skin, select the tumor tissue that tumor growth is good, do not have necrosis or liquefaction, add physiological saline solution, make the cell suspension that contains about 3,000 ten thousand/ml with Potter-Elvehjem Tissue Grinders, in 120 above-mentioned tumor cell suspension 0.2ml/ of C57BL/6 mice right hind groin position subcutaneous vaccination only, inoculation position skin is earlier with iodine tincture and alcohol disinfecting.Inoculate back 10 days, select existing tumor tissue growth and major diameter mice greater than 1cm, be divided into 9 groups at random, every group 12, be respectively lotus tumor matched group, radiation alone group, cisplatin group, isoliquiritigenin 1mg/kg group, isoliquiritigenin 10mg/kg group, isoliquiritigenin 100mg/kg group, isoliquiritigenin 1mg/kg+ combination radiotherapy group, isoliquiritigenin 10mg/kg+ combination radiotherapy group, isoliquiritigenin 100mg/kg+ combination radiotherapy group.Grouping back radiotherapy is respectively organized mice and is shone (Philips company, Germany) with Stabilipan every day, exposure dose 2Gy, and irradiation back isoliquiritigenin is respectively organized mouse stomach and is given the corresponding dosage isoliquiritigenin, and all the other each group filling stomaches give the equal-volume distilled water.Once a day, continuous 5 days.Shone back 24 hours in last, the eye socket blood sampling, anticoagulant heparin takes off cervical vertebra and puts to death animal, strips tumor tissue and weighs, and calculates tumour inhibiting rate.
According to each group tumour inhibiting rate, [Yu Renjiang studies Shandong Traditional Chinese Medicine University's journal, 2003 etc., Ganderma lucidum mixture antitumor and efficacy enhancing and toxicity reducing effect for Hu Zhili, Wen Shougong press the Burgi correction formula; 27:466] the drug combination group is carried out the curative effect judgement.That is:
If q value is 0.85～1.15 for simple addition, q＞1.15 are enhancing, and q＜0.85 is an antagonism.
With reference to Schmid[Schmid W.The micronucleus test.In:Hollaender, A. (Eds.), Chemical Mutagens, Principles and Methods for Their Detection, Plenum Press, New York.1976; Pp.31.] scheme, adopt the acridine orange fluorescence developing observe [Hu Yongning still learns the skin of bamboo, and Liu Lannv is etc. the application of acridine orange fluorescence staining in micronucleus test. tumor .1985; 5 (02): 56-59] mouse Bone marrow cells micronucleus rate.Take off cervical vertebra and put to death mice, flush out medullary cell with 1% sodium citrate after separating the right side femur, piping and druming evenly the back centrifugal (1000g * 5min), supernatant discarded, cell mass with the remaining liq mixing after smear.Methanol is fixed.100 μ g/ml (in pH6.8 phosphate buffer) acridine orange dyeing 3min places pH6.8 phosphate buffer rinsing 3min, adds coverslip, in 1000 polychromatic erythrocytes of counting (PCEs) the micronucleus cell number is arranged down in 40 times of object lens.Calculate micronuclear rates, represent with permillage.After acridine orange dyeing, cellular morphology is intact, and nucleated cell is yellow green, and PCE shows salmon pink fluorescence, and contained micronucleus is circular, sends yellow-green fluorescence, is easy to differentiate; Mature erythrocyte does not have fluorescence, is shown as shadow.
Mice peripheral blood leucocyte DNA damage is measured and is adopted alkaline unicellular electrophoretic analysis (Singlecell micro gel electrophoresis (SCGE), or title comet assay).This is a kind of quick, easy and sensitive method [McKelvey-Martin VJ that measures single DNA in mammalian cells damage, Green MH, Schmezer P, Pool-Zobel BL, De Meo MP, Collins A.The single cell gel electrophoresis assay (comet assay): a European review.Mutat Res.1993; 288 (1): 47-63.].[Franke SI such as Franke are pressed in experiment, Pra D, da Silva J, et al.Possible repair action of VitaminCon DNA damage induced by methyl methanesulfonate, cyclophosphamide, FeS04 and CuS04 in mouse blood cells in vivo.Mutat Res.2005; 583 (1): 75-84.] scheme is carried out.Particular content is as follows: (normal melting agarose NMA), solidifies it under 4 ℃ to be coated with the normal fusing point agarose of one deck 0.5% on the microscope slide of slightly polishing.Mice heparin anticoagulation cirumferential blood 7 μ l and 93 μ l hang down the melting point agarose, and (LMA 0.75%inPBS) at 37 ℃ of mix homogeneously, drops on the microscope slide.In 4 ℃ of placement a period of times it is solidified after adding coverslip.Remove coverslip, add one deck LMA again and add coverslip, carefully remove coverslip after solidifying.With embedding the microscope slide of cell carefully insert cell pyrolysis liquid and (include 1% sodium lauroyl sarcosine, 2.5mol/L NaCl, 100mmol/L EDTA-Na2 and 10mmol/L Tris-HCl, pH10, face with preceding adding 10%DMSO and 1%Triton X-100) in, placed about 1 hour down in 4 ℃.Take out microscope slide and place the horizontal strip electrophoresis groove, add electrophoretic buffer (including 1mmol/L EDTA-Na2 and 300mmol/L NaOH), place after 20 minutes, adjust the buffer liquid level and make voltage reach 25V, electric current reaches 300mA, electrophoresis 20min.Electrophoresis finishes, and (0.4mol/L Tris-HCl pH7.5), placed 5 minutes, and the neutralizer that renews was again placed 5 minutes equally, to get rid of the interference of alkali to ethidium bromide staining carefully microscope slide to be dipped in neutralizer.Take out the back with 20 μ g/ml ethidium bromide stainings, adds coverslip, and under fluorescence microscope, observe as early as possible and take pictures.Excitation wavelength is 515-560nm under the fluorescence microscope, and the optical filter wavelength is 590nm.The DNA of damaging cells is not circular, and the cell DNA that sustains damage has comet sample tail.Select 100 WBCs in every mice photo at random for use, utilize CASP software that the DNA damage situation is analyzed.Olive tail moment (OTM) is proportionate with the DNA damage situation among this software analysis result, therefore adopt OTM as DNA damage evaluation index [Konca K, Lankoff A, Banasik A, et al.A cross-platform public domain PC image-analysis program forthe comet assay.Mutat Res.2003; 534 (1-2): 15-20.].
The mice peripheral white blood cell adopts the full-automatic blood-counter system of three classification to measure.
Organize a statistical analysis with the t check.
1.3 experimental result
The result shows (table 1), x-ray bombardment can cause the damage of mice peripheral blood DNA, the bone marrow micronuclear rates obviously raises, the peripheral white blood cell amount obviously reduces, isoliquiritigenin itself is to not obviously influence of These parameters, but but 1-100mg/kg isoliquiritigenin dose dependent ground suppresses the peripheral blood DNA damage of caused by radiation, the increase of bone marrow micronuclear rates and the decline of peripheral white blood cell amount.Show that isoliquiritigenin has obvious protective effect to body normal tissue injury due to the x-ray bombardment.
The tumor growth situation shows (table 2), and the 1-100mg/kg isoliquiritigenin is not seen obvious inhibitory action to tumor growth in vivo, and effect is not as good as traditional chemotherapeutic cisplatin.Radiation alone can reach 48.6% to inhibition rate of tumor growth, and isoliquiritigenin can obviously strengthen the curative effect of radiotherapy, 1,10 and the 100mg/kg isoliquiritigenin can improve radiotherapy respectively the suppression ratio of tumor is reached 58.4%, 68.1% and 70.0.According to the Jin Shi formula calculate both couplings collaborative situation [Ke Dan is as. the extracorporeal anti-tumor function of curcumin and amycin drug combination for Lin Xi, Xu Jianhua. Chinese Pharmacological circular .2000; 16 (5): 522-525], show that 1mg/kg isoliquiritigenin and radiotherapy share and have summation action, 10 and 100mg/kg isoliquiritigenin and radiotherapy share and have obvious synergism.Radiotherapy has the notable synergistic effect to X ray to the result shows isoliquiritigenin.
Table 1 isoliquiritigenin causes the Attenuation of mice normal tissue injury to x-ray bombardment
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: *, P＜0.05; *, P＜0.01.
Table 2 isoliquiritigenin suppresses the potentiation of Lewis lung cancer growth to X ray
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: *, P＜0.05; *, P＜0.01.
Embodiment 2: the efficacy enhancing and toxicity reducing effect of isoliquiritigenin counterweight ion exposure tumor
2.1 experiment material: isoliquiritigenin, available from Jiangxi book on Chinese herbal medicine work of nature Science and Technology Ltd., purity 99.8% (HPLC method mensuration).The strain of U14 cervical cancer cell available from institute of materia medica, Chinese Academy of Medical Sciences Beijing, is inoculated in the preservation of going down to posterity of Kunming mouse abdominal cavity.
2.2 experimental technique:
Get the mice of going down to posterity of the U14 cervical cancer ascites of inoculating 7 days, get milky ascites with asepsis injector behind the sterilization abdominal part leather belly, add the injection normal saline dilution of 5 times of volumes.120 of mices, behind right back the groin position skin of sterilizing, the above-mentioned tumor cell suspension 0.2ml of subcutaneous vaccination.Connect after the tumor the 10th, choose tumor enclosed mass major diameter greater than the 1cm mice, be divided into 9 groups at random, every group 12, be respectively lotus tumor matched group, radiation alone group, cisplatin group, isoliquiritigenin 1mg/kg group, isoliquiritigenin 10mg/kg group, isoliquiritigenin 100mg/kg group, isoliquiritigenin 1mg/kg+ combination radiotherapy group, isoliquiritigenin 10+ combination radiotherapy group, isoliquiritigenin 100mg/kg+ combination radiotherapy group.The radiotherapy of grouping back is respectively organized and is produced with the Lanzhou heavy ion avcceleration (HIRFL) of The CAS Institute of Modern Physics mice every day
12C
6+The ion irradiation tumor locus, drawing energy is 80MeV/u, has adopted the range manipulator to obtain spread-out Bragg peak.Be 48h the blanking time of each irradiation, exposure dose 4Gy, continuous irradiation 3 times.Each irradiation back isoliquiritigenin is respectively organized mouse stomach and is given the corresponding dosage isoliquiritigenin, and all the other each groups are irritated stomach and given the equal-volume distilled water.Shone back 24 hours in last, the eye socket blood sampling, anticoagulant heparin takes off cervical vertebra and puts to death animal, strips tumor tissue and weighs, and calculates tumour inhibiting rate, and the aseptic spleen of getting is measured the splenocyte conversion capability.
Mouse spleen carefully grinds with piston on 100 order stainless (steel) wires, after the ice Hanks flushing, collects filterable Hanks liquid to the 15ml centrifuge tube.1000rpm * 10min abandons supernatant, adds behind the 0.83% ammonium chloride 1ml piping and druming mixing 30s rapidly, splitting erythrocyte, add contain 1% hyclone ice Hanks liquid 10ml centrifuge washing once, again with the ice Hanks liquid 10ml washing that contains 1% hyclone 2 times.Adjusting splenocyte concentration with 1640 complete culture solutions that contain 10% hyclone is 1 * 106 cell/ml.Every hole adds 100 μ l splenocyte suspensions in 96 orifice plates, and every mouse boosting cell adds 6 holes, and wherein 3 holes add the complete culture solution 100 μ l contain 10 μ g/ml ConA and make test hole, add the complete culture solution 100 μ l that do not contain ConA in 3 holes in addition and compare the hole.Add good back in micro oscillator vibration mixing.Culture plate is put 37 ℃, cultivated 68 hours in the 5%CO2 incubator.The MTT solution that adds 10 μ l 5mg/ml in every hole continues to cultivate 4 hours.Discard culture fluid in the culture plate, every hole adds DMSO 150 μ l, and the mixing that fully vibrates is with the crystallization of Rong Xie Jia Za.Microplate reader is measured 570nm light absorption, 630nm wavelength for referencial use.Calculate the transformation index of every mouse spleen lymphocyte according to each hole absorbance:
The damage of mice peripheral blood DNA is measured with reference to embodiment 1.
The mouse bone marrow cells micronucleus test is with reference to embodiment 1.
Organize a statistical analysis with the t check.
2.3 experimental result
Compare with the low LET roentgenotherapia tumor of routine, high LET HIB irradiation treatment tumor is that proposition is later, but has been applied to clinical treatment measure.Heavy ion is different with conventional ray, and it is a heavy charged particle, therefore has some unique physical propertys, and its low LET ray of clinical treatment that is used for tumor has clear superiority.Can be summed up as: 1. the physical dosage depth profile is better than X ray, gamma-ray photon, neutron, at the range end Bragg peak (energy deposition concentration zones) is arranged, therefore, can utilize the heavy ion energy loss to concentrate on the characteristic of range end, when oncotherapy, can make ion stop at the appointed part of tumor by the energy of regulating them, reach maximum lethal effect tumor, and the normal structure of passing at tumor front ion.The damage that is subjected to is less, as for the normal structure of tumor back, because ion has been parked in tumor locus, so be impregnable; 2. low at target area relative biological effect height, oxygen enhancement ratio, better than proton, photon; 3. range straggling and transverse scattering are little, and be better than proton; 4. utilize positron emission transaxial tomography (PET) technology to monitor in real time, this is the exclusive characteristics of high-energy heavy ion; 5. because the charging property of heavy ion has determined them can adopt magnetic scanning technology guiding line that tumor is carried out accurately " conformal therapy "; 6. sublethal damage is repaired little; Phase when 7. radiosensitivity does not rely on cell cycle.Aspect biological effect, its relative biological effect (RBE) height during heavy particle therapy is bigger than low LET ray to the lethality of tumor hypoxia cell.The cell growth cycle relies on less.Aspect physics, HIB is by medium the time, speed can reduce gradually and lose its energy and form tangible bragg peak (Bragg), the depth at peak and width all can be regulated to adapt to the different focus of size shape by special device, and the position that heavy ion arrives in vivo also is convenient to observe and is determined.These features, for heavy ion the application of treatment aspect the tumor provide the condition more more superior than traditional ray [Luo Guanghui, Li Wenjian, Su Xinggui. the comparison of heavy ion and other radiotherapy tumors. Guangdong medical science .2007; 28 (1): 159-161].
Although the conventional low LET roentgenization treatment tumor of heavy ion irradiation has a clear superiority in, but current difficulty is accomplished accurate conform irradiation, and ion beam passes the secondary ray that forms in body normal structure and the irradiation process and can damage the body normal structure unavoidably during in addition for body deep tumor irradiated tissue.Experimental result shows (table 3),
12C
6+Ion beam irradiation also can cause serious peripheral blood DNA damage and bone marrow micronucleus and form, and also can cause the splenocyte conversion capability and reduce.But 1-100mg/kg isoliquiritigenin dose dependent ground suppresses the peripheral blood DNA damage of caused by radiation, the increase of bone marrow micronuclear rates and the decline of splenocyte conversion capability.Show that the body normal tissue injury has obvious protective effect due to the isoliquiritigenin counterweight ion beam irradiation.
The tumor growth situation shows (table 4), and itself only has the dose-dependent inhibition effect to tumor growth the 1-100mg/kg isoliquiritigenin, but effect is not as good as radiation alone or cyclophosphamide curative effect.
12C
6+Radiation alone can reach 53.8% to inhibition rate of tumor growth, and isoliquiritigenin can obviously strengthen the curative effect of radiotherapy, 1,10 and the 100mg/kg isoliquiritigenin can improve radiotherapy respectively the suppression ratio of tumor is reached 61.8%, 74.4% and 79.1%.According to the Jin Shi formula calculate both couplings collaborative situation [Ke Dan is as. the extracorporeal anti-tumor function of curcumin and amycin drug combination for Lin Xi, Xu Jianhua. Chinese Pharmacological circular .2000; 16 (5): 522-525], show that 1mg/kg isoliquiritigenin and HIB radiotherapy share and have summation action, 10-100mg/kg isoliquiritigenin and HIB radiotherapy are share has obvious synergism.Radiotherapy has the notable synergistic effect to HIB to the result shows isoliquiritigenin.
Table 3 isoliquiritigenin is right
12C
6+Irradiation causes the Attenuation of mice normal tissue injury
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: *, P＜0.05; *, P＜0.01.
Table 4 isoliquiritigenin is right
12C
6+Bundle suppresses the potentiation of U14 cervical cancer growth
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: *, P＜0.05; *, P＜0.01.
Embodiment 3: isoliquiritigenin is to the potentiation of gamma-rays radiotherapy
3.1 experiment material
Isoliquiritigenin is available from Jiangxi book on Chinese herbal medicine work of nature Science and Technology Ltd., purity 99.8% (HPLC method mensuration).The H22 hepatoma cell strain available from institute of materia medica, Chinese Academy of Medical Sciences Beijing, is inoculated in the preservation of going down to posterity of Kunming mouse abdominal cavity.
3.2 experimental technique:
Get the mice of going down to posterity of the H22 hepatic ascites of inoculating 7 days, get milky ascites with asepsis injector behind the sterilization abdominal part leather belly, add the injection normal saline dilution of 5 times of volumes.120 of mices, behind right back the groin position skin of sterilizing, the above-mentioned tumor cell suspension 0.2ml of subcutaneous vaccination.Connect after the tumor the 10th, choose tumor enclosed mass major diameter greater than the 1cm mice, be divided into 9 groups at random, every group 12, be respectively lotus tumor matched group, radiation alone group, paclitaxel group, isoliquiritigenin 1mg/kg group, isoliquiritigenin 10mg/kg group, isoliquiritigenin 100mg/kg group, isoliquiritigenin 1mg/kg+ combination radiotherapy group, isoliquiritigenin 10+ combination radiotherapy group, isoliquiritigenin 100mg/kg+ combination radiotherapy group.The radiotherapy of grouping back is respectively organized mice every day with 60Co gamma-ray irradiation mice right hind tumor locus, each exposure dose 2Gy, and Continuous irradiation is 6 days once a day.Each irradiation back isoliquiritigenin is respectively organized mouse stomach and is given the corresponding dosage isoliquiritigenin, and all the other each groups are irritated stomach and given the equal-volume distilled water.Shone back 24 hours in last, the eye socket blood sampling, anticoagulant heparin takes off cervical vertebra and puts to death animal, strips tumor tissue and weighs, and calculates tumour inhibiting rate.
Mice peripheral blood DNA damage mensuration, mouse bone marrow cells micronucleus test and peripheral blood leucocyte method of counting are with embodiment 1.
Organize a statistical analysis with the t check.
3.3 experimental result
Radiation gamma also is one of conventional means of tumor radiotherapy, but there are some researches show, radiation itself also can cause tumor generation [Li Bailong waits the .60Co radiation gamma to bring out the mice malignant tumor for Han Ling, Cai Jianming. the journal .2003 of The 2nd Army Medical College; 24 (7): 745-748].Radiation induced tumor be meant accept to take place after the ionizing radiation, suffered this irradiation has the to a certain degree malignant tumor of etiology contact, is one of important after effect far away behind the roentgenization, it comprises leukemia, osteosarcoma and lymphosarcoma etc., belongs to stochastic effect.Zoopery and human epidemiology's investigation all prove ionizing radiation energy induced tumor, but can't determine at present whether ionizing radiation may cause certain specific tumor.Mortality rate data according to average life research is established, and the cancer of excess danger is leukemia (removing chronic lymphocytic leukemia), women with breast cancer, bladder cancer, colon cancer, hepatocarcinoma, the esophageal carcinoma, ovarian cancer, multiple myeloma and gastric cancer etc. on statistical significance.
Fracture of caused by ionizing radiation cell chromosome and DNA damage are one of immediate causes of radiation carcinogen, and alkaline comet electrophoresis experiment and bone marrow micronucleus test can be used as the quantitative target of caused by ionizing radiation cell DNA double-strand break and chromosome damage.Experimental result shows (table 5), and radiation gamma can cause serious peripheral blood DNA damage and bone marrow micronucleus and form, and causes the hemopoietic function of bone marrow obstacle simultaneously, and peripheral blood leucocyte reduces.Peripheral blood DNA damage, the bone marrow micronuclear rates of caused by radiation increase and the peripheral white blood cell order reduces but 1-100mg/kg isoliquiritigenin dose dependent ground suppresses.Show that isoliquiritigenin has obvious protective effect to body normal tissue injury due to the radiation gamma, to gamma-ray carcinogenic certain protective action that also has.
The tumor growth situation shows (table 6), and itself only has slight inhibitory action to tumor growth the 1-100mg/kg isoliquiritigenin, and 100mg/kg isoliquiritigenin tumour inhibiting rate is 23.2% (P＜0.05), not as good as paclitaxel curative effect (tumour inhibiting rate 54.7%).The gamma-rays radiation alone can reach 38.4% to inhibition rate of tumor growth, and isoliquiritigenin can obviously strengthen the curative effect of radiotherapy, 1,10 and the 100mg/kg isoliquiritigenin can improve radiotherapy respectively the suppression ratio of tumor is reached 55.4%, 63.0% and 71.6%.Calculate the collaborative situation of both couplings according to the Jin Shi formula, show that 1-100mg/kg isoliquiritigenin and gamma-rays radiotherapy share and all have obvious synergism.Radiotherapy has the notable synergistic effect to gamma-rays to the result shows isoliquiritigenin.
Table 5 isoliquiritigenin is to the attenuation influence of radiation gamma lotus H22 liver cancer mouse normal structure
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: * *, P＜0.01.
Table 6 isoliquiritigenin suppresses the potentiation of H22 liver cancer growth to gamma-rays
Compare with lotus tumor matched group:
##, P＜0.01.Compare with the radiation alone group: *, P＜0.05; *, P＜0.01.
Above institute there are some researches prove, but isoliquiritigenin dose dependent ground alleviates caused by ionizing radiation body normal structure and cells injury such as X ray, gamma-rays and HIB, and the tumor-inhibiting action to above-mentioned ray has the notable synergistic effect simultaneously.These presentation of results isoliquiritigenins can be used as antiradiation drug, in order to prevent or to treat the damage of various ionizing radiation to normal body; In addition, isoliquiritigenin can also can strengthen the curative effect of various radiotherapy measures to various tumors as the synergism medicine of tumour radiotherapy.
The above only is preferred embodiment of the present invention, and is in order to restriction the present invention, within the spirit and principles in the present invention not all, any modification of being done, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. the application of isoliquiritigenin in the medicine of the auxiliary x-ray bombardment treatment of preparation malignant tumor attenuation synergistic.
2. the application of isoliquiritigenin in the medicine of the auxiliary radiation gamma treatment of preparation malignant tumor attenuation synergistic.
3. the application of isoliquiritigenin in the medicine of the auxiliary heavy ion irradiation treatment malignant tumor attenuation synergistic of preparation.
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