CN101579328A - Application of combretastatin - Google Patents

Abstract

The invention discloses the application of a compound shown as a formula I or a formula II. The application is characterized in that the compound is used for preparing medicine for destroying tumor vessels.

Description

The purposes of combretastatin

Technical field

The present invention relates to drug world, relate in particular to the new purposes of combretastatin.

Background technology

People just find before more than 100 year, tumor tissues is more normally organized and is rich in blood vessel, but it is to provide nutrition by the blood vessel that has existed that people are arguing tumor always, still provide nutrition by new vessels, and generally believing that this vascular reaction is a kind of inflammatory reaction, is not that tumor growth institute is essential.Folkman proposed angiogenesis theory (AngiogenesisTheory) the earliest in 1971, courageously make following imagination: the living necessities of tumor rely on the generation of new vessels, tumor can initiatively stimulate the generation of this blood vessel, tumor can be secreted certain material and be lured that blood vessel grows towards them into, and can grow branch (Folkman J.Tumorangiogenesis[J] .Adv Cancer Res, 1985,43:175-203).But this at that time viewpoint is not accepted by people.Foundation up to capillary endothelial cell culture technique in 1979, nineteen eighty-two first angiogenesis inhibitor discovery, the finishing of a series of activities such as the proteic purification of first angiogenic activity in 1984 (Folkman J.What is the evidence that tumors are angiogenesisdependent[J] .J Natl cancer Inst, 1990,82 (1): 4-6.), this viewpoint is supported by more and more evidences, and is made this field become the focus of tumor research and the New Policy of oncotherapy.

Growth of tumor has two visibly different stages, and promptly changing into from avascular slow growth stage has the fast breeding of the blood vessel stage, and angiogenesis makes tumor can obtain enough nutrient substance, is the key link of facilitating above-mentioned transformation.If there is not angiogenesis, the growth of primary tumo(u)r can not surpass 1-2mm ³It is the main cause of oncotherapy failure that tumor invasion shifts.In the rapid process of multistep of tumor generation Invasion and Metastasis, in the eventually last stage of the initial sum of neoplasm metastasis, angiogenesis is all being brought into play important effect.Angiogenesis with tumor is a target spot, and the exploitation angiogenesis inhibitor can make the therapeutic effect of solid tumor obtain bigger raising.

Chemotherapeutics almost comprises that to the cell of all quick division growths in the body cancerous cell produces inhibition or toxic action, and promptly they lack the specificity of anticancer cell proliferation.In anticancer cell proliferation, quick splitted cell in medullary cell, gastrointestinal mucosa epithelial cell and the hetero-organization organ thereof there is very big toxic and side effects.Tumor is easy to chemotherapeutics is developed immunity to drugs in addition, reason is because unstability, the multiformity of cancerous cell kind and the high mutation rate of gene of cancerous cell gene, make that the chances of survival of the tumor patient that focus has shifted is little, these cancer therapy drugs are difficult to overcome to toxic and side effects and the drug resistance effect that normal cell produces.

Combretum Racemosum (Combretastaceae) plant is that a class is distributed in the torrid zone and semi-tropical shrub and trees, has crucial medical application and is worth.There are 25 kinds in the plant that known Caulis Hiptages benghalensis (Combretum) belongs to.They are used to treat leprosy and cancer etc. in Africa and India.At the end of the seventies, find that this kind of plant has very high inhibitory action to mice P388 leukemic lymphoblastoid cell in the wide sieve in American National cancer research place.The eighties, this Study on plants has been caused extensive interest.This period, the ICR chief of U.S. University of Arizona, the special George professor of chemist's skin (G.Robert Pettit) and four colleagues are to extract Combretastatins the South Africa seeds of " Combretum caffrum " from formal name used at school, " once accorded with as the incantation of repulsing the enemy " before this tree by the Zulus, the skin special education is awarded at " Canadian chemical periodical " and is so write, and the crust of tree root has anticancer effect really.Not only have later on a large amount of highly active chemical compounds separated, identify, and its pharmacological mechanism and structural modification work are also being deepened continuously.Carry out the work of this respect at first by Pi Te group.The combretum platymiscium is furtherd investigate the phenanthrene of a series of active anticancers of purifying out, the derivant of stilbene and dibenzyl benzene.Wherein CombretastatinA-1 and A-4 (being abbreviated as CA-1 and CA-4) are so far, the strongest tubulin agglutination inhibitor (Pettit G R, Singh S B, Can.J.Chem. (1987) 652390-2396) known in this compounds.This low dose of compounds can also be used as neovascularization inhibitor.So-called neovascularization inhibitor is the generation that suppresses blood vessel, but also medicine is not available targetedly for the tumor vessel that has grown up to.

Therefore, this area presses for provides a kind of medicine that the tumor vessel that has generated is had destruction.

Summary of the invention

The present invention aims to provide the application of chemical compound in the medicine of preparation destruction human tumor blood vessel suc as formula I or formula II, particularly relies on the tumor that blood vessel provides oxygen and nutrient.

Among the present invention, provide a kind of purposes of the chemical compound suc as formula I or formula II, described chemical compound is used as or is used for preparation and destroys tumor vascular medicine:

In another preference, described chemical compound is used as or is used to prepare the medicine that destroys tumor vascular endotheliocyte.

In another preference, described tumor is to rely on the tumor that blood vessel provides oxygen and nutrient.

In another preference, described tumor comprises hepatocarcinoma, gastric cancer, melanoma, breast carcinoma, nonsmall-cell lung cancer, colon cancer, small cell lung cancer, ovarian cancer, glioma, carcinoma of prostate, lymphoma and osteosarcoma; Preferred gastric cancer, lymphoma or osteosarcoma.

In another preference, described medicine contains:

(a) the 20-250 weight portion is suc as formula the chemical compound of I or formula II; With

(b) the pharmaceutically acceptable carrier of 10-1000 weight portion;

Wherein the weight of (a)+(b) accounts for the 50-100w/w% of medicine gross weight.

In another preference, described medicine contains:

(a) the 30-200 weight portion is suc as formula the chemical compound of I or formula II; With

(b) the pharmaceutically acceptable carrier of 20-900 weight portion.

In another preference, described medicine is selected from following dosage form: freeze dried powder, granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture or suspension.

In view of the above, the invention provides a kind of medicine that the tumor vessel that has generated is had destruction is provided.

Description of drawings

Fig. 1 has shown that the combretastatin of various dose induces the situation of human colon carcinoma Ls174t neoplasm necrosis.

Fig. 2 is H﹠amp; E (4 times) collection of illustrative plates that dyes has shown that combretastatin induces the situation of human colon carcinoma Ls174t neoplasm necrosis; Wherein A is a matched group, and B is a CA4P50mg/kg body weight group, and C is a vinorelbine 10mg/kg body weight group.

Fig. 3 has shown that combretastatin suppresses the situation of Human umbilical vein endothelial cells propagation.

Fig. 4 is living cells microphotograph (10 times), has shown that combretastatin suppresses the situation of Human umbilical vein endothelial cells propagation; Wherein A is contrast, and B is the combretastatin of 0.01 μ M.

Fig. 5 has shown the situation of tumor tissues frozen section Hoechst33342 dyeing (10 times) after the combretastatin administration; Wherein A is contrast, and B is that combretastatin was handled 1 hour, and C is that combretastatin was handled 6 hours, and D is that combretastatin was handled 24 hours.

The specific embodiment

The inventor is surprised to find that through extensive and deep research, has the tumor vascular effect of destruction suc as formula the chemical compound of I or formula II, thereby makes tumor death.

As used herein, " combretastatin " is meant the disodic alkaliine (being abbreviated as CA4P) of CombretastatinA-4 (CA-4 or CA4), and its structure is suc as formula shown in the II:

Compound shown by formula I (CA4) is the combretastatin free acid:

In the present invention, described destruction tumor vessel is meant and reduces tumor tissues function vascular bed volume, be preferably and suppress tumor vessel propagation, and more preferably be that tumor vascular endotheliocyte is had destruction.Thereby described destruction for tumor vascular endotheliocyte comprises inhibition of endothelial cell proliferation, makes the endotheliocyte distortion, makes the endotheliocytic swelling artery-clogging.

In the present invention, contain formula I or the formula II chemical compound and the pharmaceutically acceptable carrier for the treatment of effective dose in the described medicine that suppresses tumor-blood-vessel growth; Wherein treat the formula I of effective dose or the 0.1-99% (w/w) that formula II chemical compound accounts for the medicine gross weight, be preferably 2-80% (w/w).

The meridional I chemical compound of the tumor cell of In vitro culture (CA-4) was handled after 72 hours, used MTT or SRB method and estimated the inhibitory action of CA4 to tumor proliferation.CA4 all has the obvious suppression effect to the tumor cell proliferation of multiple In vitro culture, its IC ₅₀Be 3.98 * 10 ^-3-1.89 μ M are stronger relatively to the effect of gastric cancer, lymphoma, osteosarcoma and endotheliocyte.Summary sees Table 1.

Table 1 combretastatin and vinorelbine compare the cytotoxicity of the tumor cell of In vitro culture

Combretastatin anti-tumor in vivo curative effect shows: combretastatin all has the obvious suppression effect to multiple mouse tumor and the growth of people's tumor Nude Mice, and induced tumor is organized downright bad widely; The prompting combretastatin is that a treatment relies on blood vessel oxygen and nutrient tumor, certain, the broad-spectrum antitumor drug of curative effect are provided.Concrete outcome sees Table 2.

Table 2 combretastatin anti-tumor in vivo curative effect is summed up

Wherein the account form of %T/C or %TGI is seen the evaluation criterion among the embodiment 1.

Combretastatin is to the inhibitory action of the tumor cell especially vascular endothelial cell proliferation nanomole level of being everlasting; Clinical pharmacokinetic studies is found CA4P18-60mg/m ²Cmax during administration is 8.4-39.6 μ M/L, and AUC is 2.54-10.58 (μ M.h) (Dowlati A, et al Cancer Res 2002; 62:3408-3416), the antitumor action that can set up enough blood drug level performance combretastatins in the body is described.Clinical using dosage is 40-120mg/m every day ², the accumulated dose in treatment in seven days is no more than 360mg/m ²Continuous three weeks are a course of treatment.

Medicine of the present invention can multiple dosage form exist.Described dosage form can be the form intravenous injection or the oral administered dosage form of freeze dried powder, granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture, suspension, solution.

For intravenous administration, can use freeze dried powder, with normal saline or glucose solution wiring solution-forming, carry out venous transfusion.

For oral administration, can use tablet, lozenge, capsule, pill, powder, granule, paste, suspensoid, Emulsion or solution.

In preference, chemical compound of the present invention can be by oral and intravenous route administration.Solid-state carrier comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline Cellulose, sucrose and kaolin, and liquid carrier comprises: sterilized water, Polyethylene Glycol, mannitol, nonionic surfactant and edible oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen and Oleum sesami), as long as be fit to the characteristic of active component and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, for example flavoring agent, pigment, antiseptic and antioxidant such as vitamin E, vitamin C, BHT and BHA.

As used herein, intravenous injection comprises peritoneal injection and drip transfusion, uses freeze dried powder, the solution that is made into normal saline or glucose solution.Wherein freeze dried powder is made by this area conventional method.

The chemical compound of formula I of the present invention or formula II is mixed with oral formulations, comprises tablet, capsule.This dosage form can mix with active component and at least a additive, these additives comprise excipient, binding agent, disintegrating agent, lubricant, coloring agent, correctives etc., and formed mixture is made dosage forms such as powder, granule, tablet, coated tablet, pill, capsule.Excipient comprises lactose, corn starch, saccharide, glucose, sorbitol, one or more in the crystalline cellulose.Binding agent comprises polyvinyl alcohol, methylcellulose, ethyl cellulose, Radix Acaciae senegalis, tragacanth gum, gelatin, lac, hydroxypropyl cellulose, hydroxypropyl starch, one or more in the polyvinylpyrrolidone.Disintegrating agent comprises starch, agar, gel powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, cyclodextrin, one or more in the pectin.Lubricant comprises magnesium stearate, Talcum, Polyethylene Glycol, Silicon stone, one or more in the hardened vegetable oils.Coloring agent comprises the pigment that allows to be added in the medicine.Correctives comprises cocoa powder, menthol, Oleum menthae, refining borneol, and Cortex Cinnamomi.If desired, these tablets and granule can be used coatings such as sucrose, gelatin.General these dosage forms can contain other additive, comprise inert diluent, antiseptic such as p-hydroxybenzoic acid esters, sorbic acid, antioxidant such as vitamin C, alpha-tocopherol and cysteine, distintegrant, binding agent, thickening agent, buffer, sweeting agent, flavoring agent and spice.Tablet and pill also can be coated with casing.Oral liquid dosage form comprises pharmaceutically useful Emulsion, syrup, tincture, suspension and solution, can contain inert diluent commonly used, as water.

The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that this case description is disclosed can with any composition forms and usefulness, each feature that is disclosed in the description can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, and the feature that is disclosed only is the general example of equalization or similar features.

Major advantage of the present invention is:

1, find that combretastatin has the tumor vascular effect of destruction in the body, find that combretastatin can obviously suppress the growth of human colon carcinoma Nude Mice, its antitumor action may be by reducing the tumor tissues blood flow, causing due to the tumor tissue necrosis;

2, the clinical dosage of combretastatin as tumor vessel destruction medicine proposed;

3, find that combretastatin has obvious suppression and destruction to Human umbilical vein endothelial cells (HUVEC) propagation;

4, find that combretastatin can reduce the tumor tissues blood flow rapidly, significantly in zoopery, cause tangible tumor tissue necrosis.

Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber by weight.

Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.

Embodiment 1

Combretastatin is to the curative effect of human colon carcinoma Ls174t Nude Mice

Cell culture: In vitro culture human colon cancer cell Ls-174t (available from the Shanghai medicine the mouse entity tumor), make cell be in exponential phase always.

Transplant: it is subcutaneous in nude mouse to get the cell inoculation for preparing, and goes down to posterity 2-3 time after waiting into tumor.

Inoculation: under aseptic condition, tumor mass is inoculated in animal one side oxter.

Grouping and dosage setting: Nude Mice vernier caliper measurement diameter, treat that tumor growth is to 100-300mm ³After, with the animal random packet.

Route of administration and time: select for use to have 80-200mm ³The nude mouse random packet of size tumor, administration behind the survey tumor volume.

With intravenous administration, 12.5mg/kg; 25.0mg/kg; 50mg/kg, d1,3,5,7,9,11 totally 6 times; Vinorelbine 10mg/kg, d1, d6, totally 2 times.Survey the tumor volume weekly 2-3 time, claim Mus heavy, record data.The 10th day, put to death mice, dissect and get tumor tissue, after the formalin fixed, carry out histopathologic examination.

Evaluation criterion:

Gross tumor volume (V) computing formula is: V=1/2 * a * b ²

Wherein a, b represent length and width respectively.

(relative tumor volume, RTV), formula is: RTV=V to calculate relative tumour volume according to measurement result _t/ V ₀

V wherein ₀(d0) measured gross tumor volume during for minute cage administration; V _tGross tumor volume during for each the measurement.

The anti-tumor activity index is T/C (%), and formula is:

T/C(％)＝T _RTV/C _RTV×100

T wherein _RTV: treatment group RTV; C _RTV: negative control RTV (with nonuser group as negative control)

Weight method is calculated the tumour inhibiting rate formula:

Tumour inhibiting rate (the %)=heavy x100% of (the average tumor of the average tumor weight-medication of matched group group is heavy)/average tumor of matched group

Tissue pathological slice is used routine paraffin wax section, H﹠amp; E dyeing under the low power optical microscope, is calculated necrosis area.Adopt double-blind method.

Table 3 intravenous injection combretastatin is to the experimental therapy effect (the gross tumor volume method is calculated T/C%) of human colon carcinoma Ls174t Nude Mice

Group	Dosage (mg/kg)	Number of animals	Go body weight (gram) after the tumor	TV x±SD	RTV x±SD	T/C(％)
									d0 dn	d0 dn	d0 dn
Contrast		12 12	21.5 20.6	171±32 880±285	5.26±1.6
							Combretastatin	12.5	6 6	21.3 19.6	142±44 687±141	4.15±2.67	78.9
Combretastatin	25.0	6 5	21.3 19.9	144±28 501±193	3.7±1.67	70.3
							Combretastatin	50.0	6 6	21.1 19.8	137±17 344±158	2.59±1.28	49.2*
Vinorelbine	10	6 6	21.0 17.7	132±21 237±58	1.82±0.49	34.6*

D0: divide the cage administration time; Dn: after the 1st administration 11 days; * P＜0.01vs contrast

Table 4 intravenous injection combretastatin is to the experimental therapy effect (weight method calculating tumour inhibiting rate) of human colon carcinoma Ls174t Nude Mice

Group	Dosage (mg/kg)	Number of animals d0 dn	Remove body weight (gram) d0 dn after the tumor	Heavy (gram) x ± SD of tumor	Tumour inhibiting rate (%)
						Contrast		10 10	21.5 20.6	1.02±0.37
Combretastatin	12.5	6 6	21.3 19.6	0.55±0.10	46.1*
						Combretastatin	25.0	6 5	21.3 19.9	0.48±0.17	60.0*
Combretastatin	50.0	6 6	21.1 19.8	0.27±0.11	73.5*
						Vinorelbine	10.0	6 6	21.0 17.7	0.17±0.04	85.8*

D0: divide the cage administration time; Dn: after the 1st administration 11 days; * P＜0.01vs contrast

The result shows that combretastatin obviously suppresses the growth of colon cancer Ls174t; During dosage 50mg/kg, T/C% reaches 49.2%; Tumor-inhibiting action has certain dose-effect relationship (see figure 1); Tumor tissue pathology checks and finds the obvious induced tumor tissue necrosis of combretastatin.Though the antitumor curative effect of control drug vinorelbine is better than combretastatin, there is not obvious induced tumor tissue necrosis (see figure 2), point out the two different mechanism of action.

Conclusion: combretastatin obviously suppresses the growth of human colon carcinoma Nude Mice.Its antitumor action may be by reducing the tumor tissues blood flow, causing due to the tumor tissue necrosis.

Embodiment 2

Combretastatin is to the influence of Human umbilical vein endothelial cells propagation

Test reagent, medicine and instrument: HUVEC: Human umbilical vein endothelial cells.Cell is available from U.S. ATCC.Passage number was no more than for 6 generations during experiment.

Condition of culture: the M199 culture medium, 20% hyclone, endothelial cell growth stimulates shadow, VEGF10ng/ml.M199, endothelial cell growth stimulating factor (ECSF) is available from GibcoBRL company; Pancreatin is available from DIFCO company; Hyclone is available from Hyclone company; Microplate reader: POLARstar model, German BMG company product; The bright B of the Sudan is available from Sigma.

Test method: analysis of cell proliferation: with the bright B method of the Sudan, i.e. srb assay.

The main test procedure of srb assay:

I) cell is cultivated to contain 10% hyclone, with 0.2% trypsinization liquid digestion, makes cell be in exponential phase when going down to posterity always;

Cell inoculation is in 96 well culture plates when ii) testing, and initial inoculation density is 2 * 104/ml.37 ℃, the 5%CO2 incubator is pre-to be cultivated 24 hours;

5 concentration are established in iii) dosing, medicine, continuous action 72 hours;

After iv) drug effect finishes, handle with trichloroacetic acid, SRB;

V) every hole adds the non-buffering of 150 μ l10mM Tris alkali.Dissolving and protein bound SRB;

Vi) measure the OD value of each aperture at 545nm wavelength place with microplate reader.

Experimental control: the blank hole adds 20 μ l culture fluid.

Concentration is provided with: combretastatin is established 5 concentration.

Therapeutic evaluation: inhibitory rate of cell growth is calculated:

Biometrics: the suppression ratio according to medicine cell growth under variable concentrations calculates the IC50 value with the Logit method.Relatively calculate P value and 95% fiducial limit scope with the blank group.The Biological Statistic Analysis Software program derives from " pharmacology calculates and program " book, People's Health Publisher's version in 1988, Zhang Wengui chief editor.

Combretastatin obviously suppresses the propagation of HUVCE; When drug level is low (＜0.01 μ M), inhibitory action has tangible dose dependent (see figure 3); But when concentration was higher, inhibitory action reached platform, and this may remain static relevant with the part cell.Combretastatin is only effective to the endotheliocyte that is in vegetative state, and to the cell of resting stage invalid (Dark G G, Hill S A, Prise V E, Tozer G M, PettitG R, Chaplin D J.Cancer Res 1997; 57:1829-1834).

Can clearly be seen that (see figure 4) from flow cytometry, the HUVCE that cultivates has the part cell to be in G0/G1 all the time, this part cell should have the part cell also to be in resting stage simultaneously, therefore, when the combretastatin of higher concentration is used, be understood that its inhibitory action can lack tangible dose-effect relationship.By calculating, combretastatin suppresses the IC of HUVCE propagation ₅₀Be 3.2nM, illustrate that HUVCE is very responsive to combretastatin, also point out combretastatin to suppress tumor neovasculature generation in the body.

The result shows that combretastatin has the obvious suppression effect to Human umbilical vein endothelial cells (HUVEC) propagation.HUVEC handles 72h through the combretastatin of variable concentrations, and its growth is subjected to obvious inhibition.Combretastatin suppresses the IC of HUVEC growth ₅₀Be 3.2nM.Illustrate that HUVEC is very responsive to combretastatin, also point out the combretastatin can be inhibited the endotheliocyte of the blood vessel of the fast breeding as tumor vessel.

Embodiment 3

Combretastatin is to the influence of tumor tissues blood flow

Nude mouse is after 1 week adapted to, and subcutaneous vaccination human colon carcinoma Ls174t cell is treated tumor length behind 0.5cm3, random packet, every group of 5 mices.Mouse mainline combretastatin 100mg/kg, volume injected 10ml/kg, the normal saline of contrast injection equal volume.After the combretastatin administration 1,6,24h, mice is intravenous injection Hoechst3334210mg/kg once more, and after 1 minute, disconnected neck is put to death mice, takes out tumor, liquid nitrogen freezing rapidly, and do frozen section.Each tumor is got the section of 3 positions, respectively at middle, outer 1/3 place, and slice thick 10 μ M.Fluorescence microscope is counting of counting stained positive (color fluorescence turns blue) down.Excitation wavelength 376nm, emission wavelength 418nm.20 visuals field are at random counted in each section at least, and each tumor is estimated 6 sections at least.

Hoechst33342 is a DNA specific fluorescence dyestuff, can combine with vascular endothelial cell or circumvascular tumor cell DNA, under burst of ultraviolel, color fluorescence turns blue, therefore, after the Hoechst33342 intravenous injection, the profile of visible vessels (Fig. 5) on the tumor tissues frozen section.On the tissue slice, what of fluorescence staining are directly proportional with the degree of opening of tumor vessel bed, and therefore in fact, fluorescence staining has reflected the volume of function vascular bed, also is blood flow.This method is a present evaluation of tissue blood flow method commonly used.As can be seen from Figure 5, the blood flow of matched group tumor tissues is abundant, and after the combretastatin administration 1 hour, it is about about 50% that promptly visible fluorescence staining obviously reduces, and during to 6 hours, fluorescence staining reduces and surpasses 90%, and is maintained at least 24 hours.After the administration 24 hours, visible inside tumor diffusivity fluorescence, this is downright bad tumor cell, at the borderline tumor blood vessel profile of visible clear dyeing still then.This phenomenon has reflected that combretastatin mainly causes the inner ischemic necrosis of tumor tissues, and less to the influence of tumor surrounding tissue.Combretastatin obviously reduces tumor tissues function vascular bed volume rapidly, also promptly reduces the tumor tissues blood flow, and causes the tumor tissues ischemic necrosis.The presentation of results combretastatin is that an effective tumor vessel destroys medicine.

Zoopery finds that combretastatin reduces the tumor tissues blood flow rapidly, significantly, after the combretastatin administration 1 hour, can make blood flow descend 50%; In the time of 6 hours, descend more than 90%; In the time of 24 hours, cause tangible tumor tissue necrosis.The presentation of results combretastatin is one and effectively destroys the human tumor blood vessel drug eluting.

The combretastatin Anticancer Effect and Mechanism studies show that: combretastatin obviously suppresses the gathering of tubulin, and inhibitory action has significant concentration dependency, IC ₅₀Be 3.0 ± 0.6 μ M.The bonded Kd of combretastatin and tubulin is 0.82 μ M, and is littler than colchicine (COL), vinorelbine (VNR), paclitaxel (PTX) and the bonded Kd of tubulin.What combretastatin suppressed COL and tubulin competitively combines IC ₅₀=0.37 μ M, Ki=0.16 μ M illustrates that there is identical binding site with COL in combretastatin on tubulin (tubulin).VNR and PTX can not suppress combining of COL and tubulin, illustrate that the binding site of combretastatin may be different with VNR, PTX.

Combretastatin causes that obviously cell cycle arrest is at G ₂/ M phase, but and inducing apoptosis of tumour cell.

More with microtubule as the antitumor drug of target spot, as clinical medicine vinca commonly used, taxanes, dust ripple mycin class etc., but with the microtubule is target spot, can close tumor function vascular bed rapidly, and the medicine of induced tumor tissue necrosis mainly is the Combretastatin compounds at present.Though vinca also can reduce the tumor tissues blood flow, required dosage usually need reach its maximum tolerated dose, therefore, does not have actual clinical meaning; And combretastatin can reduce the tumor tissues blood flow rapidly when using its 1/10 maximum tolerated dose, and this is that it can be used as the key reason that destroys the tumor vessel medicine.As if combretastatin is closed tumor tissues function vascular bed rapidly, promptly observes this effect in 10-20 minute after the medicinal application, and this phenomenon is difficult to suppress tumor cell proliferation, inducing tumor cell and apoptosis of vascular endothelial cell with combretastatin and explains.Therefore, the status of combretastatin inducing apoptosis of tumour cell in tumor tissue necrosis also is not very clear.The neonatal blood vessels endotheliocyte makes its strike that at first is subjected to combretastatin because actin (actin) is immature, and this is to constitute new vessels and the ripe blood vessel basis to the combretastatin difference reaction.In addition, this difference between new vessels and the ripe blood vessel also may be to constitute tumor tissues at first to be subjected to the reason that combretastatin hits, because the new vessels of tumor tissues is obvious abundanter than normal structure.It should be noted that the inductive tumor tissue necrosis of combretastatin mainly occurs in the central authorities of tumor, the tumor tissues central area is owing to lack blood supply, relative anoxia, this part cell pair cell drug toxicity relative insensitivity.The tissue necrosis of the main induced tumor central area of combretastatin makes the pharmacological action of combretastatin be different from other anti-microtubule cytotoxic drugs.Therefore combretastatin destroys the more traditional cell toxicant antitumor drug of medicine as tumor vessel tangible advantage, and that does not have obvious toxic and side effects exactly.Combretastatin will be a very promising anti-cancer agent.

The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.

Claims (7)

1. the purposes suc as formula the chemical compound of I or formula II is characterized in that, is used as or is used for preparation and destroy tumor vascular medicine:

2. purposes as claimed in claim 1 is characterized in that, is used as or is used to prepare the medicine that destroys tumor vascular endotheliocyte.

3. purposes as claimed in claim 1 is characterized in that, described tumor is to rely on the tumor that blood vessel provides oxygen and nutrient.

4. purposes as claimed in claim 1, it is characterized in that described tumor comprises hepatocarcinoma, gastric cancer, melanoma, breast carcinoma, nonsmall-cell lung cancer, colon cancer, small cell lung cancer, ovarian cancer, glioma, carcinoma of prostate, lymphoma and osteosarcoma; Preferred gastric cancer, lymphoma or osteosarcoma.

5. purposes as claimed in claim 1 is characterized in that, described medicine contains:

(a) the 20-250 weight portion is suc as formula the chemical compound of I or formula II; With

(b) the pharmaceutically acceptable carrier of 10-1000 weight portion;

Wherein the weight of (a)+(b) accounts for the 50-100w/w% of medicine gross weight.

6. purposes as claimed in claim 5 is characterized in that, described medicine contains:

(a) the 30-200 weight portion is suc as formula the chemical compound of I or formula II; With

(b) the pharmaceutically acceptable carrier of 20-900 weight portion.

7. purposes as claimed in claim 5 is characterized in that, described medicine is selected from following dosage form: freeze dried powder, granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture or suspension.

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