CN1159017C - Antimony halide medicine composition for treating leukemia and lymphoma - Google Patents
Antimony halide medicine composition for treating leukemia and lymphoma Download PDFInfo
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- CN1159017C CN1159017C CNB021130698A CN02113069A CN1159017C CN 1159017 C CN1159017 C CN 1159017C CN B021130698 A CNB021130698 A CN B021130698A CN 02113069 A CN02113069 A CN 02113069A CN 1159017 C CN1159017 C CN 1159017C
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Abstract
The present invention relates to a medical composition of antimony halides for the treatment of leukemia and malignant lymphomata. The present invention is characterized in that the composition contains antimony halides in an effective dose, a carrier which can be used in medicines and/or excipient, wherein the antimony halides comprise antimony trichloride, antimony tribromide, antimony triiodide, antimony trifluoride, antimony pentafluoride and antimony pentachloride. Active components in the composition comprise one of the antimony halides or the combinations of more than one of the antimony halides. The present invention involves treating different leukemia and malignant lymphomata through the antimony halides, particularly antimony trichloride (SbCl3).
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of malignant tumor, be specifically related at least with antimony halides to be used for the treatment of malignant tumor, the pharmaceutical composition of preferred therapeutic leukemia and malignant lymphoma as active component.
Background technology
One, about the introduction of leukemia and malignant lymphoma
Leukemia is meant the malignant tumor of hemopoietic tissue.In individual cells, generally be through two or more steps to virulent conversion, propagation and clonal expansion take place subsequently.In some leukemia, with consistent leukaemia's morphology and special Clinical symptoms identified the transposition of specific stain body (for example, in chronic myelocytic leukemia, 9 and 22 chromosomal transpositions; In acute promyelocytic leukemia, 15 and 17 chromosomal transpositions).Acute leukemia is dominant mainly to be undifferentiated cell colony, and chronic leukemia is dominant mainly to be mature cell colony.
Acute leukemia is divided into acute lymphoblastic (ALL) property leukemia and acute nonlymphocytic leukemia (ANLL or AML) type.Can be according to France-U.S.-Britain (FAB) pigeon-hole principle or according to their type and differentiation degree, can be by its morphology and cytochemistry with they further segmentations.Use specific b-cell and T-cell and myeloid antigens monoclonal antibody, cell chromosome, detections such as molecular biology are the most helpful for diagnosis and classification, and judging prognosis is had the certain significance.ALL betides childhood disease, and it is to detect by experiment with bone marrow to measure establishment.The ANLL or the AML that might take place at all age brackets are acute leukemia more common in the adult; Its radiation common and as paathogenic factor, virus, chemical substances etc. are relevant.
One class acute leukemia---acute promyelocytic leukemia (APL) accounts for about 10% of acute myelocytic leukemia, is that to be obstructed with promyelocyte differentiation be feature, at molecular level, has t (15 at most of APL (＞95%); 17) relevant, this transposition causes promyelocyte to produce the PML/RAR alpha fusion protein.Someone proposes PML/RAR α and can react and block the medullary cell differentiation by suppressing nuclear receptor, just as dominant RAR α sudden change takes place.The leukemia ability that causes of PML/RAR alpha fusion protein is confirmed on the transgenic mice animal model.The diagnosis of acute promyelocytic leukemia (APL) is main to be clear and definite by the morphological feature of APL cell in blood and the bone marrow.Chromosome translocation t (15; 17) also be the typical characteristic of APL, and can show by showing band or fluorescence in situ hybridization (FISH) staining technique.This transposition can be found in the APL patient that is everlasting, and especially can find in the APL before disease is alleviated fully, and the polymerase chain reaction of patient's bone marrow (PCR) also can show PML/RAR α mRNA.In addition, for example CD33+, CD13+, CD9+, CD34-and HLA-DR-mainly are present in the medullary cell some immune markers.Oral all-trans-retinoic acid (RA) can make and have t (15; 17) first pattern of cancer differentiation therapy is alleviated and become to the APL of transposition fully.Some clinical researches have shown that RA combines with chemotherapy and can obviously improve patient's APL prognosis, but still had most of patient APL to recur the back to the RA drug resistance.
Chronic leukemia is described with chronic lymphocytic leukemia (CLL) or chronic myelocytic leukemia (CML).CLL is that the outward appearance by the mature lymphocyte in blood, bone marrow and the lymphatic organ shows its feature.The labelling of CLL is that lymphocytosis that continue, absolute (＞5000/ μ L) and bone marrow medium-sized lymphocyte increase.Most of CLL patients have the lymphocytic clonal expansion of B-cell characteristic.CLL mainly is the disease that older crowd suffered from.In CML (chronic myelocytic leukemia or chronic myelogenous leukemia), genius morbi is that the granulocyte of all differential periods in blood, bone marrow, liver, spleen and other organ is occupied an leading position.In showing the patient diagnosis of symptom, total WBC number is generally about 200000/ μ L, but also can reach 1000000/ μ L.CML is easy to diagnosis relatively, and this is that promptly t (9 because there is the chromosomal cause of Fei Shi (philadelphia); 22).
Malignant lymphoma is heterogeneous (heterogeneousgroup) disease, and about 15% malignant lymphoma patient is a Hokdkin disease, and all the other patients are the sick lymphoma of Fei Hejiejinshi.Lymphadenomatous etiology, epidemiology, pathology, Clinical symptoms, diagnostic evaluation and progress, treatment and control are disclosed among the Maiignant Lymphomas, according to clinical disease course NHL is classified, for example severe, moderate or slight NHL, perhaps, also can NHL be classified according to immunophenotype (as T-cell, B-cell) or cytogenetics (chromosomal aberration).At the branch apoplexy due to endogenous wind of NHL, histopathology and morphological change are extremely important.According to current taxonomic hierarchies, the sick lymphoma of Fei Hejiejinshi is divided into the folliculus small cleaved cell again and folliculus Combination small nut splits and large celllymphoma, the small lymphocyte lymphoma, the adventitial cell lymphoma, lymphoma mucosa associated lymphoid tissue, the monokaryon B cell lymphoma, the folliculus large celllymphoma, diffusibility small cleaved cell lymphoma, diffusibility Combination small nut splits and large celllymphoma, and the diffusibility large celllymphoma becomes immune lymphoma, the thymus B cell lymphoma, the little non-cleaved cell lymphoma of diffusibility, lymphoblast lymphoma, lymphoma peripheral T cell, the sick lymphoma of maxicell anaplasia lymphoma and the Fei Hejiejinshi in acquired immune deficiency syndrome (AIDS).
Leukemic ins and outs make people need the using system chemotherapy to be used as the base therapy means.Concrete leukemia of foundation and the selected medicine of lymphadenomatous sensitivity are normally with the associated form medication.Can use radiotherapy to treat the leukaemia of concentration of local as supplementary means.Operation still can be used to control some complication seldom as the base therapy means.Sometimes take from the crowd that HLA is complementary, to carry out allogeneic bone marrow transplantation or allogeneic peripheral blood hematopoietic stem cell transplantation.
Two, antimony and medical applications thereof
For a long time, antimony both had been considered to poisonous substance, also was considered to medicine.
Antimonial (as antimony potassium tartrate) once was used to treat schistosomicide and kala azar at twentieth century.
WO00/21506 is openly with antimony and/or arsenical associating glutathion instrumentality treatment cancer, and can make NB4 at external confirmation antimony oxide associating buthionine sulfoximine (BSO) with experiment, malignant cell strain growth in vitro such as PLB-985 are suppressed.Though show that from the disclosed data of WO00/21506 antimony oxide associating BSO can make the external apoptosis of some malignant cell strains, never the people proposes to use separately antimony halides, particularly Butter of antimony. (SbCl
3) treat cancer, especially leukemia or lymphoma.In addition, no matter be to use separately or unite the use chemotherapeutics, never the people proposes to use antimony halides to treat and comprises arbitrary types of cancer of leukemia or lymphoma.On the contrary in field of medicaments, Butter of antimony. (SbCl
3) and some antimony agent such as antimonous bromide, antimony triiodide etc. be considered to Toxic.
Cancer is the disease of serious harm human health, and Therapeutic Method is mainly operation, radiotherapy, chemotherapy at present, but all curative effect is limited.People need to treat cancer effectively consumingly, particularly comprise leukemia and lymphoma., the invention provides with antimony halides for this reason, be used for the treatment of the pharmaceutical composition of leukemia and malignant lymphoma as active component.
Summary of the invention
For achieving the above object, the technical solution used in the present invention is: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, it is characterized in that: the antimony halides that contains in the said composition and pharmaceutically suitable carrier and/or excipient, wherein, the content＜50mg/m of antimony halides
2D, mg represents milligram, m
2Expression people's body surface area, d represents every day.
Related content and change interpretation in the technique scheme are as follows:
1, in the technique scheme, described antimony halides comprises Butter of antimony. (SbCl
3), antimonous bromide (SbBr
3), antimony triiodide (SbI
3), Antimony fluoride (SbF
3), antimony pentafluoride (SbF
5), Antimony pentachloride (SbCl
5), the active component in the described compositions is one or more the combination in the above-mentioned antimony halides.
2, in the technique scheme, can also comprise therapeutic agent in the described compositions, described therapeutic agent is selected from the Semen Sinapis chemical compound, chlormethine, chlorambucil, the phenylalanine ammonia mustard, cyclophosphamide, busulfan, Ismipur, 6-thioguanine, cytosine arabinoside, arabinosylcytosine, 5-fluorouracil, floxuridine, methotrexate, vincristine, vinblastine, vincaleucoblastine, paclitaxel, the etoposide dactinomycin, daunorubicin, amycin, epirubicin, Perarubicin, mitoxantrone, bleomycin, mitomycin, aklavine, cisplatin, carboplatin, the phosphoric acid semustine, hydroxyurea, carmustine, procarbazine, teniposide, interferon, prednisone and all-trans retinoic acid.
3, about the toxicity and the dosage problem of antimony.
Though antimony halides is a noxious substance as you know, harmful, but the applicant's using dosage only 1 μ mol/L-10 μ mol/L can make malignant lymphatic tumor cell strain apoptosis and necrosis external, well below toxic dose 0.1-2.0g/ people (being equivalent to 500 μ mol/L-2000 μ mol/L approximately), and the antimony agent is inexpensive, on market, easily buy, dosage 0.1-0.2g/d (being equivalent to 100 μ mol/L-200 μ mol/L approximately) when this experiment is less than also with dosage that nineteen fifties, winestone phenol antimony potassium was used for the treatment of schistosomicide, therefore, to treat effectively but not the antimony halides of lethal dose or non-toxic dose can use in mammal safely and effectively.Even poisoning symptom takes place, also can detoxify with sodium dimercaptosuccinate or sodium dimercaptopropanesulfonate.The present invention generally is controlled at the content of antimony halides＜50mg/m
2D.
In the acute or chronic treatment of leukemia or lymphadenomatous cancer, the big young pathbreaker of antimony halides therapeutic dose is difference with the difference of the sanatory order of severity of desire and route of administration.Dosage and administration frequency will be with patient's age, body weight, disease and reaction different and different.Can keep the desired blood level of determining by blood plasma level by the continuous infusion antimony halides.Should be pointed out that how and when the clinicist understands is ended when toxicity or bone marrow, liver or kidney malfunction occurring, therapy discontinued maybe is adjusted to reduced levels with treatment.On the contrary, if clinical response is not when insufficient (comprising toxic side effects), how and when the clinicist also understands is adjusted to higher level with treatment.
4, about the administering mode of aforementioned pharmaceutical compositions.
According to the present invention, can with antimony halides and physiologically acceptable salt thereof or solvated compounds be mixed with oral or the parenteral administration preparation, wherein parenteral administration comprises mode of administration such as intravenous, subcutaneous, intramuscular, intrathecal drug delivery, intranasal, specifically can be according to the type of cancer and patient and different.
For oral administration, can be tablet, capsule or liquid dosage form.Liquid dosage form can be solution, syrup or suspending agent.This liquid preparation can make with pharmaceutically acceptable additive by conventional method, and described additive has suspending agent (for example sorbitol syrups, cellulose derivative or hydrogenation edible fat); Emulsifying agent (for example lecithin or arabic gum); Nonaqueous carrier (for example almond oil, oily ester or fractionated vegetable oil); And antiseptic (for example methyl parahydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid).Described tablet or capsule can make with pharmaceutically acceptable excipient by conventional method, and described excipient has for example binding agent (for example pregel corn starch, polyvinylpyrrolidone or hydroxypropyl emthylcellulose); Filler (for example lactose, microcrystalline Cellulose or calcium hydrogen phosphate); Lubricant (for example magnesium stearate, Talcum or silicon dioxide); Disintegrating agent (for example potato starch or sodium starch glycolate); Or wetting agent (for example sodium lauryl sulphate).Can be by method well-known in the art with tablet coating.
In order to pass through inhalation, for example dichlorodifluoromethane, Arcton 11, dichlorotrifluoroethane, carbon dioxide or other suitable gas are sent with aerosol form medicine of the present invention from pressurized package or aerosol apparatus can to use suitable propellant.For pressurised aerosol, can decide dosage unit by the valve of sending dosing is provided.Contain halogenide and the suitable powder substrate pulverulent mixture of lactose or starch for example for being used in capsule in inhaler or the insufflator and cartridge case for example gelatine capsule and cartridge case, it can being mixed with.Halogenide can be mixed with the preparation that is used for by injection, for example being undertaken parenteral administration by bolus injection or continuous infusion.Injection can provide with unit dosage forms, for example provides in ampoule that adds antiseptic or multi-dose container.Compositions can be suspending agent, solution or the Emulsion in oil or water carrier, and can contain reagent preparation for example suspending agent, stabilizing agent and/or dispersant.Perhaps, active component can be in powder, and this powder is prepared again with for example aseptic water (Sterilepyrogen-free water) or other solvent that does not contain thermal source of suitable carrier before use.
The present invention can also provide the medicine box of therapeutic scheme.Described medicine box comprises the antimony halides of the treatment effective dose of pharmaceutically acceptable form in one or more containers.Antimony halides in the bottle of medicine box of the present invention can be the dosage form in pharmaceutically acceptable solution, for example with the solution of Sterile Saline, glucose solution, buffer or other pharmaceutical acceptable sterile liquid.Perhaps, can be with the complex lyophilization; In this case, medicine box is optional pharmaceutically acceptable solution (for example saline, glucose solution etc.), the preferred aseptic pharmaceutically acceptable solution of comprising in container also, so that complex is mixed with injection again.
Medicine box of the present invention also comprises and is used to inject pumping needle or syringe this complex, that preferably pack with sterile form, and/or the alcohol pads of packing.Be used to instruct clinicist or patient to use the indication explanation of antimony halides optional comprising in the medicine box.
Equally, for the antimony halides of effective dose is provided to the patient, can adopt arbitrary suitable route of administration.For example, can adopt oral administration, transdermal administration, electron ion to infiltrate administration, parenteral administration (subcutaneous administration, intramuscular administration, intrathecal drug delivery etc.).Dosage form comprises tablet, lozenge, cachet, dispersant, suspending agent, solution, capsule, patch etc.
In actual applications, can antimony halides be become immixture as active component with pharmaceutically suitable carrier or mixed with excipients according to the conventional medicine hybrid technology.According to the required dosage form of administration for example peroral dosage form or parenteral administration dosage form (comprising tablet, capsule, powder, intravenous injection agent or infusion agent), carrier can take various forms.In the preparation of oral dosage form composition, can use any common drug medium, for example,, can make water, glycol, oil, alcohol, correctives, antiseptic, coloring agent etc. for oral liquid for example suspending agent, solution, elixir, liposome and aerosol; For oral solid formulation for example powder, capsule and tablet, can use for example starch, sugar, microcrystalline Cellulose, diluent, granulation agent, lubricant, binding agent, disintegrating agent etc.In the preparation of parenteral administration dosage form composition, can use similar drug media, for example drug medias well known by persons skilled in the art such as water, ethanol, oil, buffer agent, sugar, antiseptic, liposome.The example of parenteral administration compositions includes but not limited to 5%w/v glucose, normal saline or other solution.The accumulated dose of antimony halides can be put into and intravenous administration is housed carries out administration, total the volume of diluent liquid will be different with the difference of dosage with the bottle of liquid.
5, about Therapeutic Method.
The used term of this description " treatment cancer method " is meant, is alleviated with the disease and the symptom of related to cancer, alleviates, and improves, prevents, remains on relieved state or maintain relieved state.For example, when the cancer of being treated was leukemia, Therapeutic Method of the present invention can reduce the leukocyte number in the patient of treatment, or alleviates lymphocytosis.
On the Therapeutic Method of the present invention with the antimony halides of effective dose with preferably with the mammal administration of pharmaceutically suitable carrier or excipient to this treatment of needs.
The present invention comprises also and uses conjoint therapy to treat cancer that especially the treatment for other type is intractable cancer.According to the present invention, antimony halides can use separately, or uses with other known treatment agent (comprising chemotherapeutics, radioprotectant and radiotherapy dose) or technical tie-up, to improve patient's quality of life or treatment cancer, especially treats leukemia or lymphoma.Can be before one or more known chemotherapeutics administrations, use antimony halides during the administration or after the administration.In addition, can be before radiotherapy, during or use antimony halides afterwards.
6, pharmaceutical composition of the present invention is used for the treatment of the scope of leukemia and malignant lymphoma.
The leukemia of medicine composite for curing of the present invention comprises acute lymphoblastic leukemia (ALL), acute lymphoblastic B-chronic myeloid leukemia, acute lymphoblastic T-chronic myeloid leukemia, acute nonlymphocytic leukemia (ANLL), acute myeloblast leukemia (AML), acute promyelocytic leukemia (APL), acute monocytic leukemia, the Di Guglielmo syndrome leukemia, acute megakaryoblastic leukemia, chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma, myelodysplastic syndrome (MDS) for example refractory anemia companion juvenile cell increases (RAEB) and the RAEB in being converted into the leukemia process (RAEB-T), chronic grain-single cell leukemia (CMML).Can be preferably acute promyelocytic leukemia (APL), chronic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL) and multiple myeloma by the leukemia of the inventive method treatment.
The lymphoma of the present invention's treatment comprises severe lymphoma, moderate lymphoma and slight lymphoma.Can be preferably non_hodgkin lymphoma by the lymphoma of medicine composite for curing of the present invention.It will be appreciated by those skilled in the art that other cancer, especially leukemia can be treated according to the present invention.
The present invention also may be used for treating other various malignant tumor, comprises breast carcinoma, carcinoma of prostate, pulmonary carcinoma, hepatocarcinoma, gastric cancer, colon cancer, carcinoma of endometrium, cervical cancer, lymphoma, renal carcinoma, cerebral glioma, skin carcinoma, osteocarcinoma, rhinocarcinoma, carcinoma of tongue, thyroid carcinoma, mediastinal tumor, carcinoma of testis, ovarian cancer, esophageal carcinoma.
The present invention can also treat the patient who is diagnosed as leukemia or lymphoma, preferred acute promyelocytic leukemia (APL), chronic myelocytic leukemia (CML), non_hodgkin lymphoma, chronic lymphocytic leukemia (CLL) or multiple myeloma recently or is in the described palindromia stage.
The present invention can also maintain the patient leukemia, preferred acute promyelocytic leukemia (APL), chronic myelocytic leukemia (CML), non_hodgkin lymphoma, the complete remission stage of chronic lymphocytic leukemia (CLL) or multiple myeloma.
The used term of this description " fully alleviate " is meant, has to be lower than 5% germinal cell and leukemia promyelocyte, and has the normal blood picture without any leukemia clinical manifestation.Be used for for example t (15 of the Clinical Laboratory of APL and morphological feature that other check comprises blood and bone marrow APL cell, chromosome translocation; 17), show the existence of PML/RARa mRNA He other immune marker of APL.
According to the present invention, antimony halides can use separately, or uses with other known treatment agent (comprising chemotherapeutics, radioprotectant and radiotherapy dose) or technical tie-up, to improve patient's quality of life or treatment leukemia, lymphoma.For example, can be before one or more known antitumor agent administrations, use antimony halides during the administration or after the administration, described known antitumor agent includes but not limited to the Semen Sinapis chemical compound, chlormethine, chlorambucil, melphalan, cyclophosphamide, busulfan, Ismipur, 6-thioguanine, cytosine arabinoside, arabinosylcytosine, 5-fluorouracil, floxuridine, methotrexate, vincristine, vinblastine, vincaleucoblastine, paclitaxel, etoposide, dactinomycin, daunorubicin, amycin, epirubicin, Perarubicin, mitoxantrone, aklavine, bleomycin, mitomycin, cisplatin, carboplatin, the phosphoric acid semustine, hydroxyurea, carmustine, procarbazine, teniposide, interferon and trans retinoic acid (ATRA), in addition, can be before radiotherapy, use antimony halides during this time or afterwards.
The used term of this description " therapeutic agent ", " therapeutic scheme ", " radioprotectant ", " chemotherapeutics ", " radiotherapy dose " are well-known in this area.
In preferred embodiments, before carrying out other type chemotherapy or radiotherapy, during or afterwards with antimony halides of the present invention all administration simultaneously treat together.
The present invention can be alleviated, alleviate, improves or prophylaxis of cancer, perhaps will keep or maintains relieved state at the relevant clinical symptoms of interior leukemia or diagnosis index with cancer, especially leukemia or lymphoma.
7, the method and the cell in vitro experimentation that prepare preparations such as Butter of antimony..
(1) experimental technique
(1). preparation SbCl
3(Shanghai chemical reagent four factories) use anhydrous alcohol solution, are made into the storage liquid of 500 μ mol/L, and filtration sterilization is deposited standbyly for 4 ℃, faces with before being diluted to desired concn.Antimonous bromide (SbBr
3), antimony triiodide (SbI
3) according to preparing with method.
(2). cell culture and cell growth condition are measured
Raji, HL-60, Daudi cell are with 2 * 10
5/ ml (and the Hela cell is with 2 * 10
4/ ml) be inoculated in the RPMI-1640 culture fluid (including 10% hyclone, 100u/ml penicillin and 100mg/ml streptomycin) and cultivate 37 ℃, 5%CO
2, thing processed group and the control cells trypan blue dyeing of getting it filled every day after the dosing, trypan blue dyeing counting living cells sum is an average of getting four parts of specimen under the light microscopic, continuous 6 days, draws growth curve.
(3). cellular morphology is observed and cells were tested by flow cytometry: the Raji cell of cultivation is through 5.0 μ mol/LSbCl
3After hatching 24 hours, collect 2 * 10
6Cell PBS washes 2 times, and the centrifugal 5min of 1500r/min abandons supernatant, and fixedly behind the 72h, 1% osmic acid is fixed for 4 ℃ of 2% glutaraldehyde, the gradient dehydration, and the EPON-812 embedding, ultrathin section, transmission electron microscope is observed down behind uranium and the plumbous double staining.
(4) .Annexin-V labelling: the description by Immuno-tech company carries out 1 * 10
6Cell washes twice with ice PBS, and adjusting cell concentration is 1 * 10
6, add 5 μ l AnnexinV (dilution in 1: 10) and 5 μ l iodate third ingots (PI) (250 μ g/ml) in 490 μ l cell suspension, place ice bath 10min, with flow cytometer (model C OULTER EPICS-XL) analysis of cells apoptosis situation.
(5). lethality detects: detect SbCl with MTT (tetramethyl azo azoles indigo plant) colorimetry
3Kill rate to the Raji cell.With well-grown Raji cell with 2 * 10
5/ ml concentration adds 96 well culture plates, every hole 100 μ l, the SbCl of adding variable concentrations
3, each concentration is established 3 multiple holes, and establishes control wells, puts 37 ℃, 5%CO
2Cultivate 48h under the condition, add MTT (5mg/ml) 10 μ l/ holes, after continuing to hatch 2h, add DMSO100 μ l/ hole again, beat even back microplate reader (model Micro Reader
TM4Plus) 570nm reads at the place absorbance A value.And utilize logarithm probability graph solution to measure the half-inhibition concentration (IC of medicine
50).
(2), experimental result is as follows:
(1) .SbCl
3Inhibitory action to the Raji cell proliferation
2.0,4.0,6.0 μ mol/L SbCl
3When handling Raji cell 72h, inhibitory rate of cell growth is respectively 25%, 68%, and 95%.SbCl
3Handle 48h, to the IC of Raji cell
50Be 3.9 μ mol/L.
(2). morphological change
The Raji cell is through 5.0 μ mol/L SbCl
3After handling 48h, visible typical apoptosis morphological feature under transmission electron microscope: cell pyknosis, endochylema concentrates, chromatin agregation is in nuclear membrane, karyorrhexis, the formation apoptotic body (see figure 8) that has also can be seen the non-viable non-apoptotic cell (see figure 9), and its cell shows as membranolysis, the cell interior structure is unclear.Visible apoptotic cell volume-diminished under inverted microscope, after birth is complete, and the cell diopter is obviously deepened, the non-viable non-apoptotic cell film rupture, diopter is poor, and living cells is then bright, and diopter is good.
(3). flow cytometer is SbCl as a result
3Concentration is respectively 1.0 μ mol/L, 2.0 μ mol/L, 3.0 μ mol/L
Handle Raji cell 36h respectively, the Raji apoptosis rate is respectively 1.56%, 3.16%, 7.68%, and the necrocytosis rate is respectively 3.16%, 6.6%, 7.68%, and blank negative control group apoptosis rate and necrosis rate are respectively 1.2% and 0.6%, improves SbCl
3Concentration is respectively 6.0 μ mol/L, 8.0 μ mol/L, 10.0 μ mol/L handle Raji cell 8h respectively, the Raji apoptosis rate is respectively 2.96%, 10.8%, 29.1%, the necrocytosis rate is respectively 5.02%, 11.5%, 29.8%, and its blank negative control group apoptosis rate and necrosis rate are respectively 0.88% and 0.84%.
Butter of antimony. induce Burkitt Lymphoma Raji Cells strain apoptosis and downright bad experimentation verified SbCl
3Can bring out its apoptosis with downright bad.Simultaneously also research is verified by experiment SbCl
3Can to cell strains such as HL-60, Daudi, Hela inhibited proliferation be arranged respectively.
We have known arsenic trioxide or realgar to just sending out or recurrent APL all has splendid curative effect at present, and its mechanism of action is by degraded PML/RAR alpha fusion protein, causes apoptosis of leukemia to be realized then.
We also are surprised to find SbCl by experiment in vitro
3Have and the similar mechanism of action of arsenical, can induce ALL, AML, lymphoma and solid tumor cell strain apoptosis with downright bad, for clinical theoretical foundation and experimental model of providing is provided for it.
8, zoopery situation
Adopt Butter of antimony. (SbCl
3) inhibitory action that the Raji cell is grown under mice scrotum film
(1), animal experiment method
The take the logarithm Raji cell of trophophase, the centrifugal 5min of 1000r/min, centrifugal with phosphate buffer washing 2 times, make cell form loose agglomerate.Added Fibrinogen (20mg/ml) and thrombin (20u/ml) 2: 1 in cell mass, total amount is no more than 10%, 37 ℃ of incubation 5～10min of cumulative volume, forms the cell fibrin clot, in the RPMI1640 culture medium, cell is cut into 1mm again
3Fritter is transplanted under the scrotum film of the kunming mice left side of anesthesia, and three-dimensional anatomical lens is measured major diameter of tumor piece and minor axis down.Tumor piece in different time taking-up culture medium is measured its volume.
With the mice of inoculation tumor piece, random packet, 5 every group.Experimental group adopts abdominal cavity or subcutaneous injection administration.Experiment finishes the left kidney of back taking-up and measures the long and short footpath of tumor down in anatomical lens, is calculated as follows gross tumor volume:
Gross tumor volume (mm
3)=major diameter (mm) * minor axis (mm)/2
(2), zoopery result: see attached list
SbCl
3The inhibitory action that the Raji cell is grown under mice scrotum film
| Dosage (mg/kg) | Ts0(mm 3) | Ts6(mm 3) | |
| Matched group | 0 | 1.0 | 4.5 |
| SbCl 3Group | 0.01 | 1.02 | 4.2 |
| 0.1 | 0.95 | 2.2 | |
| 0.2 | 0.96 | 0.8 | |
| 0.3 | 0.98 | 0.32 | |
| 0.4 | 1.03 | 0.2 |
Remarks: Ts0 and Ts6 were respectively the 0th day and the size of the 6th day tumor
Can find out SbCl from above experimental result
3It is inhibited that the Raji cell is grown under mice scrotum film, and along with SbCl
3Concentration improves its inhibitory action and also progressively increases.
Description of drawings
Accompanying drawing 1 shows SbCl
3Inhibited proliferation to the Raji cell strain;
Accompanying drawing 2 shows SbCl
3Inhibited proliferation to the HL-60 cell strain;
Accompanying drawing 3 shows SbCl
3Inhibited proliferation to the Hela cell strain;
Accompanying drawing 4 shows SbCl
3Inhibited proliferation to the Daudi cell strain;
Accompanying drawing 5 shows SbBr
3Inhibited proliferation to the Daudi cell strain;
Accompanying drawing 6 shows SbI
3Inhibited proliferation to the HL-60 cell strain;
Accompanying drawing 7 shows SbI
3Inhibited proliferation to the Raji cell strain;
Accompanying drawing 8 is a Raji apoptotic cell ultrastructure (* 8000);
Accompanying drawing 9 left sides are Raji non-viable non-apoptotic cell ultrastructure (* 8000), and the right is a Raji normal cell ultrastructure (* 8000).
The specific embodiment
Embodiment one: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3), its content is 10mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment two: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3) and cytosine arabinoside, Butter of antimony. (SbCl
3) content be 8mg/m
2D, the content of cytosine arabinoside are 50mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment three: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3) and vincristine, Butter of antimony. (SbCl
3) content be 5mg/m
2D, the content of vincristine are 2mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment four: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3) and prednisone, Butter of antimony. (SbCl
3) content be 3mg/m
2D, the content of prednisone are 60mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment five: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain antimonous bromide (SbBr in the said composition
3) and cyclophosphamide, antimonous bromide (SbBr
3) content be 2mg/m
2D, the content of cyclophosphamide are 400mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment six: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain antimony triiodide (SbI in the said composition
3) and amycin, antimony triiodide (SbI
3) content be 6mg/m
2D, the content of amycin are 30mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment seven: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3) and antimony triiodide (SbI
3), Butter of antimony. (SbCl
3) content be 2mg/m
2D, antimony triiodide (SbI
3) content be 6mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Embodiment eight: a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition, contain Butter of antimony. (SbCl in the said composition
3), antimonous bromide (SbBr
3) and antimony triiodide (SbI
3), Butter of antimony. (SbCl
3) content be 2mg/m
2D, antimony triiodide (SbI
3) content be 3mg/m
2D, antimony triiodide (SbI
3) content be 2mg/m
2D, remaining is pharmaceutical carrier and/or excipient.
Claims (4)
1, a kind of treatment leukemia and lymphadenomatous antimony halides pharmaceutical composition is characterized in that: the antimony halides that contains in the said composition and pharmaceutically suitable carrier and/or excipient, wherein, the content＜50mg/m of antimony halides
2D, mg represents milligram, m
2Expression people's body surface area, d represents every day.
2, pharmaceutical composition according to claim 1, it is characterized in that: antimony halides comprises Butter of antimony., antimonous bromide, antimony triiodide, Antimony fluoride, antimony pentafluoride, Antimony pentachloride, and the active component in the described compositions is one or more the combination in the above-mentioned antimony halides.
3, pharmaceutical composition according to claim 2 is characterized in that: described antimony halides is a Butter of antimony..
4, pharmaceutical composition according to claim 1, it is characterized in that: also comprise therapeutic agent in the described compositions, described therapeutic agent is selected from the Semen Sinapis chemical compound, chlormethine, chlorambucil, the phenylalanine ammonia mustard, cyclophosphamide, busulfan, Ismipur, 6-thioguanine, cytosine arabinoside, arabinosylcytosine, 5-fluorouracil, floxuridine, methotrexate, vincristine, vinblastine, vincaleucoblastine, paclitaxel, etoposide, dactinomycin, daunorubicin, amycin, epirubicin, Perarubicin, mitoxantrone, bleomycin, mitomycin, aklavine, cisplatin, carboplatin, the phosphoric acid semustine, hydroxyurea, carmustine, procarbazine, teniposide, interferon, prednisone and all-trans retinoic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021130698A CN1159017C (en) | 2002-05-27 | 2002-05-27 | Antimony halide medicine composition for treating leukemia and lymphoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021130698A CN1159017C (en) | 2002-05-27 | 2002-05-27 | Antimony halide medicine composition for treating leukemia and lymphoma |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1385167A CN1385167A (en) | 2002-12-18 |
| CN1159017C true CN1159017C (en) | 2004-07-28 |
Family
ID=4742417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021130698A Expired - Fee Related CN1159017C (en) | 2002-05-27 | 2002-05-27 | Antimony halide medicine composition for treating leukemia and lymphoma |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1159017C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019134070A1 (en) * | 2018-01-02 | 2019-07-11 | Rui Jin Hospital, Shanghai Jiao Tong University School Of Medicine | Panda as novel therapeutic |
| CN112870225B (en) * | 2021-02-05 | 2023-01-06 | 北京大学人民医院 | Combination therapy medicine for induction phase of high-risk acute promyelocytic leukemia |
-
2002
- 2002-05-27 CN CNB021130698A patent/CN1159017C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1385167A (en) | 2002-12-18 |
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