CN1176665C - Medicine for treating maligant leucoma and its compounding process - Google Patents
Medicine for treating maligant leucoma and its compounding process Download PDFInfo
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- CN1176665C CN1176665C CNB011075368A CN01107536A CN1176665C CN 1176665 C CN1176665 C CN 1176665C CN B011075368 A CNB011075368 A CN B011075368A CN 01107536 A CN01107536 A CN 01107536A CN 1176665 C CN1176665 C CN 1176665C
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Abstract
The present invention discloses a medicine for treating malignant lymphoma and a preparation method thereof. The medicine basically comprises 0.5 to 2.0 mu mol/L of arsenic trioxide, sodium ions, chloride ions and water. The preparation method comprises the steps: the arsenic trioxide is titrated with sodium hydroxide solution until complete dissolution, tri-distilled water is added to the mixture to obtain a required concentration, and then, the pH value is adjusted to 7.2 to 7.4 by a hydrochloric acid solution. Arsenic trioxide has the favorable action of killing tumor cells on malignant lymphoma, and drug resistance is hardly generated; arsenic trioxide has low toxicity to normal tissues, and recovery can be realized after medication discontinues.
Description
The present invention relates to a kind of medicine and compound method thereof that is used for the treatment of malignant lymphoma.
The treatment malignant lymphoma, the past is adopted conventional chemotherapeutics, but is prone to recurrence and produces the drug resistance phenomenon.Chinese scholar is used arsenical in recent years as antitumor drug clinical treatment acute promyelocytic leukemia (APL), obtained satisfied curative effect, the complete remission rate height, few side effects, and there is not the crossing drug resistant phenomenon with all-trans-retinoic acid, still effective to the patient of recurring or all-trans-retinoic acid is failed to respond to any medical treatment." Chinese combination of Chinese and Western medicine magazine " 170 to 172 pages of reports that publish in March, 1992, use ' No. 1, cancer spirit ' (containing 0.1% arsenic trioxide) in conjunction with differential diagnosis in tcm treatment acute promyelocytic leukemia 32 examples, complete remission rate reaches 65.6% (21/32), 50% survival is more than 5 years, and 18.8% survival is more than 10 years.The Chinese patent 95108768.1 that open day was on May 8th, 1996 discloses the leukemic " Ailing " anticancer injection of a kind of treatment, mainly by arsenic trioxide 1～10 gram, sodium chloride 8 restrain, 1000 milliliters of waters for injection, make " Ailing " anticancer injection through boiling filtration sterilization.Discover that its mechanism of action induces APL apoptosis and part differentiation exactly, encouraged the further research and development of people the arsenic agent treatment tumor.
Whether arsenic trioxide has therapeutical effect to malignant lymphoma, does not appear in the newspapers as yet both at home and abroad at present.
Purpose of the present invention just provide a kind of treat malignant lymphoma, to normal cell and organize toxic and side effects little, tumor cell is not easy to produce chemical sproof medicine and compound method thereof.
For reaching above-mentioned purpose, medicine of the present invention is made up of arsenic trioxide, sodium ion, chloride ion and water substantially, the concentration of arsenic trioxide is in 0.5～2.0 μ mol/L scope, its compound method is: earlier with sodium hydroxide solution with the arsenic trioxide titration to finishing dissolving, add tri-distilled water again and be configured to required concentration, adjust pH value to 7.2～7.4 with hydrochloric acid solution at last.
The mechanism of action of arsenical:
1, cell death inducing and part differentiation: apoptosis is meant to keeping homeostasis, by the death of the autonomous order of cell control.Apoptosis is a kind of initiative cell oneself extinction process that is subjected to Gene Handling, at the regulation and control fetal development and keep rise in the process such as stable machine important, it is a kind of important form of cell physiological committed suicide, apoptotic process can be subjected to " heredity " control, start by internal clocking, also can be by the outside controlling factors, as hormone, cytokine, killer cell etc.Discover that arsenic trioxide can cause the various tumor cell strains apoptosis.
2, the regulation and control expressed of gene participating in apoptosis: tumor be a multistage, multistep is rapid and polygenic process.In the tumor generating process, how to realize the apoptotic speed of modulate tumor artificially, be a focus in the current treatment tumor research.During Arsenic Trioxide Induced bone-marrow-derived lymphocyte apoptosis of leukemia, the isogenic expression of downward modulation bcl-2.
3, the approach of biological effect: arsenic is a kind of protoplasmic toxin, with sulfydryl very strong affinity is arranged, and after containing the sulfydryl enzyme and combining, enzymatic activity is suppressed, interferases physiological function, structure and metabolism.Sulfhydryl oxidase or crosslinked be the key factor of cell death inducing, its main mechanism is to induce the opening in mitochondrial membrane permeability transhipment hole, and then cause the decline of mitochondrial inner membrane transmembrane potential and the pro-apoptotic factor to be released into endochylema, and activate some apoptosis effect molecules from mitochondrion.
4, prolong doubling time or inhibitory cell cycle progression: cell cycle by DNA the presynthetic phase (G1), DNA synthesis stage (S), DNA post-synthetic phase (G2), 4 stages of mitotic phase (M) form, G1/S phase and G2/M phase are two restriction point of conversion, wherein the conversion of G1/S phase decision cell cycle time.Discover that after arsenic trioxide was handled tumor cell, cell doubling time prolonged or makes cell prevent the phase at G1.
The lymphoma tissue cell that the inventor chooses human Burkitt lymphoma cell strain Raji cell, T lymphoma cell strain Jurkat cell, patient (obtains the surgical patient specimen, be prepared into unicellular) as object of study, adding arsenic trioxide hatches jointly, the consumption of arsenical is controlled in the usual range (＜10 μ mol/L), observe the regulation and control that its cell death inducing and pair cell apoptosis-related genes are expressed, observe arsenic trioxide simultaneously to former generation malignant T, the active influence of B lymphoma cell, for arsenic trioxide clinical treatment malignant lymphoma provides foundation.Observe with Ji's nurse Sa (Giemas) staining pair cell apoptosis form, detect apoptotic cell with situ end labeling (TUNEL), detect the dna content of cell and carry out the analysis of cell cycle with flow cytometer, expression with Flow Cytometry binding immunoassay fluoremetry bcl-2, P53 gene protein, use the statistical analysis experimental data, judge significant difference with P＜0.05, significant differences is judged in P＜0.01.Table 1 to table 10 is an experimental result.
The arsenic trioxide of table 1 variable concentrations is to the inhibitory action of Raji cell growth.
| As 2O 3 (μmol/L) | Viable count (10 5/ml) | ||||
| 0 | 0.25 | 0.5 | 1.0 | 2.0 | |
| 24 hours | 4.47±0.38 | 4.30±0.52 | 4.13±0.32 | 3.70±0.26 | 2.60±0.20 ** |
| 48 hours | 7.00±0.26 | 6.83±0.47 | 6.07±0.25 * | 5.60±0.17 ** | 3.53±0.53 ** |
| 72 hours | 9.67±0.25 | 9.46±0.51 | 8.37±0.51 * | 5.90±0.20 ** | 2.70±0.26 ** |
| 96 hours | 14.87±0.21 | 14.13±0.61 | 10.07±0.15 ** | 7.67±0.21 ** | 1.23±0.11 ** |
Shown in the table, the Raji cell that inoculation is in exponential phase of growth is on 24 well culture plates, and every hole inoculum concentration is 1.0ml, and cell density is 2.0 * 10
5/ ml, 37 ℃, saturated humidity is cultivated in 5% CO2 gas incubator, and the blank group adds equivalent RPMI-1640 culture fluid, through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 24,48,72 hours, the viable count of surveying.Reflection 0.5～2.0 μ mol/L As
2O
3Cell growth inhibiting, and present dose-dependent effect, and 0.25 μ mol/LAs
2O
3Compare there was no significant difference with matched group.Curve chart is seen Fig. 2.
The arsenic trioxide of table 2 variable concentrations is to the effect of Jurkat cell growth.
| As 2O 3 (μmol/L) | Viable count (10 5/ml) | ||||
| 0 | 0.5 | 1.0 | 2.0 | 4.0 | |
| 24 hours | 3.53±0.11 | 3.46±0.06 | 3.43±0.06 | 3.37±0.15 | 3.30±0.17 |
| 48 hours | 5.87±0.12 | 5.90±0.20 | 5.83±0.15 | 5.77±0.15 | 5.70±0.26 |
| 72 hours | 8.53±0.12 | 8.50±0.17 | 8.40±0.26 | 8.37±0.35 | 8.10±0.36 |
| 96 hours | 12.53±0.21 | 12.13±0.38 | 12.00±0.30 | 11.73±0.65 | 11.57±0.67 |
Shown in the table, the Jurkat cell that inoculation is in exponential phase of growth is on 24 well culture plates, and every hole inoculum concentration is 1.0ml, and cell density is 2.0 * 10
5/ ml, 37 ℃, saturated humidity is cultivated in 5% CO2 gas incubator, and the Jurkat cell is through 0.5,1.0,2.0,4.0 μ mol/L As
2O
3Act on 24,48,72 hours, the viable count of surveying.Reflection 0.5～4.0 μ mol/L As
2O
3Cell growth inhibiting not.Curve chart is seen Fig. 3.
The arsenic trioxide of table 3 variable concentrations is to the apoptotic percentage rate of Raji (%).
| As 2O 3(μ mol/L) | 0 | 0.5 | 1.0 | 2.0 | 4.0 |
| 24 hours | 0.06±0.01 | 0.34±0.05 ** | 0.79±0.08 ** | 3.11±0.13 ** | 14.61±0.02 ** |
| 48 hours | 0.97±0.02 | 1.49±0.03 ** | 4.57±0.45 ** | 8.24±0.65 ** | 41.29±0.88 ** |
| 72 hours | 1.64±0.35 | 4.01±0.20 ** | 15.05±0.50 ** | 26.55±1.50 ** | 79.55±2.00 ** |
Shown in the table, the Raji cell is through 0.5,1.0,2.0,4.0 μ mol/L As
2O
3Act on 24,48,72 hours, the content of flow cytometry analysis Raji cell DNA.Reflection 0.5～4.0 μ mol/L As
2O
3Act on after 24,48,72 hours, compared highly significant difference with matched group.See Fig. 4.
Table 4 flow cytometer detects Raji cell oncogene protein The positive expression rate (%) (72 hours) under the arsenical effect.
| As 2O 3(μ mol/L) | 0 | 1.0 | 2.0 | 4.0 |
| Bcl-2 | 74.86±1.70 | 40.46±3.14 ** | 23.69±1.83 ** | 13.64±1.44 ** |
| P53 | 20.34±6.07 | 34.14±4.58 * | 36.66±2.41 * | 20.74±8.26 |
Shown in the table, 1.0,2.0,4.0 μ mol/L As
2O
3Handled the Raji cell 72 hours, fluidic cell detects bcl-2, p53 The positive expression rate (%).Experimental group has been compared significant differences with matched group.
The arsenic trioxide of table 5 variable concentrations is to the influence (72 hours) of former generation lymphoma cell vigor.
6 routine lymphoma case specimen are collected in experiment altogether, 4 routine non-Hodgkin lymphomas (3 routine B cellular types, 1 routine T cellular type) wherein, 2 routine Hodgkin (1 routine B cellular type, 1 routine T cellular type), male's 4 examples in the case, women's 2 examples, 10～45 years old age.In former generation,, cultured cells was when no somatomedin etc. exists, and propagation seldom occurred, and cell viability descends gradually.Inoculate former generation lymphoma cell on 24 well culture plates, every hole inoculum concentration is 1.0ml, and cell density is 1.0 * 10
6/ ml, 37 ℃, saturated humidity is cultivated in 5% CO2 gas incubator.
| Case | Viable count (10 5/ml) | |||
| (As 2O 3)0 | 0.5 | 1.0 | 2.0 | |
| NHL(B)1 | 8.27±0.25 | 7.37±0.21 ** | 7.35±0.15 ** | 7.16±0.15 ** |
| NHL(B)2 | 8.36±0.25 | 7.70±0.35 ** | 6.27±0.21 ** | 2.67±0.32 ** |
| NHL(B)3 | 8.13±0.32 | 6.91±0.25 ** | 4.10±0.17 ** | 2.63±0.65 ** |
| HD(B)4 | 7.80±0.30 | 6.50±0.30 ** | 2.87±0.31 ** | 2.23±0.49 ** |
| NHL(T)5 | 8.17±0.32 | 7.40±0.26 * | 7.30±0.17 * | 7.20±0.17 * |
| HD(T)6 | 8.13±0.38 | 7.33±0.31 * | 7.20±0.26 * | 7.10±0.20 * |
Shown in the table, in former generation,, lymphoma cell was through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 72 hours, the viable count of surveying.Along with the increase of drug level and the prolongation of action time, cell viability obviously descends, 4 example effects are (3 routine NHL, 1 routine HD obviously, all belong to B cellular type), experimental group has been compared significant differences with matched group, other 2 examples also have certain effect (1 routine NHL, 1 routine HD all belong to T cellular type), and experimental group has been compared significant difference with matched group.Can find that B cellular type lymphoma cell is responsive more to arsenic trioxide than T cellular type lymphoma cell.
The arsenic trioxide of table 6 variable concentrations is to the influence (48 hours) of former generation acute lymphoma leukaemia vigor.
3 examples are becoming impatient property Lymphocytic leukemia case specimen just, are the male, 10～25 years old age, and two routine L2 types wherein, 1 routine L3 type, immunological type is B cellular type (original inmature lymphocyte＞80%).2 routine normal person's rib BMNCs in contrast.Inoculate former generation lymphoma cell on 24 well culture plates, every hole inoculum concentration is 1.0ml, and cell density is 1.0 * 10
6/ ml, 37 ℃, saturated humidity is cultivated in 5% CO2 gas incubator.
| Case | Viable count (10 5/ml) | |||
| (As 2O 3)0 | 0.5 | 1.0 | 2.0 | |
| 1 (L2 type) | 9.27±0.06 | 8.67±0.25 * | 8.17±0.21 ** | 7.60±0.26 ** |
| 2 (L2 types) | 9.50±0.17 | 8.57±0.21 ** | 8.23±0.15 ** | 7.80±0.44 ** |
| 3 (L3 types) | 9.77±0.15 | 9.37±0.12 * | 9.00±0.20 ** | 8.60±0.26 ** |
Shown in the table, in former generation,, acute lymphoblastic leukemia cell was through 0.5,1.0,2.0 μ mol/LAs
2O
3Act on 48 hours, the viable count of surveying, reflection 0.5～2.0 μ mol/L As
2O
3Can suppress former generation acute lymphoblastic leukemia cell vigor, and present dose-dependent effect.
The arsenic trioxide of table 7 variable concentrations is to the influence (48 hours) of normal person's BMNC vigor.
| Case | Viable count (10 5/ml) | |||
| (As 2O 3)0 | 0.5 | 1.0 | 2.0 | |
| 1 | 9.67±0.15 | 9.47±0.21 | 9.23±0.31 | 9.10±0.26 * |
| 2 | 9.70±0.10 | 9.63±0.06 | 9.53±0.06 | 9.17±0.25 * |
Shown in the table, inoculation normal person BMNC is on 24 well culture plates, and every hole inoculum concentration is 1.0ml, and cell density is 1.0 * 10
6/ ml, 37 ℃, saturated humidity is cultivated in 5% CO2 gas incubator, through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 48 hours, the viable count of surveying is observed 0.5～2.0 μ mol/L As
2O
3Acted on the normal marrow mononuclearcell 48 hours, (2.0 μ mol/L) vigor also capable of inhibiting cell during high concentration, experimental group has been compared significant difference with matched group, but the normal cell of malignant cell is responsive more.
The percentage rate (%) (72 hours) of the Arsenic Trioxide Induced of table 8 variable concentrations lymphoma cell apoptosis of former generation.
| | 0 | 0.5 | 1.0 | 2.0 |
| NHL(B)1 | 5.32 | 11.33 | 12.80 | 18.13 |
| NH(B)2 | 7.92 | 19.34 | 27.12 | 66.86 |
| NHL(B)3 | 11.59 | 24.42 | 46.79 | 70.48 |
| HD(B)4 | 13.97 | 23.63 | 62.80 | 73.43 |
| NHL(T)5 | 7.37 | 10.63 | 13.89 | 15.20 |
| HD(T)6 | 9.96 | 10.36 | 12.68 | 17.09 |
In former generation,, lymphoma cell was through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 72 hours, the content of flow cytometry analysis cell DNA, as seen hypodiploid peak, with the prolongation of action time and the increase of drug level, the quantity of apoptotic cell increases gradually, and 4 example effects are (3 routine NHL, 1 routine HD all belong to B cellular type) obviously, other 2 examples also have certain effect (1 routine NHL, 1 routine HD all belong to T cellular type).
The percentage rate (%) (48 hours) of the Arsenic Trioxide Induced of table 9 variable concentrations acute lymphoblastic leukemia cell apoptosis of former generation.
| | 0 | 0.5 | 1.0 | 2.0 |
| 1 (L2 type) | 4.86 | 6.33 | 10.59 | 15.38 |
| 2 (L2 types) | 3.14 | 8.42 | 10.90 | 12.36 |
| 3 (L3 types) | 1.88 | 3.11 | 5.84 | 7.94 |
In former generation,, acute lymphoblastic leukemia cell was through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 48 hours, the content of flow cytometry analysis cell DNA, with the increase of drug level, the quantity of apoptotic cell increases gradually.
The percentage rate (%) (48 hours) of Arsenic Trioxide Induced normal person's BMNC apoptosis of table 10 variable concentrations.
| | 0 | 0.5 | 1.0 | 2.0 |
| 1 | 1.89 | 2.68 | 3.16 | 3.62 |
| 2 | 1.83 | 2.00 | 2.24 | 2.97 |
The normal marrow mononuclearcell is through 0.5,1.0,2.0 μ mol/L As
2O
3Act on 48 hours, the content of flow cytometry analysis cell DNA, with the increase of drug level, the quantity of apoptotic cell increases gradually.
By above-mentioned a series of experiment, can reach a conclusion:
1, arsenic trioxide suppresses B Lymphoma Raji Cells propagation, and cell death inducing to T lymphoma Jurkat cell, is not observed propagation and the apoptosis-induced effect of suppressing.
2, arsenic trioxide is induced B Lymphoma Raji Cells apoptosis by suppressing the proteic expression of bcl-2.
3, arsenic trioxide can be induced former generation T, B lymphoma cell apoptosis, for arsenic trioxide clinical treatment malignant lymphoma provides foundation.
As seen, in treatment common dose scope, arsenic trioxide has the effect of kill tumor cell preferably to malignant lymphoma, is not easy to produce drug resistance; Little to normal tissue toxicity, after discontinuing medication, can recover.
Fig. 1 is the growth curve chart of Raji and Jurkat cell;
Fig. 2 is the As of variable concentrations
2O
3Inhibitory action curve chart to the growth of Raji cell.
Fig. 3 is the As of variable concentrations
2O
3Inhibitory action curve chart to the growth of Jurkat cell.
Fig. 4 is As
2O
3Induce the apoptotic percentage diagram of Raji.
Embodiment:
Arsenic trioxide medicament state is internal energy a large amount of synthetic; Take by weighing 197.8 milligrams of arsenic trioxide, to finishing dissolving, add 0.989 liter of tri-distilled water, stir evenly, adjust pH value to 7.2～7.4, be preferably pH=7.2 with about 1 milliliter of 1mmol/LHCl with 10 milliliters of 1mmol/L NaOH titration, filtration sterilization, packing is standby.Can adopt the mode administration of intravenous drip.
Claims (4)
1, a kind of medicine for the treatment of malignant lymphoma is characterized in that: be made up of arsenic trioxide, sodium ion, chloride ion and water substantially, described arsenic trioxide concentration is 0.5～2.0 μ mol/L.
2, medicine according to claim 1 is characterized in that: described Na ion concentration is 0.01mmol/L; Chlorine ion concentration is 0.001mmol/L.
3, a kind of method of preparing claim 1 or 2 described medicines is characterized in that: earlier with sodium hydroxide solution with the arsenic trioxide titration to finishing dissolving, the reuse tri-distilled water is formulated into required concentration, adjusts pH value to 7.2～7.4 with hydrochloric acid solution at last.
4, compound method according to claim 3 is characterized in that: described pH value is 7.2.
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|---|---|---|---|
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|---|---|---|---|
| CNB011075368A CN1176665C (en) | 2001-02-15 | 2001-02-15 | Medicine for treating maligant leucoma and its compounding process |
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| CN1176665C true CN1176665C (en) | 2004-11-24 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1332672C (en) * | 2001-03-15 | 2007-08-22 | 张鹏 | Arsenic trioxide powder for injection |
| US8906422B2 (en) | 2002-10-09 | 2014-12-09 | The University Of Hong Kong | Method for inhibiting cancer using arsenic trioxide |
| US7521071B2 (en) * | 2002-10-09 | 2009-04-21 | Versitech Limited | Formulation of oral compositions comprising arsenic trioxide and methods of use thereof |
| CN103142648B (en) * | 2011-12-07 | 2015-04-15 | 浙江中医药大学 | Arsenic compound solution, and alhumin nanoparticles encapsulated with arsenic compound and freeze-drying preparation prepared by same |
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