CN102648917A - Application of vitamin D3 in preparing medicine for treating multiple myeloma - Google Patents
Application of vitamin D3 in preparing medicine for treating multiple myeloma Download PDFInfo
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- CN102648917A CN102648917A CN2012101254754A CN201210125475A CN102648917A CN 102648917 A CN102648917 A CN 102648917A CN 2012101254754 A CN2012101254754 A CN 2012101254754A CN 201210125475 A CN201210125475 A CN 201210125475A CN 102648917 A CN102648917 A CN 102648917A
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- vitamin
- multiple myeloma
- medicine
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- bortezomib
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Abstract
The invention discloses medicine for treating multiple myeloma, and particularly relates to application of vitamin D3 and derivatives thereof in preparing a pharmaceutical composition for treating multiple myeloma. The medicine has the principle of treatment that vitamin D3 is mainly acted on a tumour cell Hedgehog (Hh) signaling pathway, and is used for inhibiting accumulation of Smoothened (Smo) protein in the pathway, so that the aim of inhibiting tumor growth is achieved. Compared with bortezomib, the vitamin D3 almost has no toxicity, and in mouse test, no accidental death caused by drug toxicity occurred. The clinical trials indicate that the medicine has a therapeutical effect on patient with types of multiple myeloma, and particularly has a better therapeutical effect for patients after the transplantation of bone marrow. 30 clinical trial patient treatment indicates that the total effective rate achieves 96.7 percent. In addition, the medicine is combined with the bortezomib, so that a synergistic effect is realized.
Description
Technical field
The invention belongs to the medicinal application field of treatment malignant tumor, particularly the medicine of treatment multiple myeloma.
Background technology
Vitamin D
3, have another name called nicotinic amine, cholecalciferol.Common vitamin D
3Following physiological function is arranged: improve the absorption of human body, make the level of plasma calcium and the blood plasma phosphorus degree that reaches capacity to calcium, phosphorus; Promote growth and skeleton calcification, promote tooth sound; Increase the absorption of phosphorus through intestinal wall, and pass through the absorption again that renal tubules increases phosphorus; Keep the normal level of citrate in the blood; Prevent that aminoacid from passing through the kidney loss.In the patent documentation, Chinese patent CN200910140552 has introduced vitamin D
3Induce apoptosis and cytotoxicity, a kind of compositions that contains vitamin D3 is provided simultaneously to the keratinocyte of hyper-proliferative.Chinese patent CN200480007470 has introduced the malignant tumor purposes of dihydroxyvitamin D 2.Chinese patent CN98801176 has introduced the biological activity of multivitamin D3, has mentioned the influence to some malignant tumor.Chinese patent CN0384324 discloses a kind of medical usage of vitamin D 3-derivatives.
Multiple myeloma (multiple myeloma; MM) be the paraplasm malignant tumor of plasma cell; Be a kind of progressive ND. it is characterized by the MIg (IgG of a bone marrow plasmocytoma and a strain integrity; IgA, IgD or IgE) or Bence Jones protein (free monoclonicity κ or γ light chain) hyperplasia.Multiple myeloma is often with multiple molten bone property infringement, hypercalcemia, and anemia, kidney damage, and the susceptibility of bacterial infection increased, the generation of normal immunoglobulin receives to press down.
Unexposed vitamin D in the prior art
3Be used for the medical usage of multiple myeloma and concrete application dose.
Summary of the invention
The present invention has disclosed vitamin D
3Preparing multiple myeloma with the application in the medical composition.
In the multiple myeloma treatment, Hedgehog (Hh) signal path abnormal expression.It is reported that the survival of Hh signal path and multiple myeloma stem cell is closely related.Propose among the inventor's the Chinese patent CN201110029986.1; Itraconazole mainly acts on tumor cell Hedgehog (Hh) signal path; Suppress the proteic accumulation of Smoothened (Smo) in the path, thereby reach the purpose that suppresses tumor growth, the inventor explores through a large amount of; In the present invention, vitamin D is disclosed
3Also has above-mentioned identical effect.
Vitamin D of the present invention
3Or derivatives thereof can be processed multiple dosage form, that is to say vitamin D of the present invention
3The treatment that is used for multiple myeloma does not receive vitamin D
3The structure restriction of changing a little, can be selected from but be not limited to following vitamin D
3Derivant: the derivant of Chinese patent CN1241999, calcipotriol etc.
Vitamin D of the present invention
3Application, be preferably and be used for oral medical composition.
Medical composition of the present invention, particularly soft gelatin capsule, a day taking dose is the 100-300 iu.
Further, a day taking dose is 250 ius.
Further, each taking dose is 125 ius, twice of every day.
Vitamin D of the present invention
3Application, be the multiple myeloma that is used for after the bone marrow transplantation.
Further, the invention discloses vitamin D
3Or derivatives thereof and bortezomib are united in the preparation multiple myeloma with the application in the medical composition.
Beneficial effect of the present invention does, product targeting property of the present invention is strong, and the mechanism of action is clear and definite.Compare with other treatment multiple myeloma medicine, like bortezomib, vitamin D
3Effect is remarkable, and toxic and side effects is little.The present invention finds vitamin D unexpectedly
3Effect with treatment multiple myeloma, the treatment principle is a vitamin D
3Mainly act on tumor cell Hedgehog (Hh) signal path, suppress the proteic accumulation of Smoothened (Smo) in the path, thereby reach the purpose that suppresses tumor growth.Compare vitamin D with bortezomib
3Almost non-toxic property, the phenomenon of not dying unexpectedly because of drug toxicity in the mouse test takes place.Clinical trial shows for various multiple myeloma patients therapeutical effect is arranged all, and is better in particular for the therapeutic effect after the bone marrow transplantation.30 routine clinical trial patient treatments are being shown that total effective rate reaches 96.7%.In addition, this medicine and bortezomib are united use, have synergism.
Face further describes invention through Test Example.
Test Example 1, animal experiment
Administrated method; Oral
Experimental condition: adopt a cleaning level C57BL/KaLwRijHsd mice, available from Dutch Harlan company.The C57BL/KaLwRijHsd mice is in cleaning level experiment indoor feeding and experiment.
Test drug: vitamin D
3Be dissolved in PBS solution.
Test method: get the C57BL/KaLwRijHsd mice in 40 6 ages in week, be divided into 4 groups immediately, male and female animal half and half in every group, the difference on the equal not statistically significant of the body weight between each treated animal.
The dosage regimen of 4 treated animals is:
Matched group: PBS, 0.1ml/kg body weight/day, lumbar injection
Treatment group 1: vitamin D
32.6mg/kg body weight/day is inferior, oral on every Fridays
Treatment group 2: bortezomib 1mg/kg body weight/day, weekly twice, lumbar injection
Treatment group 3: vitamin D
3With the bortezomib drug combination, dosage is the same
1000000 5T33 multiple myeloma cells of C57BL/KaLwRijHsd mouse tail vein injection are pressed the such scheme administration after one week.Weigh every day during the animals administer, confirms the dosage on the same day according to body weight, and successive administration is to dead mouse.Gather mouse vein blood weekly and preserve the death time of record mice.
The experimental result of table 1 and table 2 shows, vitamin D
3Can prolong the life span of the C57BL/KaLwRijHsd mice that suffers from multiple myeloma, and reduce the tumor load amount in the mice serum.Though the therapeutic effect of bortezomib is superior to vitamin D3, bortezomib and vitamin D
3Drug combination has synergism.Through statistical test, the time-to-live of matched group C57BL/KaLwRijHsd mice has been compared significant difference P＜0.05 with the treatment group.Tumor load amount in the serum of matched group C57BL/KaLwRijHsd mice has been compared significant difference P＜0.05 with the treatment group.Fig. 1 is the survival curve of C57BL/KaLwRijHsd mice after the medication.Fig. 2 is the tumor load discharge curve in the C57BL/KaLwRijHsd mice serum after the medication.
Table 1 injection vitamin D
3And the survival natural law of C57BL/KaLwRijHsd mice behind the bortezomib
Test Example 2 Liver and kidney toxicity tests
Trial drug: vitamin D
3
Control drug: bortezomib.
Animal subject: mice.
Test method: carry out with reference to " medicine toxicological study guideline "
Result of the test: compare vitamin D with bortezomib
3Almost do not have liver toxicity, the phenomenon of not dying unexpectedly because of drug toxicity in the mouse test takes place.
Test Example 3 human trials
With reference to " antitumor drug clinical trial technological guidance principle "; Select 30 routine patients; Male's 20 examples, women's 10 examples; Age 30-65 year, observation index comprises the improving of result and quality of life, sings and symptoms (alleviating of the increase of body weight, pain) of total life cycle, DFS phase, the life cycle of getting nowhere, PD time, treatment Time To Failure, subjects reported.
Cardinal symptom is renal insufficiency 18 examples, anemia 18 examples, bone damage 14 examples, weak 4 examples, EMP 2 examples.Part patient has two or more symptoms.Clinical stages: I phases 4 example, II phases 9 example, III phases 17 example.Bone damage is made a definite diagnosis through x line, CT or MRI, whole body bone scanning.Result of the test, IgG type 12 examples among the 30 routine patients, light chain type 9 examples, IgA type 6 examples, IgD type 1 example, IgE type 1 example, IgM type 1 example, nonsecreting type 1 example.Total effective rate is 96.7%.Tolerant invariably toxic and side effects.
Further specify the present invention through specific embodiment below.
Description of drawings
Fig. 1 bortezomib and vitamin D
3Act on the survival curve of C57BL/KaLwRijHsd mice;
Fig. 2 bortezomib and vitamin D
3Tumor load discharge curve after the medication in the C57BL/KaLwRijHsd mice serum.
The specific embodiment
Embodiment 1 vitamin D
3Soft gelatin capsule
Get vitamin D
3Add vegetable oil, after the dissolving, according to the soft gelatin capsule method for preparing, preparation promptly gets.Every capsules: contain 125 iu vitamin D
3
Model case
1, man, 75 years old, once bone marrow transplantation was diagnosed as the light chain type multiple myeloma, and κ/λ ratio is 1.2: 1, with Bence Jones proteinuria, renal insufficiency, amyloidosis are arranged, gives 125 iu vitamin D
3 soft gelatin capsules, every day twice, bortezomib, drug administration by injection, 4 months courses of treatment, prognosis bona.
2, woman, 43 years old, hemoglobin＜85g/L was diagnosed as IgD type multiple myeloma, and κ/λ ratio is 1: 9.The renal function injury of concurrent plasma cell leukemia, and merging simultaneously gives 125 iu vitamin D
3Soft gelatin capsule, every day twice, bortezomib, drug administration by injection, was survived 14 months at 2 months courses of treatment.
3, man, 39 years old, hemoglobin＞100g/L (＜0.6 * 1012 cells/m2); M albumen synthetic ratio low IgG＜50/L IgA＜30g/L, urine κ or lambda light chain＜4g/24 hour, blood calcium is normal; The bone X-ray film is normal or have only indivedual bones that dissolve to sexually revise; Be diagnosed as the I phase, IgG type multiple myeloma gives 125 iu vitamin D
3Soft gelatin capsule, every day twice, 3 weeks of the course of treatment, prognosis bona.
4, the woman is 21 years old, hemoglobin 0.6-1.2 * 10
12Individual cell/m
2, be diagnosed as IgA type multiple myeloma: give 125 iu vitamin D
3Injection, every day twice, 2 months courses of treatment, prognosis is general.
5, man, 21 years old, bone marrow transplantation once, hemoglobin＞1.2 * 10
12Individual cell/m
2Be diagnosed as IgE type multiple myeloma, merge plasma cell leukemia simultaneously, give 125 iu vitamin D
3The injecting glue ball, 4 months courses of treatment, was survived 4 years at every day twice.
Claims (8)
1. vitamin D
3Preparing multiple myeloma with the application in the medical composition.
2. application as claimed in claim 1 is characterized in that: said medical composition mainly acts on tumor cell Hedgehog signal path, suppresses the proteic accumulation of Smoothened in the path.
3. application as claimed in claim 1 is characterized in that: said medical composition is to be used for oral medical composition.
4. medical composition as claimed in claim 3, a day taking dose is the 100-300 iu.
5. medical composition as claimed in claim 4, a day taking dose is 250 ius.
6. medical composition as claimed in claim 3, each taking dose is 125 ius.
7. like the described application of claim 1-6, be the multiple myeloma that is used for after the bone marrow transplantation.
8. vitamin D
3Or derivatives thereof and bortezomib are united in the preparation multiple myeloma with the application in the medical composition.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101254754A CN102648917A (en) | 2012-04-25 | 2012-04-25 | Application of vitamin D3 in preparing medicine for treating multiple myeloma |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012101254754A CN102648917A (en) | 2012-04-25 | 2012-04-25 | Application of vitamin D3 in preparing medicine for treating multiple myeloma |
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| CN102648917A true CN102648917A (en) | 2012-08-29 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827584A (en) * | 2020-06-08 | 2021-12-24 | 沈阳药科大学 | Vitamin K2And vitamin D3Composition and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596115A (en) * | 2001-11-28 | 2005-03-16 | 骨疗国际公司 | Treatment of hyperproliferative diseases using active vitamin D analogues |
| CN1646136A (en) * | 2001-12-03 | 2005-07-27 | 诺瓦西股份有限公司 | Pharmaceutical compositions comprising active vitamin D compounds |
| CN1856251A (en) * | 2003-06-11 | 2006-11-01 | 诺瓦西股份有限公司 | Pharmaceutical compositions comprising active vitamin D compounds |
-
2012
- 2012-04-25 CN CN2012101254754A patent/CN102648917A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596115A (en) * | 2001-11-28 | 2005-03-16 | 骨疗国际公司 | Treatment of hyperproliferative diseases using active vitamin D analogues |
| CN1646136A (en) * | 2001-12-03 | 2005-07-27 | 诺瓦西股份有限公司 | Pharmaceutical compositions comprising active vitamin D compounds |
| CN1856251A (en) * | 2003-06-11 | 2006-11-01 | 诺瓦西股份有限公司 | Pharmaceutical compositions comprising active vitamin D compounds |
Non-Patent Citations (1)
| Title |
|---|
| M. KAISER ET AL: "BORTEZOMIB STIMULATES OSTEOBLASTIC DIFFERENTIATION VIA INCREASED NUCLEAR VITAMIN D RECEPTOR LEVELS AND ENHANCED VITAMIN D RECEPTOR SIGNALING", 《HAEMATOLOGICA》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827584A (en) * | 2020-06-08 | 2021-12-24 | 沈阳药科大学 | Vitamin K2And vitamin D3Composition and application thereof |
| CN113827584B (en) * | 2020-06-08 | 2023-09-12 | 沈阳药科大学 | Vitamin K 2 And vitamin D 3 Compositions of (2) and uses thereof |
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Free format text: FORMER OWNER: WAN LI WANG MIN ZHOU YAQIONG GU CHUNYAN Effective date: 20121225 Owner name: CHINA PHARMACEUTICAL UNIVERSITY Free format text: FORMER OWNER: YANG YE Effective date: 20121225 |
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Effective date of registration: 20121225 Address after: Tong Xiang, Xuanwu District, Nanjing City, Jiangsu Province, No. 24 210038 Applicant after: China Pharmaceutical University Address before: Tong Xiang, Xuanwu District, Nanjing City, Jiangsu province 210038 No. 24 School of life science and technology China Medicine University room 2213 Applicant before: Yang Ye Applicant before: Wan Li Applicant before: Wang Min Applicant before: Zhou Yaqiong Applicant before: Gu Chunyan |
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Application publication date: 20120829 |