CN102648917A - Application of vitamin D3 in preparing medicine for treating multiple myeloma - Google Patents

Abstract

The invention discloses a medicine for treating multiple myeloma, and particularly relates to the application of vitamin _D3 or its derivatives in preparing a medical composition for multiple myeloma. The therapeutic principle of the product of the present invention is that vitamin _D3 mainly acts on the Hedgehog (Hh) signaling pathway of tumor cells, and inhibits the accumulation of Smoothened (Smo) protein in the pathway, thereby achieving the purpose of inhibiting tumor growth. Compared with bortezomib, vitamin D ₃ is almost non-toxic, and no accidental death due to drug toxicity occurred in the mouse test. Clinical trials have shown that it has a therapeutic effect on patients with various types of multiple myeloma, especially after bone marrow transplantation. In the treatment of 30 clinical trial patients, the total effective rate reached 96.7%. In addition, the drug is used in combination with bortezomib, which has a synergistic effect.

Description

Application of vitamin D3 in preparation of medicine for treating multiple myeloma

technical field

The invention belongs to the application field of medicines for treating malignant tumors, in particular to medicines for treating multiple myeloma. the

Background technique

Vitamin D ₃ , also known as niacinamide and cholecalciferol. Usually vitamin _D3 has the following physiological functions: improve the body's absorption of calcium and phosphorus, and make the levels of plasma calcium and phosphorus reach saturation; promote growth and bone calcification, and promote healthy teeth; increase phosphorus absorption through the intestinal wall, and through Renal tubules increase reabsorption of phosphorus; maintain normal levels of citrate in the blood; prevent loss of amino acids through the kidneys. In the patent literature, Chinese patent CN200910140552 describes that vitamin _D3 induces apoptosis and cytotoxicity against hyperproliferative keratinocytes, and also provides a composition containing vitamin D3. Chinese patent CN200480007470 describes the use of dihydroxyvitamin D2 for malignant tumors. Chinese patent CN98801176 has introduced the biological activity of multivitamin D3, mentioned the impact on some malignant tumors. Chinese patent CN0384324 discloses the medical use of a vitamin D3 derivative.

Multiple myeloma (multiple myeloma, MM) is a malignant tumor with abnormal proliferation of plasma cells, and it is a progressive neoplastic disease. IgA, IgD, or IgE) or Bence Jones protein (free monoclonal kappa or gamma light chain) hyperproliferation. Multiple myeloma is often accompanied by multiple osteolytic lesions, hypercalcemia, anemia, kidney damage, increased susceptibility to bacterial infection, and inhibited normal immunoglobulin production. the

The medical use of vitamin _D3 for multiple myeloma and the specific application dosage are not disclosed in the prior art.

Contents of the invention

The invention discloses the application of vitamin _D3 in the preparation of a pharmaceutical composition for multiple myeloma.

In the treatment of multiple myeloma, the Hedgehog (Hh) signaling pathway is abnormally expressed. It has been reported that the Hh signaling pathway is closely related to the survival of multiple myeloma stem cells. The inventor’s Chinese patent CN201110029986.1 proposes that itraconazole mainly acts on the Hedgehog (Hh) signaling pathway of tumor cells and inhibits the accumulation of Smoothened (Smo) protein in the pathway, thereby achieving the purpose of inhibiting tumor growth. After much research, in the present invention, it is disclosed that vitamin D ₃ also has the same effect as above.

The vitamin _D3 of the present invention or its derivatives can be made into various dosage forms, that is to say that the vitamin _D3 of the present invention is used for the treatment of multiple myeloma and is not limited by slightly changing the structure of vitamin _D3 , and can be selected From but not limited to the following vitamin _D3 derivatives: derivatives of Chinese patent CN1241999, calcipotriol, etc.

The application of vitamin D ₃ of the present invention is preferably a pharmaceutical composition for oral administration.

The daily dosage of the pharmaceutical composition of the present invention, especially the capsule, is 100-300 international units. the

Further, the daily dosage is 250 international units. the

Further, each dose is 125 international units, twice a day. the

The application of vitamin D ₃ of the present invention is for multiple myeloma after bone marrow transplantation.

Furthermore, the present invention discloses the application of vitamin _D3 or its derivatives in combination with bortezomib in the preparation of a pharmaceutical composition for multiple myeloma.

The beneficial effect of the invention is that the product of the invention has strong targeting and clear mechanism of action. Compared with other drugs for the treatment of multiple myeloma, such as bortezomib, vitamin _D3 has a significant effect and less toxic side effects. The present invention unexpectedly found that vitamin _D3 has the effect of treating multiple myeloma, and the therapeutic principle is that vitamin _D3 mainly acts on the Hedgehog (Hh) signaling pathway of tumor cells, inhibiting the accumulation of Smoothened (Smo) protein in the pathway, thereby achieving tumor suppression purpose of growth. Compared with bortezomib, vitamin D ₃ is almost non-toxic, and no accidental death due to drug toxicity occurred in the mouse test. Clinical trials have shown that it has a therapeutic effect on patients with various types of multiple myeloma, especially after bone marrow transplantation. In the treatment of 30 clinical trial patients, the total effective rate reached 96.7%. In addition, the drug is used in combination with bortezomib, which has a synergistic effect.

The invention will be further described by way of test examples. the

Test example 1, animal test

Medication method; Oral

Experimental conditions: Clean grade C57BL/KaLwRijHsd mice were used, purchased from Harlan Company in the Netherlands. C57BL/KaLwRijHsd mice were raised and tested in a clean laboratory. the

Test drug: Vitamin D ₃ was dissolved in PBS solution.

Test method: Take 40 6-week-old C57BL/KaLwRijHsd mice and divide them into 4 groups, with half male and half male animals in each group. There is no statistically significant difference in body weight among the animals in each group. the

The dosing regimen of the 4 groups of animals is:

Control group: PBS, 0.1ml/kg body weight/day, intraperitoneal injection

Treatment group 1: Vitamin D ₃ 2.6mg/kg body weight/day, five times a week, orally

Treatment group 2: Bortezomib 1mg/kg body weight/day, twice a week, intraperitoneal injection

Treatment group 3: Combination of vitamin D ₃ and bortezomib at the same dose as above

One week after C57BL/KaLwRijHsd mice were injected with 1,000,000 5T33 multiple myeloma cells through the tail vein, they were administered according to the above scheme. During the administration period, the animals were weighed every day, and the dosage of the day was determined according to the body weight, and the administration was continued until the mice died. The venous blood of the mice was collected and stored every week, and the time of death of the mice was recorded. the

The experimental results in Table 1 and Table 2 show that vitamin D ₃ can prolong the survival time of C57BL/KaLwRijHsd mice with multiple myeloma, and reduce the tumor burden in mouse serum. Although the therapeutic effect of bortezomib is better than that of vitamin D3, the combination of bortezomib and vitamin _D3 has a synergistic effect. After statistical test, the survival time of C57BL/KaLwRijHsd mice in the control group was significantly different from that in the treatment group (P<0.05). The tumor burden in the serum of the control group C57BL/KaLwRijHsd mice had a significant difference P<0.05 compared with the treatment group. Figure 1 is the survival curve of C57BL/KaLwRijHsd mice after administration. Fig. 2 is the tumor load curve in serum of C57BL/KaLwRijHsd mice after administration.

Table 1 Survival days of C57BL/KaLwRijHsd mice after injection of vitamin D ₃ and bortezomib

Test Example 2 Liver and kidney toxicity test

Test drug: vitamin _D3 ;

Comparing drug: bortezomib. the

Test animals: mice. the

Test method: refer to the "Guiding Principles of Drug Toxicology Research"

Test results: Compared with bortezomib, vitamin D ₃ has almost no liver toxicity, and no accidental death due to drug toxicity occurred in the mouse test.

Test Example 3 Human Test

Referring to the "Technical Guidelines for Clinical Trials of Antineoplastic Drugs", select 30 patients, 20 males and 10 females, aged 30-65 years, and the observation indicators include overall survival, disease-free survival, progression-free survival, and disease progression. time to treatment failure, subject-reported outcomes and quality of life, improvement in signs and symptoms (weight gain, pain reduction). the

The main symptoms were renal insufficiency in 18 cases, anemia in 18 cases, bone damage in 14 cases, fatigue in 4 cases, and extramedullary plasmacytoma in 2 cases. Some patients have more than two symptoms. Clinical stage: 4 cases of stage I, 9 cases of stage II, and 17 cases of stage III. Bone damage was confirmed by x-ray, CT or MRI, and whole-body bone scan. The test results showed that among the 30 patients, there were 12 cases of IgG type, 9 cases of light chain type, 6 cases of IgA type, 1 case of IgD type, 1 case of IgE type, 1 case of IgM type and 1 case of non-secretory type. The total effective rate is 96.7%. No intolerable toxic and side effects. the

The present invention is further illustrated below by specific examples. the

Description of drawings

Figure 1 Bortezomib and vitamin _D3 act on the survival curve of C57BL/KaLwRijHsd mice;

Fig. 2 Curve of tumor burden in serum of C57BL/KaLwRijHsd mice after administration of bortezomib and vitamin _D3 .

Detailed ways

Embodiment 1 vitamin D ₃ capsules

Take vitamin D ₃ and add vegetable oil, after dissolving, prepare according to the preparation method of capsules, and the product is obtained. Each Capsule: Contains 125 IU Vitamin D ₃ .

Typical cases

1. Male, 75 years old, had bone marrow transplantation, was diagnosed with light chain multiple myeloma, the κ/λ ratio was 1.2:1, accompanied by coagulopathy, renal insufficiency, and amyloidosis, and was given 125 international units Vitamin D _{3 capsules} , twice a day, bortezomib, injection administration, the course of treatment is 4 months, the prognosis is good.

2. Female, 43 years old, with hemoglobin <85g/L, diagnosed with IgD multiple myeloma, with a κ/λ ratio of 1:9. At the same time, he had plasma cell leukemia and renal impairment. He was given 125 international units of vitamin D ₃ capsules, twice a day, and bortezomib by injection. The course of treatment was 2 months, and he survived for 14 months.

3. Male, 39 years old, hemoglobin>100g/L (<0.6×1012 cells/m2), low synthesis rate of M protein IgG<50/L IgA<30g/L, urinary κ or λ light chain<4g/24 hours , normal blood calcium, normal bone X-ray films or only individual osteolytic changes, diagnosed as stage I, IgG multiple myeloma, given 125 international units of vitamin D ₃ capsules, twice a day, for 3 weeks, the prognosis good.

4. A 21-year-old female, with a hemoglobin of 0.6-1.2×10 ¹² cells/m ² , was diagnosed with IgA multiple myeloma: given 125 international units of vitamin D ₃ injection, twice a day, for 2 months, the prognosis was fair .

5. Male, 21 years old, had bone marrow transplantation, hemoglobin>1.2×10 ¹² cells/m ² . Diagnosed with multiple myeloma of IgE type and combined with plasma cell leukemia, he was given 125 international units of vitamin D ₃ injection capsules, twice a day, for 4 months, and survived for 4 years.

Claims (8)

1. Application of vitamin D ₃ in the preparation of a pharmaceutical composition for multiple myeloma. 2. The application according to claim 1, characterized in that: the pharmaceutical composition mainly acts on the Hedgehog signaling pathway of tumor cells, and inhibits the accumulation of Smoothened protein in the pathway. 3. The application according to claim 1, characterized in that: the pharmaceutical composition is a pharmaceutical composition for oral administration. 4. The pharmaceutical composition according to claim 3, the daily dosage is 100-300 international units. 5. The pharmaceutical composition according to claim 4, the daily dosage is 250 international units. 6. The pharmaceutical composition according to claim 3, each dosage is 125 international units. 7. The application according to claims 1-6, which is used for multiple myeloma after bone marrow transplantation. 8. The application of vitamin _D3 or its derivatives in combination with bortezomib in the preparation of a pharmaceutical composition for multiple myeloma.

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