JP2002302447A - Cancer therapeutic agent for topical administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cancer therapeutic agent for topical administration comprising vitamin D or a vitamin D derivative which can provide a safe and effective treatment by topical administration to a cancer, especially undifferentiated solid carcinomas such as prostatic cancer, cancer of the breast, large intestinal tumor, pancreatic cancer, without causing hypercalcemia in spite of a small amount of administration in comparison with oral administration or intravenous administration since the action is topical. SOLUTION: This cancer therapeutic agent for topical administration comprises vitamin D or a vitamin D derivative as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to a cancer therapeutic agent for topical administration of cancer containing vitamin D or a vitamin D derivative as an active ingredient, in particular, undifferentiated solid cancer.

[0002]

2. Description of the Related Art In 1980, the results of an epidemiological study that showed an increase in colorectal cancer mortality in high-latitude regions with low sunlight exposure were reported, and the relationship between vitamin D and cancer began to attract attention. Later, a more direct result was reported in colon cancer, breast cancer, and prostate cancer that the serum 25 (OH) D concentration, which reflects vitamin D supplementation status, was inversely correlated with the incidence of cancer. In 1981, a vitamin D receptor (vitamin D rec) was added to malignant melanoma and leukemia cells.
(VDR) is present, and relatively high concentrations of 1,2 are present.
5 (0H) ₂ D ₃ (10 ⁻⁹ to 10 ⁻⁷ M, blood concentration of about 10 ⁻¹⁰ M) was found to suppress tumor cell proliferation and induce differentiation. Furthermore, 1,25 (O
H) ₂ D ₃ is, it is shown to extend to exert an anti-tumor effect in mice transplanted with leukemia cells lifetime, the potential as a cancer therapeutic agent active vitamin D was to be noted. As described above, active vitamin D has a differentiation-inducing action and a growth-inhibiting action, and
It is effective in treating breast cancer, colon cancer, pancreatic cancer, etc.
Oral administration or intravenous administration causes hypercalcemia, making it difficult to administer a sufficient dose. Research on vitamin D derivatives with a weak calcium-increasing effect is also underway. However, when administered orally or intravenously, the dose will be reduced in order to exert a therapeutic effect because it acts systemically. As a result, there was a problem that hypercalcemia could not be sufficiently reduced. In fact, even in clinical practice, one of the prodrugs that is converted to 1,25 (OH) ₂ D ₃ in vivo
α is (OH) D _3, Hodgkin's lymphoma, is administered to cutaneous T-cell lymphatic and myelodysplastic plastic syndrome, although observed some improvement effects, despite the calcium restricted diet, half of the patients high Because of the side effects of calcemia, there was a problem that the required amount could not be administered for a sufficient period. Since then, a number of vitamin D derivatives having a low blood calcium-increasing effect and a stronger inhibitory effect on proliferation and differentiation have been developed, and clinical trials for breast cancer, colorectal cancer, pancreatic cancer and the like have been advanced. The effects of activated vitamin D on cell differentiation and proliferation include breast cancer, prostate cancer, colon cancer,
Not only malignant tumors such as blood system, but also skin, cartilage, bone,
It has important physiological significance in normal tissues such as the small intestine. In particular, the importance of vitamin D in the skin and skeletal system is suggested by the phenotype of VDR knockout mice. However, the mechanism by which activated vitamin D controls the differentiation and proliferation processes of various cell types via VDR remains a mystery, and a candidate molecule that could be a target of VDR was reported only a few years ago. It is a situation that it is beginning to be done.

[0003]

The present invention solves these problems, and aims to treat cancer with a small amount of a cancer therapeutic agent for topical administration of vitamin D or a vitamin D derivative.

[0004]

Means for Solving the Problems The present invention relates to a cancer treatment agent for topical administration, which comprises vitamin D or a vitamin D derivative as an active ingredient.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Cancers that are the object of the present invention cannot be classified into any tissue type such as adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, etc. because cancer cells are undifferentiated. It is preferably a differentiated cancer, and more preferably a solid cancer in which tumor cells proliferate massively and solidly.

[0006] The undifferentiated solid cancer is preferably prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, lung cancer, liver cancer, uterine cancer or bladder cancer, and is prostate cancer, breast cancer, colon cancer or pancreatic cancer. This is particularly preferred.

The vitamin D or vitamin D derivative of the present invention is a natural vitamin D of 1,25 (OH) ₂ D
₃ and derivatives such as 25 (OH) D ₃ and synthetic derivatives, or active vitamin D ₂ (1,25 (O
H) ₂ D ₂ ), active vitamin D ₂ (1, 25 (OH)
₂ D ₃₎ and vitamin D derivatives and synthetic derivatives, and the like. The vitamin D derivative is 1,25 (OH) ₂ D ₃
Or derivatives having affinity to its equivalent of vitamin D receptor, for _{example, 1,25 (OH) 2 D 2} · 1,24 (OH) 2 D 2, 22- oxa 1,25
_{(OH) 2} D 8 · 1,24S- dihydroxy -22-25,26,27
- cyclopropyl vitamin _D 3, 1,25- dihydroxy -22,24- diene -24,26,27- tri homo vitamin _D 3, 1,25- dihydroxy-16-ene -
Cholecalciferol is preferred.

[0008] The cancer therapeutic agent for topical administration of the present invention is a PBS (phosphate buffered saline) containing ethanol and Tween 20 commonly used for vitamin D injection.
(Phosphate-buffered salin
e) It is particularly preferred to prepare it as a solution. Also,
It is preferable that vitamin D or a vitamin D derivative is emulsified with soybean oil, egg yolk lecithin and concentrated glycerin before use. It can also be administered by directly dissolving in an oily solvent such as soybean oil.

[0009] The vitamin D or vitamin D derivative of the present invention is preferably injected at a dose of 0.5 to 0.9 mL per cm ^{3 of} tumor. The effective concentration at that time is preferably 10 ⁻¹⁰ to 10 ⁻⁶ M. In order to obtain the effective concentration, 0.1 to 2000 μM is required.
g / mL, 0.1-100 per cm ^{3 of} tumor
Preferably, 0 μg is injected. Vitamin D derivatives include 1,25 (OH) ₂ D ₃ or equivalent V
A derivative having an affinity for DR is preferable, and the effective load at that time is preferably 10 ⁻¹⁰ to 10 ⁻⁷ M, and 1
0 ^-9 ~10 ^-8 M is particularly preferred. In order to obtain the effective concentration, the concentration is adjusted to 0.1 to 200 μg / mL, and 0.1 to 100 μg is preferably injected per 1 cm ^{3 of} the tumor, more preferably 1 to 10 μg.

For the administration of the therapeutic agent for topical administration of the present invention, a conventional topical administration method capable of injecting an injection into an affected part without affecting the whole body, for example, a conventional syringe, transdermal, A needle used for ethanol injection therapy or the like can be used.
L) or the like.

By the way, in the method of oral administration or intravenous administration, since the drug is distributed throughout the whole body after administration, the dose to the affected part is small. On the other hand, since local administration is performed directly to the affected area, it is necessary to accurately grasp the affected area of cancer.
As a diagnostic method for finding a cancer for accurately grasping the affected part, an ultrasonic examination, an ultrasonic-guided tumor biopsy ultrasonic examination, a CT examination, an MRI, and an angiography are preferable.

[0012]

EXAMPLES The invention of the present application will be specifically described below with reference to examples, but the invention of the application is not limited to the examples. Example 1 104.16 μg of 1,25 (OH) ₂ D ₃ was dissolved in 25 μl of ethanol, and then dissolved in 5% fetal bovine serum-containing cell culture medium (RPMI1640) to prepare a 10 ⁻⁵ M solution. The solution was then serially diluted 10-fold to a final concentration of 10 ⁻⁷ , 10 ⁻⁸ , 10 ⁻⁹ , 10 ⁻¹⁰ , 10
^A medium containing ⁻¹¹ M of 1,25 (OH) ₂ D ₃ was prepared. Human prostate cancer-derived cultured cells LNCaP were placed on a 6-well plate for tissue culture at about 50,000 cells / we.
After culturing in a 5% CO ₂ /95% air incubator for 72 hours, the culture supernatant was prepared at the previously prepared concentrations of 1,25 (OH) ₂ D ₃ containing medium or 1,25
The medium was replaced with a (OH) ₂ D ₃ -free medium and cultured for 6 days.
Medium containing 1,25 (OH) ₂ D _{3 at} each concentration and 1,2
The 5 (OH) ₂ D ₃ -free medium was replaced every 3 days and the DNA content after 6 days was measured. As a result, the DNA content was 1,
The amount was small depending on the concentration of 25 (OH) ₂ D ₃ , and clearly showed a cancer cell growth inhibitory effect.

EXAMPLE 2 20 μg of 1,25 (OH) ₂ D ₃ was added to 20 μl of ethanol.
After dissolving in L, 1 mg of Tween 20 and PBS were added to make a total volume of 10 mL, and 2 μg / mL of 1,25 (O
_H) was prepared 2 _{D 3} formulations. The comparison solution was ethanol 20
PBS (phosphate buffered saline) was added to μL and 1 mg of Tween 20 to prepare a total volume of 10 mL. R3327 cell derived from rat prostate cancer cell which is easy to metastasize
Mat-lylu (MLL) 5 × 10 5 pieces of male rats (body weight: 182 ± 9g, n = 10 ) flank subcutaneously implanted in a tumor to 1,25 _(OH) 2 _{D 3} formulations or Comparative solution immediately after transplantation 0.5 mL per cm ³ was administered every other day. 2
One day later, the rat tumor weight and serum calcium concentration were measured. As a result, the tumor weight 21 days after transplantation was 25.3 ± 7.6 g in the comparative liquid administration group and 1,25 (OH) ₂ D
2.3 ± 2.0 g in the _three preparation administration groups and 1,25 (O
H) ₂ D ₃ formulations administered group showed significant tumor growth inhibition compared to comparative liquid administration group. The serum calcium concentration was 9.5 ± 0.2 mg / dL, 1,2
9.9 ± 1.7 mg / d in the 5 (OH) ₂ D ₃ preparation administration group
L, and no increase was observed.

[0014]

EFFECT OF THE INVENTION The invention of the present application is intended to reduce the amount of oral administration or intravenous administration by direct injection into cancer, especially undifferentiated solid cancer, especially prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, etc. Nevertheless, it is possible to administer high concentrations of vitamin D or vitamin D derivatives locally to the cancer. Since the action is local, there is an excellent effect that a safe and effective treatment can be provided without causing hypercalcemia.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA14 BB11 CC27 DD07E DD37E DD46E FF15 4C086 AA01 AA02 DA15 DA16 MA01 MA02 MA04 MA05 MA08 MA09 MA17 MA66 NA02 ZB26

Claims (11)

[Claims] 1. A topically administered cancer therapeutic agent comprising vitamin D or a vitamin D derivative as an active ingredient. 2. The therapeutic agent for local administration according to claim 1, wherein the cancer is an undifferentiated solid cancer. 3. The cancer therapeutic agent for local administration according to claim 2, wherein the undifferentiated solid cancer is prostate cancer, breast cancer, colon cancer or pancreatic cancer. 4. The method according to claim 1, wherein the vitamin D derivative is 1,25 (OH)
Topical administration for treating cancer agent according to claim 1, characterized in that a derivative having an affinity for ₂ D ₃ or its equivalent vitamin D receptor. 5. The vitamin D derivative is 1,25 (OH)
_{2 D 2, 1,24 (OH)} 2 D 2, 22- oxa -1,
_{25 (OH) 2 D 8,} 1,24S- dihydroxy -22
-25,26,27- cyclopropyl vitamin _D 3,
1,25-dihydroxy-22,24-diene-24,
26,27- tri homo vitamin _D 3, 1,25- dihydroxy-16-ene - topical cancer therapeutic agent according to any one of claims 1 to 4, characterized in that it is cholecalciferol. 6. The vitamin D or vitamin D derivative,
The cancer therapeutic agent for topical administration according to any one of claims 1 to 5, which is dissolved in an emulsion or an oily solvent. 7. The vitamin D or vitamin D derivative,
The cancer therapeutic agent for local administration according to any one of claims 1 to 6, which is dissolved in PBS (phosphate buffered saline) containing ethanol and Tween20. 8. The vitamin D or vitamin D derivative,
The cancer therapeutic agent for topical administration according to any one of claims 1 to 7, which is contained at 0.1 to 2000 µg / mL. 9. The vitamin D or vitamin D derivative,
The cancer therapeutic agent for topical administration according to any one of claims 1 to 7, which is contained at 0.1 to 200 µg / mL. 10. Vitamin D or vitamin D derivative
The dose is 1 cm of tumor ³0.1 to 100 μg per
8. A local according to claim 1, characterized in that:
Cancer therapeutic agent for administration. 11. A method for local administration of a therapeutic agent for cancer comprising locally administering the therapeutic agent for topical administration of vitamin D or a vitamin D derivative according to claim 1 to an affected part.