JP3815736B2 - Tumor metastasis inhibitor - Google Patents

Description

The present invention relates to a tumor metastasis inhibitor comprising parthenolide as an active ingredient and suppressing metastasis of tumors such as cancer and sarcoma to distant organs.

  In recent years, the treatment of tumors has made innovative progress, and the success rate for removal of the primary tumor (cancer) by surgical operation or radiation therapy has been particularly remarkable. However, tumor cells released from the primary lesion enter the vascular system, and when they reach a distant organ, they take a process of engrafting and starting to grow, so-called “metastasis” is likely to occur. Even if the removal of) is complete, there are many cases where cancerous cells metastasize and cause the patient to die. For example, in the case of osteosarcoma, “metastasis to the lung” causes direct or indirect death of the patient, that is, “suppressing lung metastasis” has been a major problem in the treatment of osteosarcoma.

  On the other hand, more tumor metastasis inhibitors (cancer metastasis inhibitors) have been invented than before (see Patent Documents 1 and 2), but the problem of strong side effects and insufficient metastasis inhibition remains. It was. In particular, there has been no report on a drug that specifically suppresses lung metastasis of osteosarcoma, and an effective drug has been desired.

Japanese Patent Laid-Open No. 06-192100 Japanese Patent Laid-Open No. 06-87847

  An object of the present invention is to provide a tumor metastasis inhibitor that effectively suppresses metastasis of a tumor to a distant organ and has no side effects.

Therefore, the present inventor conducted intensive studies to find clues to solve the above-mentioned problems, and found that parthenolide specifically acts on suppression of metastasis of malignant tumors, thereby completing the present invention.

That is, the present invention has the general formula

[Wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ are the same or different and each represents a hydrogen atom, a hydroxyl group or a lower alkyl group;
R ₄ and R ₈ are the same or different and each represents a lower alkyl group or an aldehyde group;
X ₁ and X ₂ are the same or different and represent an oxygen atom or a single bond (that is, when X and X are each a single bond, C at the 1st position, C at the 10th position, C at the 4th position and 5th position) And each C is a double bond)]
Is a tumor metastasis inhibitor that suppresses metastasis of a tumor to an organ different from its primary focus. Here, the tumor includes malignant tumors such as cancer and sarcoma, and benign tumors.

  The sesquiterpene lactone as an active ingredient may be obtained by synthesis or may be extracted from plants such as feverfew and ginkgo, algae, and the like. In the case of the extract, it is desirable to purify sesquiterpene lactone and to have a high purity, but it may contain other substances, for example, as long as it contains a considerable amount.

  The sesquipene lactone, which is an active ingredient of the present invention, naturally includes its stereoisomers and optical isomers.

In a particularly effective embodiment of the present invention, sesquiterpene lactone is

And those that are parthenolides represented by That is, in the above general formula, R ₁ , R ₂ , R ₃ , R ₅ , R ₆ and R ₇ are hydrogen atoms, R ₄ and R ₈ are methyl groups, X ₁ is a single bond, and X ₂ is It is an oxygen atom. This parthenolide is a sesquiterpene lactone having an α-methylene-γ-buthyrolactone structure as in the above structural formula, for example, a known substance contained in a lot of feverfew (Tanacetum parthenium). The extract of feverfew containing a large amount of parthenolide is known to be effective in treating fever and migraine, and has been used as a folk remedy or as a dietary supplement. Thus, although parthenolide has been reported to have various pharmacological effects, it has not been known at all that it has an “effect of suppressing metastasis of cancer cells and tumor cells”.

  If it is a drug using parthenolide, it is a substance that has been conventionally used as a folk remedy drug or a health supplement as described above, and thus can be a safe tumor metastasis inhibitor without side effects.

  The effect of the present invention is remarkably obtained when the tumor is osteosarcoma and used as a tumor metastasis inhibitor that suppresses the metastasis of the osteosarcoma to the lung, which is an organ different from the primary lesion.

  The present invention is implemented in the form as described above, and has the effects described below.

  That is, the tumor metastasis inhibitor comprising the sesquiterpene lactone of the present invention as an active ingredient can markedly and specifically inhibit tumor metastasis.

  In particular, when parthenolide is employed as the sesquiterpene lactone, it is possible to provide a tumor metastasis inhibitor that is guaranteed to be safe in addition to a remarkable and specific tumor metastasis inhibitory effect.

  Hereinafter, an embodiment of the present invention will be described with reference to the drawings.

  The tumor metastasis inhibitor of the present embodiment employs parthenolide as the active ingredient sesquiterpene lactone.

Examples of the administration mode of the tumor metastasis inhibitor of this embodiment include oral preparations and parenteral preparations in dosage forms such as solid preparations, ointments and liquid preparations. The parenteral preparation is not particularly limited, and examples thereof include suppositories, transdermal absorption agents, intravenous injections, and the like.
Then, an amount of parthenolide that exerts an inhibitory effect on tumor metastasis is formulated in a conventional manner in combination with a suitable pharmaceutical carrier or other adjuvant. As used herein, “amount that exerts a tumor metastasis-suppressing effect” (hereinafter referred to as an effective amount) is an amount that exerts a desired pharmacological activity. Preferably, the amount is such that the desired pharmacological activity is exhibited with few side effects. The exact dosage in each individual case will also depend on a number of factors, such as mode of administration, individual differences in the patient being administered, tumor status, and the like.

  The pharmaceutical carrier and other adjuvants generally used together with the parthenolide according to the present embodiment may be solid or liquid, and is selected in consideration of the usual administration route. For example, examples of the individual carrier include lactose, sucrose, gelatin, and agar. Examples of the liquid carrier include water, physiological saline, buffer solution, syrup, and vegetable oil. In addition, an appropriate carrier known to those skilled in the art may be used. Furthermore, parthenolide may be combined with a predetermined carrier to form various acceptable dosage forms such as tablets, injections, capsules, suppositories, solutions, emulsions, powders and the like. Moreover, when shaping | molding in these forms, all the well-known various things generally used as a diluent, for example, water, ethyl alcohol, propylene glycol etc., can all be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin for preparing an isotonic solution may be contained in the preparation of this embodiment, and various commonly known preparations may be used in the preparation. Additives such as solubilizing agents, buffering agents, soothing agents and the like can also be added. Furthermore, it is possible to contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.

  The present invention is not limited to the above embodiment.

  For example, a powder or extract of a plant leaf such as feverfew containing a large amount of parthenolide may be used so as to correspond to an effective amount.

  Moreover, sesquiterpene lactones other than parthenolide may be formulated into various forms in accordance with the above-described embodiment to form a tumor metastasis inhibitor.

  Moreover, you may make it administer with another anticancer agent. In this way, it is possible to reduce the number of tumor cells in both primary and metastatic lesions, which is extremely effective in treating tumors.

  In addition, the specific configuration of each part is not limited to the above embodiment, and various modifications can be made without departing from the spirit of the present invention.

  Lung metastasis inhibitory effect was examined using a mouse bone and meat species natural lung metastasis model using LM8 cells, a mouse bone and meat species high lung metastasis cell line.

25 healthy C3H / He mice (5-week-old male) were transplanted with 1 × 10 ⁵ cultured LM8 cells subcutaneously in the back. At the same time, parthenolide (Parthenolide, manufactured by Sigma, Cat # P 0667) was dissolved in distilled water, and the daily abdominal cavity was adjusted to 1 μg / kg, 100 μg / kg or 1 mg / kg per day according to the body weight of the mouse. It was administered internally. A phosphate buffer (PBS) was administered to the control group. After 25 days, the mice were sacrificed and the dorsal tumor and lungs were removed. The lungs were fixed with 4% paraformaldehyde solution and embedded in paraffin according to a conventional method. On the hematoxylin and eosin-stained specimen of the section passing through the maximum cleavage plane of the lung, the area of the metastatic lesion relative to the lung area was measured under a microscope. The volume of the back tumor was measured. The results are shown in the graphs of FIGS. 1 and 2 and lung tissue images of FIGS. 3 shows lung tissue images in the control group, FIG. 4 shows the case where parthenolide is administered at 1 μg / kg / day, FIG. 5 shows the case where parthenolide is administered at 100 μg / kg / day, and FIG. Shows a pulmonary histology when 1 mg / kg / day was administered.

  As is clear from the graph shown in FIG. 1 and FIGS. 3 to 6, in the control group (A), about 25% of the total lung area was occupied by the tumor (dark black portion), whereas 1 μg of parthenolide was occupied. / B / day (B), when parthenolide was administered at 100 μg / kg / day (C), and when parthenolide was administered at 1 mg / kg / day (D), the area of metastases was about 3 % Or less was observed, that is, an extremely high lung metastasis suppressing effect of about 90% or more was exhibited. On the other hand, as shown in FIG. 2, the volume of the back tumor (primary focus) did not show a significant difference between the groups, so it is considered that the volume of dorsal tumor (primary focus) exhibits extremely high effects of specifically suppressing metastasis. Furthermore, the mice administered with the tumor metastasis inhibitor in this example showed behavior such as running around like normal mice even if they were affected by the back tumor, and the deterioration of the general condition was suppressed by the high metastasis inhibitory effect. At the same time, there are no side effects.

The graph which shows the effect in the metastatic focus at the time of administering the tumor metastasis inhibitor of this embodiment. The graph which shows the effect in the primary lesion at the time of administering the tumor metastasis inhibitor of this embodiment. The figure which shows the image of the lung cell of the control group which shows the effect of the tumor metastasis inhibitor of this embodiment. The figure which shows the image of the lung cell which shows the effect of the tumor metastasis inhibitor of this embodiment. The figure which shows the image of the lung cell which shows the effect of the tumor metastasis inhibitor of this embodiment. The figure which shows the image of the lung cell which shows the effect of the tumor metastasis inhibitor of this embodiment.

Claims (2)

The tumor metastasis inhibitor which suppresses that the tumor metastasize | transfers to the organ different from the primary focus which consists of a parthenolide represented by these. The tumor metastasis inhibitor according to claim 1, wherein the tumor is osteosarcoma and the organ different from the primary lesion is lung.