Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2001-09-18
2004-11-09
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C514S001000, C514S706000, C514S708000
Reexamination Certificate
active
06814952
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of
99m
Tc(V)-dimercaptosuccinic acid for detecting cancerous bone metastasis of the osteoclastic or mixed type by means of bone scintigraphy, and facilitating selection of a therapy for the cancerous bone metastasis.
2. Description of Related Art Including Information Disclosed under 37 CFR 1.97 and 1.98
Whether cancerous bone metastasis has occurred is an important factor that affects prognosis, and also influences the therapeutic plan for the primary lesion. Furthermore, since options of therapies for bone metastasis and accompanying symptoms are increasing, diagnosis of presence or absence, or spread of bone metastasis plays an important role in deciding a therapeutic plan. Bone metastasis can be seen more or less in every cancer. The diagnosis of bone metastasis would be of particular importance in breast cancer, prostatic cancer, lung cancer, thyroid cancer and renal cancer since these cancers are generally considered higher in risk of bone metastasis than other cancers.
Bone metastasis can be pathologically classified into four types: osteoblastic type, osteoclastic type, mixed type in which the aforementioned two types are mixed together, and inter-trabecular type in which neither osteoblastic nature nor osteoclastic nature is exhibited. Among the cancers high in the risk of bone metastasis, it is likely that prostatic cancer causes the osteoblastic type, renal cancer and thyroid cancer causes the osteoclastic type, lung cancer causes both the osteoclastic and the mixed types, and breast cancer causes the mixed type. Among the four types, the osteoclastic type is characterized by bone resorption due to growth of osteoclastic cells, and is likely to result in bone fracture. For this reason, the osteoclastic type of bone metastasis is said to have a significantly higher incidence of pains than other types. Among the patients of breast cancer with bone metastasis, it is said that patients of the osteoblastic type survive the longest, being followed by patients of mixed type and osteoclastic type, in this order. So, the identification of metastasis type is also considered important.
Bone scintigraphy is generally used to examine the presence or absence of bone metastasis in cancer patients. Usually, a
99m
Tc-labelled bisphosphonate (
99m
Tc-BP) such as
99m
Tc-MDP (methylene diphosphonate),
99m
Tc-EHDP (ethane hydroxy-diphosphonate) or
99m
Tc-HMDP (hydroxymethylene diphosphonate) is intravenously injected as a diagnostic imaging agent, and then scintigrams are taken. Mechanism of bone accumulation of the
99m
Tc-BP is still unclear, but it is found that the
99m
Tc-BP highly accumulates in osteoblastic lesions. So, the
99m
Tc-BP is useful for detecting the osteoblastic type bone metastasis. However, the
99m
Tc-BP does not appear to depict lesions of osteoclastic type bone metastasis as positive images, and this is a problem.
On the other hand, as for
99m
Tc-dimercaptosuccinic acid (
99m
Tc-DMS), the trivalent
99m
Tc-DMS is well known as a diagnostic imaging agent for kidney, while pentavalent
99m
Tc(V)-DMS is reported to accumulate in tumor lesions such as of thyroid carcinoma (MTC), osteosarcoma, and benign and malignant tumors of various soft tissues. JP-A-56-7725 proposes the use of
99m
Tc(V)-DMS as a tumor scanning agent. Furthermore, it is also reported that
99m
Tc(V)-DMS depicts lesions of bone metastasis caused by various cancers as positive images.
As described above,
99m
Tc(V)-DMS is a polynuclear complex having a nature of accumulating in both cancers and bones. The accumulation in cancers is presumed to depend on pH values, but no mechanism of the accumulation in bones has been known even though there are clinical reports that the
99m
Tc(V)-DMS would accumulate in lesions of osteoclastic type metastasis.
Meanwhile, bone fractures involved in the bone metastasis of tumors are considered to include those caused directly by protease secreted from tumor cells and those caused by way of activated osteoclast. In recent years, it has been clarified that bone resorption is inhibited by bisphosphonate compounds such as pamidronate, clodronate, etidronate, tiludronate and alendronate, and that these compounds would be effective for preventing bone fractures associated with osteoporosis and tumorous bone metastasis. Mechanism of the inhibitory action on bone resorption has not yet been sufficiently clarified, but it is said that the inhibitory action results from bisphosphonate compounds that act directly or indirectly on osteoclast, thereby inactivating and decreasing osteoclast. Therefore, if any diagnostic method using any compound specifically taken up by osteoclast is established, it will become possible to accurately select patients who are suited to therapy targeted at osteoclast by use of the recently developed bisphosphonate compounds.
Under the above-mentioned circumstances, the object of present invention is to allow a precise diagnostic imaging of cancerous osteoclastic type or mixed type bone metastasis using a compound capable of being specifically taken up by osteoclast, thereby enabling an appropriate selection of a therapy based on the diagnosis.
SUMMARY OF THE INVENTION
In order to achieve the above-mentioned object, the inventors have intensively studied on the mechanism of
99m
Tc(V)-DMS accumulation in the lesions of bone metastasis, and as a result, have found that while the
99m
Tc-BP used as a conventional diagnostic imaging agent is remarkably taken up by osteoblast but is hardly taken up by osteoclast,
99m
Tc(V)-DMS shows the following characters (1)-(5): (1)
99m
Tc(V)-DMS is less taken up by osteoblast than
99m
Tc-BP, but is taken up by osteoclast in an especially large amount. (2) The amount of the
99m
Tc(V)-DMS taken up by osteoclast remarkably increases at low pH values. (3) The phenomenon of the above (2) is presumed to have relation with activation of function of the osteoclast in an acidic environment. (4)
99m
Tc(V)-DMS shows a behavior similar to phosphate anion when taken up by osteoclast, and it is taken up by osteoclast through Na
+
-dependent phosphate transporter that relates to the transport of inorganic phosphate to osteoclast. (5)
99m
Tc(V)-DMS shows a distribution in vivo that corresponds to the distribution of osteoclast, and thus is preferentially taken up by osteoclast rather than osteoblast. On the basis of these evidences, the present invention has been completed.
According to the present invention, provided is a diagnostic imaging agent useful for selecting a therapy for cancerous bone metastasis, comprising
99m
Tc(V)-dimercaptosuccinic acid as an effective ingredient. Cancerous bone metastases include those of the osteoclastic or mixed type which accompanies localization and activity rise of osteoclast, and those of the osteoblastic or inter-trabecular type which is considered to receive no or little contribution of osteoclast. Since
99m
Tc(V)-dimercaptosuccinic acid is highly specific to osteoclast, it allows the osteoclastic type or mixed type bone metastasis to be accurately identified, and facilitates the decision as to whether or not a therapy targeted at osteoclast should be applied.
DETAILED DESCRIPTION OF THE INVENTION
There is no limitation in kinds of the therapy targeted at osteoclast as long as they are expected to give a therapeutic effect in a way that directly or indirectly acts on osteoclast and thereby inhibits bone resorption or palliates bone pain. Typically, such a therapy includes one using a bisphosphonate compound.
The bisphosphonate compound means germinal bisphosphonates having a P-C-P skeleton structure, and includes many therapeutic agents that are commercially available or clinically being developed, such as etidronate, clodronate, pamidronate, alendronate, ibandronate, incadronate, olpadronate, zoledronate, tiludronate, neridronate, risedronate, YH592 and EB-1053.
Besides, a therapy is practiced in which
89
SrCl
2
or another compound having affinity with bones is intravenous
Saji Hideo
Suzuki Kazuko Horiuchi
Yokoyama Akira
Fitch Even Tabin & Flannery
Jones Dameron L.
Nihon Medi+Physics Co., Ltd.
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