Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2000-10-06
2003-05-06
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C424S009200, C546S249000
Reexamination Certificate
active
06558650
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to increasing the uptake of gallium into cells for diagnostic and therapeutic purposes.
BACKGROUND OF THE INVENTION
Gallium (Ga), a Group IIIa transition metal, has a number of isotopes with many medical uses. For decades, gallium-67, a gamma-emitter, has been used in nuclear medicine for tumor imaging by gamma emission scintigraphy (1). Currently, gallium-67 is most widely used in staging and assessing the therapeutic response of lymphomas (2, 3, 4, 5). Other isotopes of gallium have potential uses in oncology. Gallium-68, a positron emitter, can be used for tumor imaging by positron emission tomography (PET). Gallium-72, a beta-emitter, may destroy tissues that concentrate gallium by local radiation. This treatment has been proposed to palliate bone pain caused by skeletal metastases (6). Gallium-67 has also been used for local radiotherapy in the treatment of hematological malignancies (48, 49, 50, 51).
Stable (non-radioactive) gallium has been used to reduce the hypercalcemia of malignancy, and as a treatment for Paget's disease of bone. It is also believed to have direct anti-neoplastic effects, and is currently under investigation as an adjunct to conventional chemotherapy (7, 8, 9).
The limitations of Ga-67 for oncologic imaging are well-recognized (10,11,12,13). Many tumors accumulate Ga poorly. Others, such as hepatomas and lymphomas, can be intensely Ga-avid but may vary in magnitude and consistency of uptake. Delineation of tumors from background tissues often requires extended intervals from the time of injection to imaging of 3-7 days or more because Ga-67 localizes slowly and initial images of the abdomen are frequently difficult to interpret because of bowel activity. Because of the extended intervals required for oncologic imaging, a relatively high dose of Ga-67 is required (typically 10 mCi for an adult). Despite its drawbacks, no other gamma-emitting radiopharmaceutical used for tumor imaging in nuclear medicine (including expensive monoclonal antibodies and receptor-avid peptides) has surpassed Ga-67 in cost-effectiveness, general availability, broad applicability and ease of imaging. Although efforts to improve the use of gallium are clearly justifiable, the techniques to accomplish this have thus far been elusive for impractical.
Despite years of imaging experience with the Ga-67 radiometal, the mechanism by which Ga-67 accumulates in normal tissues and tumors remains controversial. For years, it has been thought that gallium is taken up by cells as a gallium-transferrin (Ga-Tf) complex via the transferrin receptor (TfR) (14,15,16). However, there is also evidence that mechanisms other than the TfR may be responsible for the uptake of Ga-67 in tumors (17,18,19). For example, gallium may dissociate from Tf in the acidic extracellular environment of tumors, which would interfere with Tf mediated transport of cellular uptake (20, 21, 22). There is also a poor correlation between TfR density and the degree of tumor uptake of gallium. Moreover, gallium uptake continues to a significant degree even in the absence of Tf, or when TfR binding sites are blocked with an antibody or when iron overload down regulates TfR expression (23, 24, 25).
Tumor bearing rats that are rendered iron-deficient (which increases TfR's in many tissues) exhibit an increased uptake of Ga-67 in tissue other than tumors (26). When Tf binding sites are saturated with iron or scandium after administration of Ga-67, uptake of gallium in tumors, relative to normal tissues, can actually increase (27, 28). Uptake of Ga-67 by nonosseous tissues and organs is markedly depressed in a hypotransferrinemic strain of mouse, suggesting that uptake of Ga-67 by most soft tissues and organs is a Tf-dependent process (29).
Nifedipine 1 (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate) is a dihydropyridine calcium channel antagonist, which causes vasodilation and lowering of peripheral vascular resistance. These characteristics make nifedipine useful in the treatment of heart disease and hypertension. This compound, like most 1,4-dihydro-4-(2-nitrophenyl)pyridine derivatives, is very sensitive to light. Photo-degradation of nifedipine has been considered a drawback to its pharmaceutical use, because the photo-degradation products have been thought to lack pharmacological activity. Hence photo-degradation of nifedipine has diligently been avoided by shielding it from the light to prevent loss of its therapeutic properties.
In the presence of light, nifedipine is converted to phenylpyridine derivative structures that include fully-aromatic compounds (FIG.
1
). With exposure to visible/fluorescent light, nifedipine is converted predominantly to the 4-(2-nitrosophenyl)pyridine homologue 2 (the nitroso derivative, also known as 2,6-dimethyl-3,5-diacetyl-4-(2′-nitrosophenyl)-pyridine). When exposed to UV light, it is converted predominantly to the 4-(2-nitrophenyl)pyridine homologue 3 (the nitro nifedipine derivative). The nitro derivative is also the primary metabolic product of nifedipine in humans. In addition to these two main structures, photo-degraded nifedipine (PDN) also includes a broad variety of phenylpyridines such as the cis and trans-azoxy derivatives, the hydroxylamine derivative, the amine derivative, the lactam derivative, and the trans-N,N′-dioxide derivative.
SUMMARY OF THE INVENTION
The present invention takes advantage of an unexpected property of nifedipine degradation products, such as photodegraded nifedipine products (PDN), or pharmaceutical analogs and their degradation products. This property can be used to improve the use of gallium for several purposes: 1) to improve tumor imaging; 2) to improve radiotherapy of tumors; and 3) to improve the use of gallium as an adjunct to chemotherapy. In particular example, the method can improve the uptake of gallium into tumor cells, to permit a total diagnostic or therapeutic dose of the radioisotope to be decreased, so that less than the normal 5-10 mCi adult dose can be administered to an adult.
There are several mechanisms by which PDN can improve the use of gallium isotopes, such as Ga-67 (for gamma scintigraphy), for tumor imaging. First, PDN selectively augments a Tf-independent uptake of gallium, and since tumors appear to accumulate gallium by this route to a greater extent than normal tissues, PDN could improve the localization of gallium selectively in tumors. Even if PDN stimulates uptake of gallium in normal tissues as well as tumors, it still has significant beneficial effect in decreasing the necessary interval between time of injection of the radio-tracer and time of imaging. Improving the efficiency of uptake of gallium in tumors or other tissues allows diagnostic images to be obtained at a lower dose of radioactivity to the patient. Tumor specific enhancement of gallium uptake by PDN improves the use of stable gallium as an adjunct to conventional chemotherapy, and concentration of unstable gallium isotopes in tumors for the purpose of administering local radiotherapy.
The present invention therefore includes exposing cells, tissues or tumors to a sufficient dose of the PDN products, for a sufficient period of time, to improve the uptake of gallium into the cells or tumors. The cells can be exposed to the PDN in vitro (for example is an assay) by providing the photo-degradation products (or biological precursors) in a surrounding medium. Alternatively, the PDN can be administered to cells, tissues or tumors in vivo to achieve a systemic blood level, or a local concentration in a tissue of interest (such as a tumor), sufficient to increase gallium uptake in that tissue. Either the PDN products themselves can be administered, or a biological precursor (such as nifedipine) can be administered and allowed to degrade. The degradation may occur by normal metabolic pathways to one of the photo-degradation products. However, the degradation may alternatively be induced by exposure to light, such as pre-irradiation of a solution of nifedipi
Morton Kathryn A.
Roullet Jean-Baptiste
Jones Dameron L.
Klarquist & Sparkman, LLP
Oregon Health and Science University
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