Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-03-09
2004-02-03
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
Reexamination Certificate
active
06685913
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the field of oncology and a method of injecting radionuclides for tumor therapy, and more particularly to the use of a class of lipid soluble radioactive metal chelate compounds for treatment of malignant, benign, or inoperable tumors.
BACKGROUND OF THE INVENTION
Intratumoral injection of certain radionuclides for therapy is drawing increasing attention. (Shyh-Jen Wang, Wan-Yu Lin, Min-Nan Chen, Ching-Shiang Chi, Jung-Ta Chen, William-L Ho, Bor-Tsung Hsieh, Lie-Hang Shen, Zei-Tsan Tsai, Gann Ting, Saed Mirzadeh and Furn F. Knapp, Jr. Intratumoral Injection of Rhenium-188 Microspheres into an Animal Model of Hepatoma. J Nucl Med 39:1752-1757, 1998). Investigators have begun to use intratumoral therapy, especially where tumors are inoperable or where incision of tumors is associated with high risks to the patient. Radionuclide therapy is particularly useful for treating a variety of tumors, including inoperable tumors; prostate tumors, for example, which are confined but are associated with high risk following surgical intervention; and brain tumors such as glioma.
The use of radioactive metal chelates, in general, and Indium-111 lipid soluble complexes, in particular, is based upon work with such agents in the diagnostic imaging field, especially for labelling cellular blood elements. For example, two of the lipid soluble chelates of Indium-111 have been prepared previously. These compunds are Indium-111-oxine (8-hydroxyquinoline; see M L Thakur, R E Coleman, and M J Welch, Indium-111-labeled leukocytes for the localization of abscesses: preparation, analysis, tissue distribution, and comparison with gallium-67 citrate in dogs.
J Lab Clin Med
89: 217-228, 1977) and Indium-111-Merc (Mercapto pyridine-N-oxide; see Thakur M L, McKenney S L, Park C H. Evaluation of Indium-111-2-mercaptopyridine-N-oxide (Merc) for labeling leukocytes in plasma: A kit preparation.
J Nucl Med
26: 518-523, 1982). The lipid soluble nature of these compounds is an important characteristic. When these lipid soluble compounds are placed in the presence of any cell, they are capable of passively diffusing through the cell membrane. As a result, Indium-111-oxine has been used to lable blood cells, bacteria, and tumor cells. (Thakur M L, Lavender J P, Arnot R N, Silvester D J, and Segal A W. Indium-111-Labeled Autologous Leukocytes in Man.
J Nucl Med
18: 1014-1021, 1977; Thakur M L. Live bacteria labeled with
111
In.
Eur J Nucl Med
13:266, 1987; Rosenberg S A, Lotze M T, Muul L M, Chang A E, Avis F P, Leitman S, Linehan W M, Robertson C N, Lee R E, Rubin J T, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone.
NEJM
316: 889-897, 1987).
A comparison between Indium-111-oxine and Indium-111-Merc has shown that Indium-111-Merc has a higher thermodynamic stability and is smaller in size than Indium-111-oxine. These differences result in the more efficient labeling of cells under physiologic conditions by Indium-111-Merc. Whereas Indium-111-Merc can label cells in the presence of plasma, Indium-111-oxine cannot efficiently label cells unless such cells are suspended in balanced salt solutions, such as isotonic saline. In either case, whether in the oxine or Merc form, once Indium-111 has entered the cells, it firmly binds to cell cytoplasmic components and does not come out of the cells. (See U.S. Pat. No. 4,443,426 by Thakur, Madhukar L.; Thakur, M L and McKenney, S M, Indium 111-mercaptopyridine-N-oxide-labeled human leukocytes and platelets: Mechanism of labeling and intracellular location of
111
In and mercaptopyridine N-oxide,
J Lab Clin Med,
107:141-147, 1986; Thakur, M L, Segal, A W, Louis, L, Welch, M J, Hopkins J, and Peters, T J, Indium-111-Labeled Cellular Blood Components: Mechanism of Labeling and Intracellular Location in Human Neutrophils,
J Nucl Med,
18:1020-1024, 1977; Thakur et al.,
J Lab Clin Med,
89: 217-228, 1977).
Through the Auger electrons Indium-111 emits during its decay (t
½
=67 hrs), each atom of Indium-111 delivers 0.135 rad of radiation dose to a cell 10&mgr; in diameter. The path range of Auger electrons is 8 to 12.5&mgr;. (Silvester, D J, Consequences of Indium-111 decay in vivo; calculated absorbed radiation dose to cells labelled by Indium-111 oxine,
J of Labelled Compounds and Radiopharmaceuticals,
13: 196-197, 1977). Indium-111 also decays by the emission of two &ggr;-rays of 173 Kev (89%) and 247 Kev (94%). These two &ggr;-rays are useful for scintigraphic imaging.
The present invention takes advantage of the lipid soluble nature of Indium-111 complexes, along with the radioactive properties of these complexes, and utilizes the radioactive metal chelate as a means of treating tumors. The present invention is distinct from receptor-specific agents, such as radiolabeled antibodies or radiolabeled peptides and is distinct from metabolic agents, such as radiodeoxyuridine. By injecting Indium-111-oxine or Indium-111-Merc into a tumor, the Indium-111 atoms enter the tumor cells, bind to tumor cell cytoplasmic components, and deliver high enough radiation dose to the cell DNA such that apoptosis will occur, thereby arresting cell proliferation and/or leading to tumor regression. Chromosomal aberrations in lymphocytes labeled with Indium-111 have been demonstrated. (ten Berge R J M, Natarajhan, A T, Hardeman M R, et al: Labeling with Indium-111 has detrimental effects on human lymphocytes: concise communication.
J Nucl Med
24:615-620, 1983).
While Indium-111 is one example of an appropriate radioactive metal chelate for tumor therapy, other lipid soluble radioactive chelate could be used, so long as such compounds bind tightly to cell cytoplasmic components. Such alternative lipid soluble compounds include Indium-111-tropolone (2-hydroxy-2,4,6-cylcoheptatrienone), Rhenium-186 or Rhenium-188 chelated with sesta-MIBI (methoxy isobutyl isonitrile), HMPAO, or tetrofosnine. (Holman B L, Jones A G, Lister-James J, et al. A new Tc-99m-labeled myocardial imaging agent, hexakis (tbutylisonitrile) technetium (I) [Tc-99m TBI]: initial experience in the human.
J Nucl Med
25:1350-1355, 1984; Volkert W A, Hoffman T J, Seger R M, Troutner D E, Holmes R A.
99m
Tc-propylene amine oxime (
99m
Tc-PnAO); a potential brain radiopharmaceutical.
Eur J Nucl Med
9:511-516 1984; Kelly J D, Forster A M, Higley B, et al. Technetium-99m-tetrofosmin as a new radiopharmaceutical for myocardial perfusion imaging.
J Nucl Med
34:222-227, 1993).
In addition to inoperable tumors, certain types of prostate tumors, and brain tumors, such radioactive metal chelates could be directed against a variety of other tumors, including hepatoma, melanoma, breast cancer, pancreatic cancer, lung cancer, sarcomas, and carcinoids. Known metastatic tumors can also be treated similarly. The success of the agent used depends upon its homogeneous distribution into the tumor mass. Such a homogeneous distribution is dependent upon the skill and judgment of a physician injecting the agent. As is customary with many therapeutic agents, repeated injections of the agent may be necessary, depending upon the individual patient and the size, location, and type of tumor targeted for therapy. Typically 1mCi of Indium-111 injected into a 1 cc tumor (1.3×10
13
atom and 10
9
cells) will deliver 17.5 Gy/cell where distribution of the compound is uniform.
In the present invention, it is important to note that the emission of gamma rays by such radioactive metal chelates may lead to delivery of some radiation to normal organs and tissue within vicinity of the targeted tumor. Such expected radiation dose the normal organs and tissue will have to be determined prior to administration of the therapeutic dose.
Nonetheless, the results of work with the present invention have shown that the radioactivity remains in the tumor and does not spread in the body (22 days observation time); tumor growth is arrested; and treated
Drinker Biddle & Reath LLP
Hartley Michael G.
Thomas Jefferson University
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