TWI231215B - Treatment of cancer and other diseases by administration of positron-emitting radiopharmaceuticals - Google Patents

Abstract

Fluorine-18, fluorine-18-incorporating radiopharmaceuticals (FRPs), and other positron-emitting isotopes and radiopharmaceuticals have been used for diagnostic purposes in positron emission tomography (PET). This invention describes the therapeutic use of positron-emitting radiopharmaceuticals such as FRPs primarily, but not exclusively, for the treatment of cancer and cancer-related illnesses. The radiopharmaceuticals are administered in dosages significantly higher than those used for diagnostic imaging.

Description

1231215

Cross-References in Related Applications This application claims the priority benefit of US Provisional Patent Application Serial No. 60 / 256,671, filed December 18, 2000. The full text of the application is attached for reference. 0 Statement of the right to an invention made under federally funded research Not applicable. Technology 蓺 圊 The present invention relates to new therapeutic uses of fluorine-18, fluorine-18 labeled compounds, and other isotopically labeled pharmaceuticals and radiopharmaceuticals in the treatment of human diseases, especially cancer. f 景 技 positron emission tomography (PET) is a widely used imaging technique. For a pET scan, the patient is given a positron-emission compound. This compound is located in various tissues of the body. When a compound decays due to positron emission, the emitted positron encounters electrons. When the 511 keV photon couple (of the photons) is generated, the matter_antimatter (matter_antimatt) destruction phenomenon is formed, which can be measured by PE scanning (10). In general, the half-life of the positron-emitting compound is short and must be produced as short as possible before administration to the patient. Radioisotopes are generated by radiation treatment with a cyclotron, and can be chemically added to a compound and supplied. Since the half-life of fluorine-18 (F) is as long as 110 minutes, the fluorine-18 isotope is a widely used radioisotope added to compounds for PET scanning. Such a long half-life is sufficient to supply labeled compounds for patients. -4- This paper size applies the Chinese National Standard (CNS) A4 specification (2i0x297). Binding

Line 1231215 A7 B7 V. Description of the invention (2) and absorbed by the patient's tissue. A typical dose of an oxygen-18-containing compound for PET scanning is 3 to 20 mCi / 50 kg body weight. A widely used compound for PET scanning is fluorodeoxyglucose (FdG). FDG has been used to detect and test cancer for more than 10 years. It is superior to other existing contrast agents in contrast imaging of colorectal cancer, lung cancer 'melanoma' lymphoma and breast cancer. FDG has been used for metabolic angiographic pET scans of cancer, heart disease and neuropathy. It has now been found that diseases are treated by administering radiolabeled positron emitting compounds at significantly higher doses than those used for diagnostic and angiographic purposes. The present invention provides methods for treating diseases using positron-emitting compounds. The present invention is exhaustive. The present invention provides a novel method for treating a patient's disease, disease 'special cancer and related diseases. In specific embodiments, the present invention provides a method for treating a patient's disease comprising administering to the patient a therapeutically effective amount of a positron-emitting compound. The positron-emitting compound may contain one or more fluorine · 18, carbon · u, nitrogen · 13, or oxygen · 15 atoms. In another embodiment, the positron-emitting compound contains one or more oxygen-18 atoms. In a specific embodiment, the positron-emitting compound is cardiac fluorodeoxyglucose. In another specific embodiment, the gas deoxyglucose is 8f_2 • gas-2-deoxyglucose. In another embodiment, the positron is emitted and combined.

The object is F-pneumobiliary test. In another example, you are shown in the example by L /, the penetrating yoke, the positron-emitting compound is [methyl-nC] choline. In a specific embodiment, the dose of this positron-emitting compound to a patient

1231215 V. Description of the invention (3 A specific embodiment in a specific embodiment A specific embodiment in a specific embodiment A specific embodiment in a specific embodiment In a specific embodiment in the specific examples are used for diagnostic purposes 1 · 5 to 2 times. In another embodiment, the dose of the positron-emitting compound is the maximum dose that the patient can tolerate. In yet another embodiment, the dose of the positron-emitting compound is about 30 to 100. Millicuries / 50 kg body weight. In yet another embodiment, the dose of the positron-emitting compound is about 30 亳 Curie / 50 kg body weight. In yet another embodiment, the dose is about 40 millicubes. Li / 50 kg body weight. This dose is about 50 亳 Curie / 50 kg body weight. This dose is about 60 mCi / 50 kg body weight. This dose is about 70 mCi / 50 kg body weight. .This dosage is about 80 亳 Curie / 50 kg body weight. This dosage is about 90 milliCurie / 50 kg body weight. This dosage is about 100 milliCurie / 50 kg body weight. Yu: -Specific In the embodiment, the positron-emitting compound administered at the above-mentioned dose is F-fluorine Oxyglucose. In another embodiment, the positron emitting compound administered at the above dose is 2ϋ deoxyglucose. In another embodiment, the positron emitting compound can be used with any immunotherapy, surgery, radiation therapy, or other Chemotherapy is given to the patient at any stage of the treatment. Yu You: In the specific embodiment, the 'positron-emitting compound is administered intravenously. In any of the above methods, the positron-emitting compound can be administered in one or two doses per day.' Up to + 夭, 彳 鱼 仏 仏 名 斗, IT-, continuous administration for ten days or non-continuous -Η, Ό every two to three weeks ”In addition, in specific embodiments, in any of the above methods, positron emission compounds One to two doses can be given every day, five to five consecutive doses or non-continuous administration every two to three weeks. In the present invention-specific embodiment, five to five doses are given daily. Paper size suitable for money_ 料 _ x 297 Gongai Factory V. Description of the invention (4) In addition-in specific embodiments, discontinuously given for five or two weeks to = S 如 ~ ^. In another specific embodiment of the present invention In the embodiment, five to ten doses are administered discontinuously, which takes two weeks. In one embodiment of the present invention, the disease to be treated is cancer. In another embodiment of the present invention, the disease is bone cancer. : Also-in a specific embodiment, the present invention includes a composition containing a hydrazone compound at a dose of at least 1.5 to 2 times higher than a diagnostic dose. This disclosure includes any of the compounds described herein. The drug is used as a drug for cancer treatment: the invention. The present invention also includes unit dose preparations of these compounds for the treatment of cancer for the treatment of cancer. The present invention defines " treatment " The significance is to prevent, eliminate, or reduce the severity of the disease, alleviate, or prevent the further development or expansion of the disease or pathology, or prevent, eliminate, reduce the severity of the disease, alleviate, or prevent the further development of disease symptoms or pathological conditions Or expand A. "Treatment" is defined as the treatment of a disease that affects the patient, individual, or patient. A "therapeutic effective amount" of a compound is sufficient to prevent, exclude, reduce its severity, alleviate, or prevent Dose for further development or expansion of disease or pathology, or to prevent, exclude, reduce its severity, alleviate, or prevent further development or expansion of disease symptoms or pathological conditions. &Quot; Individual " or " patient " Means vertebrate, preferably mammal, more preferably human. &Quot; Patient " refers to an individual or patient who has undergone, is undergoing, or is about to undergo treatment. This paper standard applies to the S time standard (CNS) ) A4 specification (21〇 × 297 public love) 1231215 A7 ___B7 V. Description of the invention (~~) '~ ^ One means to introduce the compound into the subject. The preferred route of administration of the compound is intravenous administration. But it can also be used Any route of administration, such as oral, topical 'subcutaneous, subperitoneal, intraarterial, inhalation, transvaginal, transrectal, nasal' is introduced into the cerebrospinal fluid, or dripped into various parts of the body. Method The present invention relates to positron-emitting radiopharmaceuticals, such as the novel therapeutic use of compounds containing fluorine · 8 in human diseases. The method of the present invention is particularly useful for treating cancer and related diseases. Compounds that can be used in the present invention are added to A positron-emitting radioisotope compound. A positron-emitting radioisotope includes, but is not limited to, fluorine-18 (half-life 10 minutes), carbon-carbon (half-life 20 minutes), nitrogen-13 (half-life 10 minutes), and oxygen. -15 (half-life 2 minutes). Compounds to which positron-emitting radioisotopes can be added include, but are not limited to, proteins such as monoclonal and polyclonal antibodies and enzymes; linear 'circular', and branched peptides, including methylated peptides And peptides with D-amino acids or unnatural amino acids; peptidomimetics, such as peptoids, peptide nucleic acids, and peptides whose peptide bonds have been reduced or not hydrolyzed; amino acids, Including twenty amino acids encoded by genes, and other natural or non-natural amino acids (including, but not limited to, 'peptide nucleic acids, D-amino acids, amino alcohols, ethyl alcohols, its Tritiated amino acids, amino esters, amino acids, β-amino acids, peptide nucleic acids, etc.); nucleic acids, including, but not limited to, DNA, RNA, nuclear acid, nuclear moss' nuclear spine Acid analogs and nuclear moss analogs; carbohydrates including, but not limited to, glucose, deoxyglucose, fluorodeoxyglucose, 2-fluoro-2 • deoxyglucose, fruit sugar, sucrose, galactose, lactose, etc. Drugs, -8-Applicable to this paper size @ Η 家 标准 (CNS) Α4 size (21GX 297 mm) '--------- 1231215 V. Description of the invention (6 A7 B7

Such as chemotherapeutic agents. Λ small organic molecules, preferably having a molecular weight of less than 1,000, and more preferably having a molecular weight of less than 600, including, but not limited to, biliary test, biliary test and acetylcholine; and Found in patients: the substrate of biochemical reactions. A compound that can be used in the present invention is fluorodeoxyglucose (referred to as fluorine-18FDG, 18F-FDG, also simply referred to as FDG). In general, 18ρ 2 -fluoro-2-deoxyglucose is used. (The synthesis of this compound is published and known to those skilled in the art.) FDG is preferably administered to a patient via intravenous injection. After intravenous administration of FDG, most radiopharmaceuticals are quickly cleared by circulation. Its half-life is less than 1 minute and is scattered in large spaces, but the half-life of some parts is as long as 1.5 hours. This substance is mainly absorbed by malignant tumor tissues, infected tissues, myocardium, and brain. Studies in dogs (7) have shown that other organs also have considerable concentrations, especially the spleen, liver, and kidney, but studies in humans have not shown that these organs have significant absorption (9). Other compounds useful in the present invention include qi 18fluorocholine and [nCfluorenyl] choline. The therapeutic dose of FDG used in the method of the present invention is at least 30 millicuries / 50 kg body weight / dose. The therapeutic dose is generally 30 to 100 millicuries / 50 kg body weight. So other available doses are 30, 40, 50, 60, 70, 80, 90, and 100 milliCurie / 50 kg body weight / dose. About 20% of the administered F-18 is excreted in the urine within the first 2 hours (8). The average urinary data obtained by Jones et al (8) can be used to guide the total amount of FDG retained in the body. For dosimetry purposes, it can be 12 minutes and a half hours (〇75) and 5 hours and a half hours (0.225). 'And infinite (0.70) multi-exponential function representation. The myocardium and the brain absorb the 004 and 006 parts at 8 minutes and a half time, respectively, and their retention time is longer than the half-life of fluorine-18. The residual activity setting throughout the body is -9-

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Line 1231215 A7 ____B7 V. Description of the Invention (7) It is evenly distributed in all tissues, not just the brain and heart. According to the renal detachment model, the 0.3 part was excreted by the renal system within 12 minutes and 5 hours (0 75). From this biodynamic deduction, the normal tissue dose equivalent (EDE) estimated from a 10 亳 Curie fluoride-18FDG dose ρEτ scan is approximately i Rem. For malignant tumors, set the diameter of the tumor to i cm and use the same dose of 10 亳 Curie '. The EDE should be 137.5 Rem and the absorption rate is 1%. When the tumor reaches 5501 Rem, the yield is 4%. Alas. -In general, tumor size and percentage absorption determine the exact dose absorbed by the malignant tumor tissue. Based on this calculation, an FDG dose of 30 mCi, which is three times the 10 mCi dose for diagnostic purposes, and a 1 cm tumor with an absorption rate of 4% will receive an EDE of 1,650 Rem ^ This 3 The dose of FD () of 〇 Curie can be given once or twice a day for five to ten consecutive days (can be used every day or intermittently at intervals), and the EDE will be accumulated accordingly. The accumulated EDE can be modified as appropriate. The dose is adjusted. The calculation is to set the FDG hypoabsorption not to be lost due to tumor shrinkage or other factors. For important organs such as brain and heart toxicity, so other organs are relatively large compared with tumors, so they are relatively Low. For myocardium, the normal EDE2.2 Rem will increase to 33 Rem after 5 treatments with% mCurie. Therefore, it can be estimated that one treatment course will damage the brain and myocardium. It is extremely small. If these organs of the patient have previously received radiation therapy, care should be taken to moderately adjust the dose to prevent major injuries. According to the commonly used international safety standards, the annual dose limit for a single organ for radiation workers is 50 Rem⑷ ... but for therapeutic purposes This number can be relaxed. -10-

V. Explanation of the invention (8) The toxicity to the brain can be further reduced by using other qi_18 labeled compounds, such as qi ::: diCH) '. FCH is not as easy to accumulate as FDG. "The hanging moon is in the tissue, especially pan right, and it has the advantage of reaching high concentrations in tumor tissue (j '2β', 3 '5). The method of the present invention can also use [methyl- 1C] choline. (1) The present invention provides a method for directly delivering a therapeutic agent to malignant tissue, which causes damage to malignant tissue and minimal damage to healthy tissue. The method of the present invention can be used alone or in combination with traditional cancer treatment methods, such as combined with radiation: treatment 'chemical treatment, immunotherapy and surgical treatment. Therefore, the invention provides a useful method for treating cancer and other diseases. Case f of case i is six months. He had had a nephrectomy and showed an MRI on the left. A 66-year-old man on the left reported that he had pain in the left hip joint with a history of renal cell carcinoma. He had invaded the renal vein two years ago. Interferon was given for six months. During the onset of the disease, there is an isolated metastasis at the intestine bone about 7 cm in diameter. Treatment with fluorine-18 FDG was subjective by injection. Six " τ ', no side effects were seen after 3 to 3 days of administration. At the end of six weeks, the major symptoms of the lesions were significantly reduced. At this time, the patient was given ascertained external radiation for months. The patient was asymptomatic and the pelvic lesions had been cured. PE scan results after each treatment and each decrease. PET was performed before and during FDG treatment. Standard absorption values were shown after each external radiation treatment. Conclusion -11-This paper size it Chinese National Standard (CNS) A4 specification (210X297 ^ 1231215 A7

V. Description of the invention (9) After the second treatment, the radiation produced by the positron emission of fluorine-18 FDG accumulated from isolated pelvic cancer metastasized from renal cancer has received a positive response. Secondary to renal cell carcinoma Metastatic bone cancer is difficult to treat, and the disease is basically resistant to immunotherapy that is now popular with chemotherapy. By virtue of the positive response obtained with fluorine-18 FDG and subsequent external beam radiation therapy, It is believed that the secondary patient will have a good quality of life during the survival period, and the long-term condition will not develop and be asymptomatic. In the case of the medical history, this result is difficult to achieve with other treatments. Chunzhe Literature 1 Roivainen A. et al., UBlood metabolism of [methyl-1 lC] choline; implications for in vivo imaging with positron emission tomography, "Eur. J.

Nucl. Med. 27 (1): 25-32 (Jan 2000). 2. Kobori 0. et al ·, "Positron emission tomography of esophageal carcinoma using nC-choline and I8F-fluorodeoxyglucose: a novel method of preoperative lymph node staging , Cancer 86 (9): 1638-48 (Nov 1 1999). 3. · Hara T. et al "" PET imaging of brain tumor with [methyl-1 々choline, "

The Journal of Nuclear Medicine, 38 (6): 842-7 (June 1997). 4. Laws of the Hong Kong Government: Radiation (Control of Irradiating Apparatus), Regulations on, (Cap. 303, Section 13) (October 1 , 1965), LN 114 of 1965 5. Coleman RE et al ·, "Preliminary Evaluation of Fl 8 Fluorcholine (FCH) as a PET Tumor Imaging Agent," Scientific Paper from 12th Annual International PET Conference, October 15-18, 2000 , Washington, DC -12- ^ Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1231215 A7 B7 V. Description of invention (1〇) 6. Calculation by Vanessa Gates, MS, and C. Oliver Wong , MBBS, PhD, MD, FACP, FACNP, Ohio State University and Michigan State University. 7. Gallagher, BM et al., ^ Radiopharmaceuticals XXVII: 18F-labelled 2-deoxy-2-fluoro-D-glucose as a radiopharmaceutical for measuring myocardial glucose metabolism in vivo. Tissue distribution and imaging studies in animals, "J. Nucl. Med. 18: 990-996 (1977). 8. Jones SC et al., uThe radiation dosimetry of 2-F -18 fluoro-2-deoxy-D-glucose in man; 1 J. Nucl. Med. 23: 613-617 (1982). 9. Phelps, ME · et al., "Investigation of [18F] 2-fluoro- 2-deoxyglucose for the measure of myocardial glucose metabolism, J. Nucl. Med. 19: 1311-1319 (1978). 10. Gopal B. Saha et al., `` Cyclotrons and Positron Emission Tomography Radiopharmaceuticals for Clinical Imaging, '' Seminars in Nuclear Medicine, Vol. XXII, No. 3 (July 1992), pp. 150-161. All patents, patent applications, and other publications mentioned herein are hereby incorporated by reference in their entirety. Although for the sake of clarity and ease of understanding, the present invention has been described in detail through descriptions and examples, those skilled in the art will clearly understand that certain changes and modifications may be pragmatic. Therefore, the foregoing descriptions and examples cannot be understood as limiting the scope of the present invention. The scope of the present invention is as described in the scope of the patent application. 0-13

Claims (1)

What is claimed is: 1. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a positron-emitting compound, which contains _18 atoms of gas. 2. The pharmaceutical composition according to item (2) of the patent application, wherein the positron-emitting compound is 18F-deoxyglucose. Among them, 18F-fluorodeoxyglucose 3. The pharmaceutical composition according to item 2 of the scope of patent application. Glucose is 18F-2 -fluoro-2 -deoxyglucose. Among them, positron emission 4 · According to the pharmaceutical composition of the application scope of the patent application ...---still ... the dose of the compound to the patient is at least twice as high as that used for diagnostic purposes: high doses. 5. The pharmaceutical composition according to the Chinese patent patent, wherein the dose of the positron-emitting compound to the patient is about 30 to 100 millicuries per 50 kg of body weight, or not less than two times the highest dose used for diagnostic purposes. Times. 6. The pharmaceutical composition according to item 1 of the Chinese patent, wherein the dose of the positron-emitting compound to the patient is about 30 millicuries / 50 kg body weight, or not less than twice the highest dose used for diagnostic purposes. 7. The pharmaceutical composition according to item 1 of the Chinese patent application, wherein the dose of the positron-emitting compound to the patient is about 50 millicuries / 50 kg body weight, or not less than twice the highest dose used for diagnostic purposes. 8. The pharmaceutical composition according to item 1 of the scope of the patent application, wherein the dose of the positron-emitting compound to the patient is about 100 millicuries / 50 kg body weight, or not less than twice the highest dose used for diagnostic purposes. 9. A pharmaceutical composition according to item 丨 of the scope of patent application, which is administered to a patient at any stage of the patient's treatment together with any kind or immunological, surgical, or other chemotherapy or radiation therapy. This paper ruler g standard (CNS) Α4 size (21Q χ 〇. The pharmaceutical composition according to item 1 of the scope of application, wherein the composition is administered intravenously. U. According to the scope of the patent application, No. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 102 < Medicine composition, wherein the positron-emitting compound is administered one or two times a day ^ 'in two weeks or Five to ten days during the Samsung period. 12. The pharmaceutical composition according to item " in the scope of the Chinese Patent Application, wherein the agent is administered for five to ten days. 13. The pharmaceutical composition according to item " in the scope of the Chinese Patent Application, wherein the dose is administered daily. 14. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the cancer is i cancer 0