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Anticancer therapyRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory CompositionsAnticancer therapy description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070025910, Anticancer therapy. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This patent application claims priority to U.S. Provisional Patent Application U.S. Ser. No. 60/703,810, filed Jul. 29, 2005, entitled "Radioisotopic Therapeutic Agent and Method" and U.S. Provisional Patent Application U.S. Ser. No. 60/764,043, filed Jan. 31, 2006, entitled "Combination Anticancer Therapy," each of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND OF THE INVENTION [0003] Somatostatin is a 14-amino acid peptide hormone (somatostatin-14; SS-14) found in many cells, particularly those of neuroendocrine origin, that acts as a neurotransmitter in the central nervous system. Reubi et al., Cancer Res. 47, 5758-64 (1987). There is also a somatostatin variant released by .beta. cells in the pancreatic islets that is a 28 amino acid peptide (somatostatin-28; SS-28). Somatostatin has an inhibitory effect on growth hormone, and a generally antiproliferative effect. Somatostatin receptors (SSTR or SSR) are found on the surface of human tumor cells, including cells with amine precursor uptake and decarboxylation properties, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, paragangliomas, small cell lung cancers, medullary thyroid carcinomas and pheochromocytomas. Reubi et al., Metabolism, 41, 104-10 (1992); Patel, Front. Neuroendocrinol. 20, 157-98 (1999). Somatostatin receptors belong to the guanine nucleotide-binding regulatory protein (G-protein)-linked receptor family. [0004] Synthetic somatostatin analogs such as octreotide and lanreotide have been used for antitumor treatment and cancer detection. Jensen et al., J. Clin. Endocrinol. Metab., 85(10), 3507-8 (2000). Analogs of somatostatin were developed because human somatostatin has a very short half-life in circulation (2-3 minutes) and is easily broken down by endogenous peptidases. Rens-Domiano et al., J. Neurochem, 58, 1987-96 (1992). Somatostatin analogs typically, but need not, retain two important molecular features of somatostatin: its cyclic form and the 4 amino acids involved in the binding to the somatostatin receptor (i.e., amino acids 7-10 of the somatostatin sequence). A number of radiolabeled somatostatin analogs (e.g., [.sup.111In-DTPA-DPhe.sup.1]octreotide) have been developed that can be used to image these tumors using somatostatin receptor scintigraphy. Krenning et al., Eur. J. Nucl. Med., 20, 716-731 (1993). Somatostatin receptor scintigraphy is the most sensitive method to localize the primary and metastatic disease in subjects with all pancreatic endocrine tumors and carcinoids. Gibril et al., Ann. Intern. Med. 125, 26-34 (1996). The localization of these tumors by somatostatin receptor scintigraphy is due to the interaction of the radiolabeled analogs with specific cell surface somatostatin receptors. [0005] Multiple subtypes of somatostatin receptors are known, and almost all neuroendocrine tumors (carcinoids, pancreatic endocrine tumors) possess at least one subtype, frequently multiple subtypes. Somatostatin receptor subtypes (sst.sub.1, sst.sub.2, sst.sub.3, sst.sub.4, and sst.sub.5) have been isolated and cloned. Both octreotide and lanreotide have high affinity for somatostatin receptor sybtypes sst.sub.2 and sst.sub.5, lower affinity for sst.sub.3 and very low affinity for sst.sub.1 and sst.sub.4. Patel, Front. Neuroendocrinol. 20, 157-198 (1999). Radiolabeled analogs of octreotide are rapidly internalized and the radiolabeled peptides can remain present in the cells for prolonged periods. Hofland et al., Proc Assoc Am Physicians. 111:63-69 (1999). [0006] Radiotherapy using high doses of [.sup.111In-DTPA-D-Phe.sup.1]octreotide (DTPA: diethylenetriaminepentacetic acid), which emits auger and conversion electrons, as well as .sup.90yttrium-labeled somatostatin analogs coupled by a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator, which can emit .beta.-particles and give high radiation doses of greater penetrance, have been reported to inhibit tumor growth in both animal studies and in preliminary human studies. deJong et al., Q. J. Nucl. Med. 43, 356-366 (1999). Additional examples of somatostatin analogs that are being evaluated for use in the radionuclide therapy of tumors include [DOTA.sup.0, Tyr.sup.3] octreotide (DOTATOC) labeled with .sup.131I, .sup.90Y or .sup.177Lu. Peptide receptor radionuclide therapy (PRRT) using radiolabeled DOTATOC has led to tumor responses in the majority of subjects, but has also posed problems with regard to renal and hematological toxicity. Reubi, Endocr. Rev. 24, 389-427 (2003). Another synthetic somatostatin-receptor targeting analog, [DOTA.sup.0, Tyr.sup.3] octreotate (DOTATATE) labeled with .sup.177Lu has recently been investigated for PRRT. J, Nucl. Med. 2005 January; 46 Suppl 1:107S-14S; J Nucl Med. 2005 January; 46 Suppl 1:83S-91S1 Endocr Relat Cancer. 2005 December; 12(4):683-99. [0007] Despite good imaging and diagnostic results with .sup.111In labeled [DTPA.sup.0] octreotide (Octreoscan.RTM.) in the last few years, there have been several reports describing new somatostatin radioligands for studying sst expression. Some like [DOTA.sup.0, Tyr.sup.3] octreotide (DOTATOC) labeled with .sup.131I, .sup.90Y and .sup.177Lu are also being evaluated for use in the radionuclide therapy of tumors (7). The new Peptide Receptor Radionuclide Therapy (PRRT) using radiolabeled DOTATOC has led to tumor responses in the majority of patients, but has also posed problems with renal and hematological toxicities Reubi, Endocr. Rev. 24, 389-427 (2003). In previous studies, kidney failures have been reported after treatment with DOTATOC labeled to .beta..sup.-particle emitter .sup.90Y (8-10). In previously completed clinical studies, it was observed that 10% to 34% patients had complete remission following .sup.90Y-DOTATOC treatment (11). The results of these studies illustrate the partial treatment potentials of this agent and the possible higher relapse rates that may occur in the future (12). The primary challenges that .sup.90Y or .sup.177Lu labeled DOTATOC faces are renal toxicities and incomplete treatments, especially in radio-resistant tumors. [0008] Recent studies indicate that the presence of somatostatin receptors on other more common non-endocrine tumors may also be used for tumor localization or treatment. Halmos et al., J Clin Endocrinol Metab., 85, 3509-12 (2000). Increased densities of somatostatin receptors are found in various tumors of the central nervous system (meningiomas, astrocytomas, gliomas), some malignant lymphoid tumors (Hodgkin's disease, non-Hodgkin's disease), and in some cancers of the prostate, breast, kidney, liver, and lung. Jensen et al., J. Clin. Endocrinol. Metab., 85(10), 3507-8 (2000). Somatostatin analogs have been shown to have antiproliferative effects on breast, gastric, colorectal, prostate, thyroid and lung tumors, and cytotoxic somatostatin analogues have been shown to inhibit growth of human breast cancer, prostate cancer, renal cell carcinomas, and human glioblastomas. Kath et al., Recent Results Cancer Res. 153, 23-43 (2000); Froidevaux et al., Curr. Med. Chem. 7, 971-994 (2000). The effect of chemotherapeutic agents on the expression of somatostatin receptors has been investigated using pancreatic tumor cells. Fueger et al., J. Nucl. Med. 42(12), 1856-62 (2001). [0009] Gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) is a pyrimidine analog that has shown activity in various solid tumors, including non-small cell lung cancer (NSCLC), small cell lung cancer, head and neck squamous cell cancer, germ cell tumors, lymphomas (cutaneous T-cell and Hodgkins' disease), mesothelioma, and tumors of the bladder, breast, ovary, cervix, pancreas, and biliary tract, as well as some hematologic malignancies. The compound was first reported by Lilly Research Laboratories, Eli Lilly and Co.; Indianapolis, Ind. Hertel et al., Cancer Res. 50, 4417-4422 (1990). Gemcitabine is a deoxycytidine analog with structural similarities to cytarabine (Ara-C). [0010] Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleoside metabolites. The cytotoxic effect of gemcitabine is generally attributed to the actions of diphosphate and the triphosphate nucleosides, which lead to inhibition of DNA synthesis. Gemcitabine diphosphate (dFdCDP) inhibits ribonucleoside reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentration of the deoxynucleotides, including dCTP. Gemcitabine triphosphate (dFdCTP) competes with dCTP for incorporation into DNA. The reduction in the intracellular concentration of dCTP (by the action of the diphosphate) further enhances the incorporation of gemcitabine triphosphate into DNA, a process referred to as self-potentiation. After the gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide is added to the growing DNA strand. Further DNA synthesis is inhibited, as DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strand, resulting in what is known as masked chain termination. Gemcitabine induces an S-phase arrest in the cell cycle, and triggers apoptosis in both human leukemic cells and solid tumors. Tolis et al., Eur. J. Cancer, 35, 797-808 (1999). In addition to its cytotoxic effect, gemcitabine is a potent radiosensitizer. Gemcitabine has been investigated as a radiosensitizer for rodent and human tumor cells, including those found in pancreatic, non-small cell lung, head and neck, colorectal, breast, and cervical cancer. Pauwels et al., Oncologist 10(1), 34-51 (2005). OBJECTS OF THE INVENTION [0011] It is an object of the invention to provide novel compounds and pharmaceutical compositions for the treatment of cancer and precancerous conditions. [0012] It is another object of the invention to provide methods for treating precancerous conditions or cancer using compounds according to the present invention. [0013] It is an additional object of the invention to provide methods for treating precancerous conditions or cancer using compounds which enhance expression of somatostatin receptors in cancer cells in combination with agents which bind to somatostatin receptors to deliver cytotoxic agents. [0014] Any one of these and/or other objects of the invention may be readily gleaned from a review of the description of the invention which follows. SUMMARY OF THE INVENTION [0015] The present invention provides a therapy effective for treating a subject afflicted with a cancer or precancerous condition. According to a first embodiment, the therapy includes administration of a radiopharmaceutical composition such as a somatostasin analog labeled with a high Linear-Energy-Transfer (LET) .alpha.-emitter. An example of the radiopharmaceutical composition is .sup.213Bi-DOTATOC, but may be any somatostatin analog, preferably selected from octreotide, lanreotide and vapreotide which have been radiolabelled with a Linear-Energy-Transfer (LET) .alpha.-emitter, preferably using a chelating moiety. In this method, the radiolabeled somatostatin analog is administered to a patient in need of treatment in an effective amount to reduce the likelihood that a precancerous condition will develop into cancer, to inhibit the growth of cancer or tumor and/or shrink the cancer or tumor in the patient or reduce the likelihood of metastasis of the cancer and/or tumor in the patient. Remission of cancer in the patient is an alternative result in the present method. [0016] According to another embodiment, the therapy is a combination therapy involving administering a first therapeutic agent that increases expression of somatostatin receptors, and a second therapeutic agent that selectively binds to a somatostatin receptor on the cancer cell and delivers a cytotoxic compound or moiety to the cancer cell. An example of the first therapeutic agent is gemcitabine or an active gemcitabine metabolite. The second therapeutic agent may include a recognition ligand that targets the somatostatin receptor, and a cytotoxic compound. Administration of the second therapeutic causes a deleterious effect on the cancererous or precancerous cell. An example of a second therapeutic agent is a radiolabelled somatostatic analog, such as .sup.213Bi-DOTATOC, among numerous others. [0017] The terminology as set forth herein is for description of the embodiments only and should not be construed as limiting of the invention as a whole. As used in the description of the invention and the appended claims, the singular forms "a", "an", and "the" are inclusive of their plural forms, unless contraindicated by the context surrounding such. BRIEF DESCRIPTION OF THE FIGURES [0018] FIG. 1 provides structural formulas for deoxycytidine (CdR), cytarabine (Ara-C), and gemcitabine (dFdC). [0019] FIG. 2 illustrates the structural relationship between somatostatin and three somatostatin analogs, as shown in Cancer Medicine, 6.sup.th edition (Frei et al., eds., Hamilton, Canada, 2003). [0020] FIG. 3 provides a bar graph showing the cytotoxic effects of .sup.177Lu and .sup.213Bi labeled DOTA and DOTATOC on the somatostatin receptor expressing cell line Capan-2. Continue reading about Anticancer therapy... 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