Abstract: Novel cytotoxic fluoropyrimidine polymers for treating cancer (e.g., colorectal cancer (CRC)) in a subject (e.g., a subject having cancer) are nucleic acid molecules including 5-fluoro-2?deoxyuridine monophosphate (FdUMP)[10] having a polyethylene glycol (PEG) spacer appended to the 5? terminus and a cytarabine (AraC) nucleotide appended to the 3?terminus. These novel cytotoxic fluoropyrimidine polymers may be used in compositions, kits and methods for treating advanced and high-risk cancers, including CRC.

Abstract: Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Abstract: Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Abstract: Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. In an embodiment of the present invention, F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days=18; p<0.001; n=16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity.

Abstract: F10 is an oligonucleotide based on the thymidylate synthase (TS) inhibitory 5-fluorouracil (5-FU) metabolite, 5-fluoro-2?-deoxyuridine-5?-O-monophosphate. The activity of F10 against preclinical ALL models was determined. F10 treatment resulted in robust induction of apoptosis that could not be equaled by 100 fold more 5-FU. F10 was more potent than Ara-C and doxorubicin against a panel of murine and human ALL cells with an average IC50 value of 1.48 nM (range 0.07 to 5.4 nM). F10 was more than 1000 times more potent than 5-FU. In vivo, F10 treatment resulted in a significant increase in survival in 2 separate syngeneic ALL mouse models and 3 separate xenograft models. F10 also protected mice from leukemia-induced weight loss. In ALL cells made resistant to Ara-C F10 remained highly active in vitro and in vivo. Using labeled F10, it was determined that uptake by the ALL cell lines DG75 and SUP-B15 was rapid and had a profound temperature dependence.

Abstract: Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Abstract: Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Abstract: A compound of the formula A-B-C, is provided, wherein: A is a first nucleic acid that specifically binds to an extracellular surface protein expressed by a cell of interest, B is an alkyl linker; and C is a second nucleic acid that hybridizes to a complementary nucleic acid. In some embodiments, the first nucleic acid is an aptamer. In some embodiments, the nucleic acid comprises an active compound, particularly cytotoxic nucleotides such as poly-FdUMP. Compositions and methods of using such compounds for treating and/or detecting cancer are also described.

Abstract: A compound of the formula A-B-C, is provided, wherein: A is a first nucleic acid that specifically binds to an extracellular surface protein expressed by a cell of interest, B is an alkyl linker; and C is a second nucleic acid that hybridizes to a complementary nucleic acid. In some embodiments, the first nucleic acid is an aptamer. In some embodiments, the nucleic acid comprises an active compound, particularly cytotoxic nucleotides such as poly-FdUMP. Compositions and methods of using such compounds for treating and/or detecting cancer are also described.

Abstract: A synthesized siRNA molecule having the sense strand with one or more uridine bases replaced by one or more respective nucleoside analogs, such as 5-fluoro-2?-deoxyuridine (FdU).

Abstract: The present invention relates to active compounds for treating acute myelogenous leukemia (AML) in a subject in need thereof and methods of treating AML carried out by administering the subject an active compound in an amount effective to treat the leukemia. The active compound comprises a 10-mer oligonucleotide covalently linked via 3? to 5? phosphodiester linkages of 5-fluorodeoxyuridine, FdUMP[10], or a pharmaceutically acceptable salt thereof.

Abstract: Provided herein are aptamers and pharmaceutical compositions comprising the same. In some embodiments, the aptamer selectively binds a protein of interest such as an extracellular receptor protein of interest (e.g., a cancer cell extracellular receptor protein, which may be differentially expressed in some embodiments). In some embodiments, the aptamer is directly linked by covalent bonding (e.g., via a geminal diamine linkage) to from 2 to 10 toxin compounds. Also provided herein is a method of selecting an aptamer that specifically binds to a protein expressed by a cell of interest, wherein in some embodiments the aptamer comprises at least one binding site for one or more active compounds. In some embodiments, primer regions flanking the variable region of the aptamers in the pool contains from 1 to 10 mismatches with respect to said forward or reverse primer.

Abstract: The present invention provides a method of generating a nucleic acid, which specifically binds to an extracellular surface protein expressed by a cell of interest, and which nucleic acid comprises a compound of interest to be delivered to the cell of interest.

Abstract: Provided herein are methods useful for treating a brain tumor in a subject in need thereof, comprising administering to said subject an active agent comprising poly-FdUMP or a pharmaceutically acceptable salt thereof. Also provided are compositions comprising poly-FdUMP and one or more additional active agents useful for treating a brain tumor.

Abstract: A synthesized siRNA molecule having the sense strand with one or more uridine bases replaced by one or more respective nucleoside analogs, such as 5-fluoro-2?-deoxyuridine (FdU).

Abstract: A method of treating acute myelogenous leukemia (AML) in a subject in need thereof is carried out by administering the subject an active compound in an amount effective to treat the leukemia. The active compound comprises FdUMP[10] or a pharmaceutically acceptable salt thereof.

Abstract: The present invention provides a method of generating a nucleic acid, which specifically binds to an extracellular surface protein expressed by a cell of interest, and which nucleic acid comprises a compound of interest to be delivered to the cell of interest.

Abstract: A compound of the formula A-B-C, is provided, wherein: A is a first nucleic acid that specifically binds to an extracellular surface protein expressed by a cell of interest, B is an alkyl linker; and C is a second nucleic acid that hybridizes to a complementary nucleic acid. In some embodiments, the first nucleic acid is an aptamer. In some embodiments, the nucleic acid comprises an active compound, particularly cytotoxic nucleotides such as poly-FdUMP. Compositions and methods of using such compounds for treating and/or detecting cancer are also described.

Abstract: A method for treating neoplastic disease in animals including humans comprises administering a first composition comprising a TS inhibitor and a second composition comprising a nucleic acid-directed chemotherapeutic agent, and a composition for treating neoplastic disease in animals including humans comprises a first composition comprising a TS inhibitor and a second composition comprising a nucleic acid-directed chemotherapeutic agent. In a preferred embodiments, the TS inhibitor is a homo-oligomer of FdUMP, and the nucleic acid-directed chemotherapeutic agent is 5-FU or a pro-drug thereof. In a further aspect, compositions of a homo-oligonucleotide of 5-fluoro-2′-deoxyuridine-5′-O-monophosphate (FdUMP) with 5-fluorouracil exhibit a synergistic biological effect on neoplastic cells when compared to the activity of the individual components, the compositions being useful in the treatment of cancer in animals, including humans.

Abstract: Homo-oligomeric 5-fluorouridine and 5-fluorodeoxyuridine (FrU.sub.n and FdU.sub.n, n=oligomer length) are synthesized and used as a polymeric drug delivery system for production of FdUMP, the potent inhibitor of thymidyalte synthase (TS) and an important target in cancer chemotherapy. Disclosed are methods of both preparing and utilizing said compositions.