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Sns-595 and methods of using the sameRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Bicyclo Ring SystemSns-595 and methods of using the same description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060063795, Sns-595 and methods of using the same. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation-in-part of application Ser. No. 11/080,102, filed Mar. 14, 2005, which claims priority under 35 USC .sctn. 119, to U.S. Provisional Application Ser. No. 60/553,578 filed Mar. 15, 2004, the entire disclosures of which are hereby expressly incorporated by reference. TECHNICAL FIELD [0002] SNS-595 is novel naphthyridine cytotoxic agent that was previously known as AG-7352 (see e.g., Tsuzuki et al., Tetrahedron-Asymmetry 12: 1793-1799 (2001) and U.S. Pat. No. 5,817,669). The chemical name of SNS-595 is (+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox- o-1-(2-thiazoyl)-1,8-naphthyridine-3-carboxylic acid and has the structure shown below [0003] The present invention relates to SNS-595 and methods for maximizing its therapeutic potential to treat cancer. DESCRIPTION OF THE FIGURES [0004] FIG. 1 illustrates the three major DNA damage and repair pathways. [0005] FIG. 2 depicts the dose-dependent responses of exemplary members of the DNA-PK pathway in HCT 116 cells treated with SNS-595. [0006] FIG. 3 depicts the activation of exemplary members of the DNA-PK pathway in tumors in mice. DETAILED DESCRIPTION [0007] Proliferating cells undergo four phases of the cell cycle: G.sub.1, S, G.sub.2, and M. These phases were first identified by observing dividing cells as the cells progressed through DNA synthesis which became known as the synthesis or S phase of the cell cycle and mitosis which became known as the mitotic or M phase or S phase of the cell cycle. The observed gaps in time between the completion of DNA synthesis and mitosis and between mitosis to the next cycle of DNA synthesis became known as the G.sub.1 and G.sub.2 phases respectfully. Non-proliferating cells that retain the ability to proliferate under the appropriate conditions are quiescent or in the G.sub.0 state and are typically characterized as having exited the cell cycle. [0008] The cell cycle has multiple checkpoints to prevent the cells from attempting to progress through the cell cycle under inappropriate circumstances by arresting the cells at these designated points. One important checkpoint occurs before the cell enters the S phase and tests, for example, whether the environment (e.g. sufficient nutrients) is suitable for cell division. Cells that fail a checkpoint in the G.sub.1 phase and are thus prevented from entering the S phase are said to be in G.sub.1 arrest. Another checkpoint occurs before the cell enters the M phase and test for example, the integrity of the synthesized DNA. Cells that fail a checkpoint in the G.sub.2 phase and thus prevented from entering the M phase are said to be in G.sub.2 arrest. Another checkpoint occurs during the M phase immediately before cytokinesis occurs and tests, for example, that the chromosomes are properly aligned. Cells that fail a checkpoint in the M phase and thus are prevented from dividing are said to be in M arrest. [0009] In practice, cell cycle arrest is often characterized by DNA content and not by checkpoint failure. Consequently, the most often reported cell arrests are G.sub.1 arrest based on 2N DNA content and the G.sub.2/M arrest based on 4N DNA content. [0010] SNS-595 is a cell cycle inhibitor and arrests cells at the G.sub.2 interface. Initially, the activity of SNS-595 was believed due to topoisomerase II inhibition. Although SNS-595 is a catalytic inhibitor of topoisomerase II (inhibits decatenation and relaxation of supercoiled DNA with no formation of cleavable complexes) with an IC.sub.50 of approximately 5 .mu.M, a dose dependent correlation could not be established between its topoisomerase II activity and its effects in cells. For example, the EC.sub.50 in various cells range from 200-300 nM, at least a ten-fold difference in increased potency from the biochemical inhibition of topoisomerase II. Moreover, when topoisomerase II levels in cells were modulated using 2-deoxyglucose (which results in the degradation of the enzyme), essentially no difference in activity was observed between the 2-deoxyglucose treated cells and untreated cells. [0011] The induction of G.sub.2 arrest also does not appear to be the significant contributor to the cytotoxicity of SNS-595. For example, in cells where G.sub.2 arrest is abrogated (by treating with caffeine which inhibits both ATM and ATR), essentially no difference in EC.sub.50 values were observed upon treatment with SNS-595 when compared to the cells in the untreated group (not treated with caffeine and where G.sub.2 arrest is observed). As shown by FIG. 1, ATM, ATR, and DNA-PK are three central DNA sensors/effectors that depending on the level of DNA damage that is detected within an individual cell, direct the cell into one of several outcomes including DNA repair, G.sub.2 arrest or apoptosis. [0012] Contrary to its initial characterization, SNS-595 mediates the activation of the DNA-PK pathway which eventually leads to apoptotic cell death. Notably, these events are S-phase specific meaning that they occur only during the S phase of the cell cycle. [0013] Treatment with SNS-595 results in an increase in the number of double-strand DNA breaks that form during the S phase. This damage impedes the ability of the cell to synthesize DNA and lengthens the time the cell spends in the S phase. Once DNA damage is detected in cells, markers for apoptosis rapidly appear. This rapid onset of apoptosis is p73 dependent as shown by a more than 11 fold decrease in SNS-595 sensitivity in p73 null cells as compared to p73 containing cells. Notably, SNS-595 mediated apoptosis is p53 independent. In other words, SNS-595 activity in cells is not related to the cells p53 mutational status. As FIG. 2 exemplifies, the formation of double-strand breaks activates, in a dose dependent manner, the DNA-PK mediated repair and apoptotic cellular machinery including but not limited to: i) DNA-PK expression; ii) H2AX phosphorylation; iii) c-Abl phosphorylation; iv) p53 phosphorylation; v) p73 phosphorylation; vi) p21 expression; vii) caspase-9 activation; and viii) caspase-3 activation. When the DNA damage is sufficiently severe such that the double-strand breaks cannot be repaired through non-homologous end joining (NHEJ), the cell rapidly enters apoptosis. Some cells are able to reach the G.sub.2 phase but are subsequently arrested (mediated by cdc2/cyclin B) because the cells are too damaged to enter into the M phase and also eventually becomes apoptotic. Notably, because SNS-595 is S-phase selective, doses of SNS-595 that are cytotoxic to proliferating cells (thus are progressing through the cell cycle including the S phase) are non-lethal to non-proliferating cells. [0014] Consistent with this mechanism, cells with induced resistance to SNS-595 also have alterations in the DNA-PK pathway. For example, a stable variant of HCT-116 cells that is approximately ten fold less sensitive to SNS-595 relative to HCT-116 cells, show for example increased levels of KU70, a protein that is an essential component of the activated DNA-PK complex. Conversely, decreased levels of DNA-PK or its activity (e.g. in the presence of an inhibitor) is associated with an increased sensitivity to SNS-595. [0015] The DNA-PK mediated cytotoxicity of SNS-595 is unusual. Known compounds that also impede DNA synthesis usually act through ATR or through both ATM and DNA-PK. Illustrative examples of ATR mediated cytotoxic compounds include antimetabolites and DNA polymerase inhibitors. Illustrative examples of ATM and DNA-PK mediated cytotoxic compounds include topoisomerase II poisons and anti-neoplastic antibiotics such as bleomycin. [0016] The present invention relates to SNS-595 and using its mechanism of action to maximize its therapeutic potential in treating human cancer. [0017] Thus, in one aspect of the present invention, a method is provided for determining whether a cancer to be treated is likely to respond to SNS-595 treatment and if the treatment is pursued, whether the cancer is responding to SNS-595 treatment. The types of cancers that are suitable for treatment with SNS-595 include but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, head and neck cancer, leukemia, liver cancer, lung cancer (both small cell and non-small cell), lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer. [0018] The method comprises determining a first amount of at least one member of the DNA-PK pathway in cells of a cancer to be treated and comparing the first amount to a second amount. [0019] When determining whether a cancer is likely to respond to SNS-595 treatment, the first amount is the amount of at least one member of the DNA-PK pathway in cells of a cancer to be treated (pretreatment amount). The second amount is the amount of a member of the DNA-PK pathway in reference cells (reference amount). Suitable reference cells include but are not limited to normal cells derived from the same tissue as the cancer to be treated. For example, if the cancer being treated is ovarian cancer, suitable reference cells include non-cancerous ovarian cells. The reference cells can be derived from the patient to be treated or can be derived from any normal tissue of the same type as the cancer being treated. Alternatively, the amount of any DNA-PK pathway member in HCT116 colon carcinoma cells (that have not been induced to show resistance to SNS-595) generally can be used as the reference amount. [0020] Suitable members of the DNA-PK pathway for the practice of the invention include but are not limited to: DNA-PK; Ku70; Ku80; MRE11, NBS1, RAD50, XRCC4, ligase IV, H2AX, c-Abl, p73, caspase-9 and caspase-3. In one embodiment, the DNA-PK pathway member is DNA-PK. In another embodiment, the DNA-PK member is Ku70. In another embodiment, the DNA-PK pathway member is Ku80. In another embodiment, the DNA-PK pathway member is MRE11. In another embodiment, the DNA-PK pathway member is NBS1. In another embodiment, the DNA-PK pathway member is RAD50. In another embodiment, the DNA-PK pathway member is XRCC4. In another embodiment, the DNA-PK member is ligase IV. In another embodiment, the DNA-PK member is H2AX. In another embodiment, the DNA-PK member is c-Abl. In another embodiment, the DNA-PK member is p73. In yet another embodiment, the DNA-PK member is caspase-9. In yet another embodiment, the DNA-PK member is caspase-3. Continue reading about Sns-595 and methods of using the same... 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