EP1727536A1 - Combinaisons de beta-lapachone et de medicament en phase s pour le traitement du cancer - Google Patents

Combinaisons de beta-lapachone et de medicament en phase s pour le traitement du cancer

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Publication number
EP1727536A1
EP1727536A1 EP05713938A EP05713938A EP1727536A1 EP 1727536 A1 EP1727536 A1 EP 1727536A1 EP 05713938 A EP05713938 A EP 05713938A EP 05713938 A EP05713938 A EP 05713938A EP 1727536 A1 EP1727536 A1 EP 1727536A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
acceptable salt
lapachone
cancer
phase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05713938A
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German (de)
English (en)
Inventor
Chiang J. Li
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Arqule Inc
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Arqule Inc
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Filing date
Publication date
Priority claimed from US11/060,747 external-priority patent/US20050192360A1/en
Priority claimed from US11/068,459 external-priority patent/US20050197406A1/en
Application filed by Arqule Inc filed Critical Arqule Inc
Publication of EP1727536A1 publication Critical patent/EP1727536A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Cancer Facts and Figures 2004, American Cancer Society, Inc. Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are mostly palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for new drugs effective in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors. Cancer cells are by definition heterogeneous. For example, within a single tissue or cell type, multiple mutational 'mechanisms' may lead to the development of cancer.
  • checkpoints are built into the machinery of the cell proliferation cycle where cells make a commitment to repair DNA damage or to undergo cell death. Many cancer cells have lost checkpoint control and have an uncontrolled proliferation drive. Major checkpoints occur at Gl/S phase and at the G2/M phase transitions where cells make a commitment to repair DNA or undergo cell death (e.g., apoptosis). Cells may undergo cell death (e.g., apoptosis) when DNA damage is irreparable (Li, CJ et al. (1999) Proc. Natl. Acad. Sci. USA 96:13369- 13374). Identification of therapeutic agents modulating the checkpoint control may improve cancer treatment.
  • the cell cycle checkpoint activator ⁇ -lapachone which acts at the Gl/S phase transition, is an agent with a reported anti-cancer activity in a limited number of cancers.
  • a method and composition for the treatment of tumors which comprises the administration of an effective amount of ⁇ -lapachone, in combination with a taxane derivative (WO00/61142).
  • 6,245,807 discloses the use of ⁇ -lapachone, amongst other ⁇ -lapachone derivatives, for use in treatment of human prostate disease.
  • ⁇ -lapachone has also been reported to decrease the number of tumors, reduce tumor size, or increase survival time, or a combination of these in xenotransplant mouse models of human ovarian cancer (Li, C . et al, (1999) Proc. Natl. Acad. Sci. USA, 96(23): 13369-13374), human prostate cancer (Li, CJ. et al, (1999) Proc. Natl Acad. Sci. USA, 96(23): 13369-13374), human breast cancer (Li, C J.
  • Taxol® paclitaxel
  • Bristol-Myers Squibb Co., N.Y., N.Y. paclitaxel
  • N.Y. Bristol-Myers Squibb Co.
  • N.Y. paclitaxel
  • N.Y. paclitaxel
  • N.Y. paclitaxel
  • N.Y. paclitaxel
  • N.Y. paclitaxel
  • N.Y. paclitaxel
  • GEMZAR ® is a nucleoside analog that exhibits antitumor activity.
  • Gemcitabine may be used in monotherapy, or in combination with other agents (e.g., cisplatin, carboplatin, TAXOL ® (paclitaxel)), to treat various cancers, including pancreatic cancer, breast cancer, non-small cell lung cancer, ovarian cancer, and bladder cancer.
  • Gemcitabine exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the Gl/S boundary. Without being limited by theory, it is believed that after a gemcitabine nucleotide is incorporated into DNA, only one additional nucleotide may be added to the growing DNA strands.
  • DNA polymerase epsilon is unable to remove the gemcitabine nucleotide and repair the growing DNA strand (e.g., masked chain termination).
  • gemcitabine induces internucleosomal DNA fragmentation, one of the characteristics of programmed cell death (e.g., apoptosis).
  • the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable ' carrier, and b) an S phase drug, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the cancer is treated.
  • the present invention also provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the pancreatic cancer is treated.
  • the present invention also provides a method of treating lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the lung cancer is treated.
  • the present invention also provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the cancer is treated.
  • the present invention also provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the pancreatic cancer is treated.
  • the present invention also provides a method of treating lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, where the lung cancer is treated.
  • the present invention also provides a method for inducing cell death in a cancer cell, comprising contacting the cancer cell with an effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, and b) an S phase drug, or a pharmaceutically acceptable salt thereof, where the contacting induces the cell death in the cancer cell.
  • the present invention also provides a method for inducing cell death in a cancer cell, comprising contacting the cancer cell with an effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, and b) gemcitabine, or a pharmaceutically acceptable salt thereof, where the contacting induces the cell death in the cancer cell.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier.
  • the present invention also provides a kit comprising a) a first container comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, b) a second container comprising a therapeutically effective amount of an S phase drug, or a pharmaceutically acceptable salt thereof, and c) instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, and the S phase drug, or a pharmaceutically acceptable salt thereof, to treat a subject.
  • the present invention also provides a kit comprising a) a first container comprising a therapeutically effective of ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, b) a second container comprising a therapeutically effective amount of gemcitabine, and c) instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, and the gemcitabine, to treat a subject.
  • the present invention also provides a kit comprising a) a container comprising a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier, and b) instructions for using the pharmaceutical composition to treat a subject.
  • the present invention also provides a method of treating a cell proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ - lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the cell proliferative disorder is treated.
  • the present invention also provides a method of treating a cell proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ - lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the cell proliferative disorder is treated.
  • the present invention also provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the cancer is treated.
  • the present invention also provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the pancreatic cancer is treated.
  • the present invention also provides a method of treating lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the lung cancer is treated.
  • the present invention also provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the cancer is treated.
  • the present invention also provides a method of treating pancreatic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the pancreatic cancer is treated.
  • the present invention also provides a method of treating lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) gemcitabine, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, where the lung cancer is treated.
  • the present invention also provides a method for inducing cell death in a cancer cell, comprising contacting the cancer cell with an effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, where the contacting induces the cell death in the cancer cell.
  • the present invention also provides a method for inducing cell death in a cancer cell, comprising contacting the cancer cell with an effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and b) gemcitabine, where the contacting induces the cell death in the cancer cell.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier.
  • the present invention also provides a kit comprising a) a first container comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, b) a second container comprising a therapeutically effective amount of an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and c) instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to treat a subject.
  • the present invention also provides a kit comprising a) a first container comprising a therapeutically effective of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, b) a second container comprising a therapeutically effective amount of gemcitabine, and c) instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the gemcitabine, to treat a subject.
  • the present invention also provides a kit comprising a) a container comprising a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier, and b) instructions for using the pharmaceutical composition to treat a subject.
  • a kit comprising a) a container comprising a pharmaceutical composition comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, a therapeutically effective amount of gemcitabine, and a pharmaceutically acceptable carrier, and b) instructions for using the pharmaceutical composition to treat a subject.
  • the present invention also provides a method of treating individuals afflicted with cancerous or pre-cancerous cells, tumors and/or malignancies.
  • This method comprises administering to a subject (e.g., a subject in need of such treatment, e.g., an individual afflicted with cancer) an effective amount of a Gl/S phase drug, such as ⁇ -lapachone or a derivative or analog thereof, together with an effective amount of an S phase drug such as gemcitabine, such that the cancer is treated.
  • a subject e.g., a subject in need of such treatment, e.g., an individual afflicted with cancer
  • an effective amount of a Gl/S phase drug such as ⁇ -lapachone or a derivative or analog thereof
  • an S phase drug such as gemcitabine
  • the present invention also provides a method for treating cancer in a subject by administering to the subject a Gl/S phase drug, which is preferably ⁇ -lapachone, or a derivative or analog thereof, together with an S-phase drug, such as gemcitabine, in a therapeutically effective amount, under conditions such that the cancer is treated.
  • a Gl/S phase drug which is preferably ⁇ -lapachone, or a derivative or analog thereof
  • an S-phase drug such as gemcitabine
  • the cancer is pancreatic cancer.
  • the invention provides compositions useful for the treatment of cancer.
  • the composition comprises a therapeutically effective amount of a combination of a Gl/S phase drug such as ⁇ -lapachone, or a derivative or analog thereof, together with an S-phase drug, such as gemcitabine.
  • the composition further includes a pharmaceutically-acceptable solvent, carrier, diluent, or excipient.
  • the invention provides kits for treating cancer.
  • the kits include a Gl/S phase drug such as ⁇ -lapachone, or a derivative or analog thereof, and an S-phase drug, such as gemcitabine.
  • the Gl/S phase drug and the S-phase drug are present in amounts effective in combination for treating cancer.
  • the combination of the present invention is particularly advantageous in the treatment of patients who have chemotherapeutically refractive metastatic cancers, including pancreatic cancer.
  • the method of the present invention comprises administering to the patient, an effective amount, in combination, of a Gl/S phase drug (such as ⁇ -lapachone) and an S phase drug.
  • the combination is (1) a cell cycle checkpoint activator such as ⁇ -lapachone or derivatives or analogs thereof (a Gl and/or S phase drug) and (2) antimetabolite drugs such as gemcitabine, 5-fluorouracil (5-FU), capacitabine, methotrexate, 5-fluorodeoxyuridine, and cytarabine (araC); and the like (S phase drug), and pharmaceutically acceptable salts thereof.
  • the cell cycle checkpoint activator is ⁇ -lapachone.
  • the antimetabolite drug is a pyrimidine antagonist such as gemcitabine, 5-FU, capacitabine or araC, and most preferably gemcitabine.
  • Figure 1 sets forth an effect of ⁇ -lapachone, administered in monotherapy or in combination with gemcitabine, on the growth of xeno grafted Panc-1 human pancreatic tumors in an athymic nude mouse model.
  • Figure 2 sets forth an effect of ⁇ -lapachone, administered in monotherapy or in combination with gemcitabine, on the growth of xeno grafted A549 human lung tumors in an athymic nude mouse model.
  • the present invention provides a method of treating a cell proliferative disorder, such as cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a) ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier, and b) an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof (e.g., gemcitabine), in combination with a pharmaceutically acceptable carrier, where the cell proliferative disorder is treated.
  • a cell proliferative disorder such as cancer
  • the invention also provides the use of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof (e.g., gemcitabine) for the preparation of a medicament useful for the treatment of cancer.
  • kits comprising ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof and an S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof (e.g., gemcitabine).
  • the present invention includes and is based in part on an understanding of, and methods for, the activation of cell cycle checkpoints by modulators of cell cycle checkpoint activation (e.g., ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof).
  • modulators of cell cycle checkpoint activation e.g., ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • ACTTM Activated Checkpoint Therapy
  • many cancer cells are defective in their cell cycle checkpoint functions secondary to mutations in one of their molecular modulators, e.g., p53. It is in part, for this reason, that cancer cells have accumulated genetic enors during the carcinogenic process.
  • Therapeutic agents that activate cell cycle checkpoint functions can selectively promote cell death in cancer cells, since cell death appears to be induced at least in part by the conflict between the uncontrolled-proliferation drive in cancer cells and the checkpoint delays induced artificially.
  • ACTTM takes advantage of the tendency of cell death to occur at checkpoints during the cell proliferation cycle by activating one or more checkpoints, thereby producing conflicting signals regarding cell cycle progression versus arrest. If more than one checkpoint is activated, cancer cells with uncontrolled proliferation signals and genetic abnormalities are blocked at multiple checkpoints, creating "collisions" that promote synergistic cell death.
  • ACTTM offers selectivity against cancer cells as compared to normal cells and is therefore safer than less selective therapies. First, the ACTTM method activates but does not disrupt cell cycle checkpoints.
  • normal cells with well-controlled proliferation signals can be delayed at checkpoints in a regulated fashion, resulting in no cell death-prone collisions.
  • normal cells with intact Gl checkpoint control are expected to arrest in Gl.
  • Cancer cells are expected to be delayed in S-, G2-, and M-phases, since most cancer cells harbor Gl checkpoint defects, making cancer cells more sensitive to drugs imposing S and M phase checkpoints, ⁇ -lapachone is a Gl and S phase compound, and contacting a cell with ⁇ - lapachone results in activation of a Gl or S cell cycle checkpoint.
  • the combination of a Gl/S phase drug e.g., ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof
  • an S phase drug results in synergistic treatment of cancer cells and/or tumors.
  • the combinations of the present invention are particularly advantageous using ⁇ -lapachone and gemcitabine, where synergistic results may be obtained.
  • molecular changes underlying cell cycle delay at checkpoints for example Gl/S phase and S phase, appear to result in the synergistic induction of cell death (e.g., apoptosis) in malignant cells.
  • the Gl/S phase compound is administered prior to, or simultaneously with, compounds that target a cell at the S phase checkpoint. More preferably, the Gl/S phase compound(s) is/are administered prior to the compounds that target a cell at the S phase checkpoint.
  • modulator of cell cycle checkpoint activation refers to a compound capable of altering checkpoint activation in cells (in prefened embodiments, activating one or more cell cycle checkpoints), preferably by activating checkpoint-mediated DNA repair mechanisms, or by reinstating checkpoint activity that has been lost due to a malfunction or mutation in the cellular pathways that regulate cell cycle activity.
  • Prefened modulators of cell cycle checkpoint activation for use in the present invention induce checkpoint activation (t.e., activate one or more cell cycle checkpoints, preferably at Gi/S phase), preferably without causing substantial DNA damage.
  • certain prefened modulators of cell cycle checkpoint activation are capable of increasing the level or activity of E2F (more preferably E2F1) in a cell.
  • Methods for screening for modulators of cell cycle checkpoint activation including compounds capable of elevating E2F activity or levels in a cell, include those that are disclosed in PCT Patent Application No. PCT/US03/22631 to Li et al.
  • prefened modulators of cell cycle checkpoint activation are capable of increasing the level or activity of E2F in a cell by an amount sufficient to cause cell death (e.g., apoptosis) if the cell is a cancerous cell. More prefened modulators of cell cycle checkpoint activation are capable of raising the level or activity of E2F1 in a cell by an amount sufficient to cause cell death (e.g., apoptosis) if the cell is a cancerous cell.
  • a modulator of cell cycle checkpoint activation is not ⁇ -lapachone. Again not limited by theory, cellular response to DNA damage is regulated by the
  • ATM/ATR signal transduction pathway in which ATM and ATR are protein kinases of the phosphatidyl-inositol-3 kinase family (PI3K).
  • PI3K phosphatidyl-inositol-3 kinase family
  • ATM and ATR phosphorylate Chk2 and Chkl respectively, which in turn activate a variety of substrates involved in arresting cells at the Gl/S phase of the cell cycle, as well as inducing and activating proteins involved in DNA repair.
  • Chk2 has been shown to activate proteins involved in DNA repair including the tumor suppressor BRCA1, thereby enhancing DNA repair capacity following DNA damage.
  • Chk2 has also been shown to stabilize p53 both by directly phosphorylating p53, and by inhibiting Mdm2, a ubiquitin ligase that targets p53 for degradation. Under such conditions, increased levels of p53 lead to Gl/S arrest, DNA repair, and apoptosis in cells with ineparable DNA damage. Again not limited by theory, it is believed that Chk2 is an important cell cycle regulator, which, depending on the conditions, can induce cell cycle arrest and DNA repair, or initiate cell death (e.g., apoptosis) if DNA damage is too severe.
  • preferred modulators of cell cycle checkpoint activation are capable of increasing the level or activity of Chk2 in a cell by an amount sufficient to cause cell death (e.g., apoptosis) if the cell is a cancerous cell.
  • E2F1 is one of related proteins in the E2F family of nuclear transcription factors, which family is critically important in regulation of the cell cycle. E2F1 is required for cellular proliferation by promoting passage through the Gl/S checkpoint. During proliferation of normal cells, transcriptionally active E2F1 is liberated from an inactive E2F1/Rb complex following phosphorylation of Rb. E2F1 levels rise, promoting progression through Gl .
  • E2F1 levels must decline for progress to continue. Sustained elevation of E2F1 at this point in the cell cycle causes activation of the S phase checkpoint, and subsequent cell death (e.g., by apoptosis).
  • this regulatory protein may either promote cellular proliferation, induce cell cycle delay, DNA repair or cell death.
  • phosphorylation of Rb results in dissociation of Rb-E2F1 complexes, liberating active E2F1, which then stimulates entry into S phase by promoting transcription of key cell cycle effectors.
  • E2F1 must be degraded for progress to continue.
  • E2F is the E2F transcription factor family (including but not limited to E2F-1, E2F-2, E2F-3).
  • a cell cycle checkpoint pathway refers to a biochemical pathway that is involved in modulation of a cell cycle checkpoint.
  • a cell cycle checkpoint pathway may have stimulatory or inhibitory effects, or both, on one or more functions comprising a cell cycle checkpoint.
  • a cell cycle checkpoint pathway is comprised of at least two compositions of matter, preferably proteins, both of which contribute to modulation of a cell cycle checkpoint.
  • a cell cycle checkpoint pathway may be activated through an activation of one or more members of the cell cycle checkpoint pathway.
  • a cell cycle checkpoint pathway is a biochemical signaling p athway.
  • cell cycle checkpoint regulator refers to a composition of matter that can function, at least in part, in modulation of a cell cycle checkpoint.
  • a cell cycle checkpoint regulator may have stimulatory or inhibitory effects, or both, on one or more functions comprising a cell cycle checkpoint.
  • a cell cycle checkpoint regulator is a protein.
  • a cell cycle checkpoint regulator is a not a protein.
  • a cell cycle checkpoint regulator is selected from the group consisting of ATM, ATR, Chkl, Chk2, E2F1, BRCA1, Rb, ⁇ 53, p21, Mdm2, Cdc2, Cdc25, and 14-4-3 [sigma].
  • cell cycle checkpoint activator refers to a compound capable of activating cell cycle checkpoints, e.g., by activating checkpoint-mediated DNA repair mechanisms, or by reinstating checkpoint activity that has been lost due to a malfunction or mutation in the cellular pathways that regulate cell cycle activity.
  • major cell cycle checkpoints occur at Gj/S phase and at the G 2 /M phase transitions.
  • Modulation of cell cycle checkpoint activation is further discussed in, e.g., C J. Li et al. Proc. Natl Acad. Sci. USA (1999), 96(23), 13369-13374, and Y. Li et al Proc. Natl. Acad. Sci. USA (2003), 100(5), 2674-2678, and PCT Publication WO 00/61142 (Pardee et al).
  • Prefened cell cycle checkpoint activators for use in the present invention induce checkpoint activation (i.e., activate one or more cell cycle checkpoints, preferably at Gi/S phase), preferably without causing substantial DNA damage.
  • prefened cell cycle checkpoint activators are capable of increasing the level or activity of E2F (more preferably E2F1) in a cell.
  • Methods for screening for cell cycle checkpoint activators including compounds capable of elevating E2F activity or levels in a cell, include those that are disclosed in PCT Patent Application No. PCT/US03/22631 to Li et al.
  • prefened cell cycle checkpoint activators are capable of increasing the level of E2F in a cell by an amount sufficient to cause cell death (e.g., apoptosis) if the cell is a cancer cell.
  • More prefened cell cycle checkpoint activators are capable of raising the level or activity of E2F1 in a cell by an amount sufficient to cause cell death (e.g., apoptosis) if the cell is a cancer cell.
  • a cell cycle checkpoint activator is not ⁇ -lapachone.
  • ⁇ -lapachone refers to 3,4-dihydro-2,2-dimethyl-2H- naphtho[l,2-b]pyran-5,6-dione and derivatives and analogs thereof, and has the chemical structure:
  • a Gl/S-phase drug refers to a drug that modulates the cell cycle (e.g., causes cell death) at the Gl and S-phase checkpoints, e.g., by activating a cell cycle checkpoint.
  • Beta-lapachone is a prefened Gl/S-phase drug.
  • an S phase drug is a drug that modulates the cell cycle (e.g., causes cell death) at the S-phase checkpoint.
  • an S phase drug exerts a therapeutic effect by inhibiting DNA synthesis.
  • the invention is directed to a method for treating a subject having malignant cells or inhibiting further growth of such malignant cells by administering a drug or compound that targets such cells at the Gl/S phase checkpoints in the cell cycle.
  • a second drug or compound that acts at the S phase checkpoint in the cell cycle is administered simultaneously with, or following, the Gl/S phase drug or compound.
  • Individual compounds satisfying these criteria are known to those of ordinary skill in the art, and may be found in reference texts such as the Physician 's Desk Reference, 59 Edition, Thomson PDR (2005).
  • ⁇ -lapachone and its derivatives are Gl/S phase drugs
  • gemcitabine and other antimetabolite drugs are S phase drugs.
  • a list of representative compounds is set forth below in Table 1.
  • an "antimetabolite drug” is any compound that exerts a therapeutic effect by inhibiting the utilization of an endogenous cellular metabolite.
  • exemplary antimetabolite drugs include folic acid antagonists (e.g., methotrextate), purine antagonists (e.g., thioguanine) and pyrimidine antagonists (e.g., fluorouracil).
  • folic acid antagonists e.g., methotrextate
  • purine antagonists e.g., thioguanine
  • pyrimidine antagonists e.g., fluorouracil
  • an antimetabolite drug is an S phase antimetabolite drug that modulates the cell cycle, e.g., by causing cell death, at the S- phase checkpoint.
  • a "nucleoside analog" is any compound that that exerts a therapeutic effect by acting as an analog to an endogenous cellular nucleoside, including analogs of deoxyribonucleosides and ribonucleosides, such as but not limited to analogs of deoxyadenosine, deoxyguanosine, deoxycytidine, deoxyuridine, thymidine, adenosine, guanosine, cytidine, uridine, and thymine ribosides.
  • nucleoside analog that exhibits antitumor activity.
  • a "nucleotide analog” is any compound that acts as an analog to an endogenous cellular nucleotide, including analogs of deoxyribonucleotides and ribonucleotides, such as but not limited to analogs of deoxyadenylic acid, deoxyguanylic acid, deoxycytidylic acid, thymidylic acid, 2'-adenylic acid, 3'-adenylic acid, 5'-adenylic acid, 3'-guanylic acid, 3'-cytidylic acid, 3'-uridylic acid, and phosphate- bearing derivatives thereof.
  • Nucleoside analogs and nucleotide analogs may be useful as chemotherapeutic agents for cell proliferative disorders such as cancer. Without intending to be limited by theory, nucleoside analogs and nucleotide analogs are believed to inhibit DNA synthesis by inhibition of DNA polymerases and prevention of elongation of DNA strands through direct incorporation into the DNA molecule. High levels of nucleoside analog drugs may lead to DNA strand breaks, inhibition of DNA synthesis, accumulation of cells in S phase or at the Gl/S junction, or cell death.
  • Prefened Gl/S phase checkpoint targeting compounds include Gl/S phase drugs (for example, ⁇ -lapachone), Gl phase drugs (for example, lovastatin, mimosine, tamoxifen, and the like) and S phase drugs (for example, gemcitabine, 5-FU, MTX, and the like).
  • Gl/S phase drugs for use in this invention preferably do not cause significant DNA damage in normal cells, ⁇ -lapachone, its derivatives and analogs are most prefened Gl/S phase drugs.
  • Prefened Gl/S phase compounds are direct activators of cell cycle checkpoint activation (see, e.g., Y. Li et al, Proc. Natl. Acad. Sci. USA (2003), 100(5), 2674-8).
  • Prefened Gl/S phase compounds are capable of elevating the amount or activity of E2F (preferably E2F1) in a cancer cell, thereby activating the checkpoint and causing cell death in cancerous or pre-cancerous cells.
  • ⁇ -Lapachone (3,4-dihydro-2, 2-dimethyl-2H-naphtho [1,2-b] pyran-5, 6-dione), a simple non- water soluble orthonapthoquinone, was first isolated in 1882 by Paterno from the heartwood ofthe lapacho tree (See Hooker, SC, (1936) /. Am. Chem. Soc. 58:1181-1190; Goncalves de Lima, O, et al, (1962) Rev. Inst. Antibiot. Univ. Recife. 4:3-17).
  • ⁇ -Lapachone The structure of ⁇ -Lapachone was established by Hooker in 1896 and it was first synthesized by Fieser in 1927 (Hooker, SC, (1936) I. Am. Chem. Soc. 58:1181-1190).
  • ⁇ -Lapachone can, for example, be obtained by simple sulfuric acid treatment ofthe naturally occurring lapachol, which is readily isolated from Tabebuia avellenedae growing mainly in Brazil, or is easily synthesized from seeds of lomatia growing in Australia (Li, CJ, et al, (1993) J. Biol. Chem. 268:22463-33464). Methods for formulating ⁇ -Lapachone or its derivatives or analogs can be accomplished as described in U.S. Patent No.
  • derivatives or analogs of ⁇ -Lapachone include, for example, 3,4-dihydro- 2,2-dimethyl-3-(3-methyl-2-butenyl)-2H-naphtho[l,2-b]pyran-5,6-dione, 3,4-dihydro-2,2- dimethyl-2H-naphtho[l,2-b]thiopyran-5,6-dione and 3,4-dihydro-4,4-dimethyl-2H- ⁇ aphtho[l,2- b]thiopyran-5,6-dione.
  • Gl/S phase checkpoint targeting drugs include reduced ⁇ -lapachone (e.g., Formula la, in which R' and R" are both hydrogen) and derivatives of reduced ⁇ -lapachone (see,e.g., Formula la, in which R' and R" are each independently hydrogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkylcarbonyl, or a pharmaceutically acceptable salt).
  • reduced ⁇ -lapachone e.g., Formula la, in which R' and R" are both hydrogen
  • derivatives of reduced ⁇ -lapachone see,e.g., Formula la, in which R' and R" are each independently hydrogen, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkylcarbonyl, or a pharmaceutically acceptable salt.
  • the term "combination ofthe present invention” means a Gl/S-phase drug ofthe present invention and an S phase drug ofthe present invention.
  • the term “compound ofthe present invention” means a Gl/S-phase drug ofthe present invention or an S phase drug ofthe present invention.
  • Prefened combinations ofthe present invention include ⁇ -lapachone with gemcitabine; ⁇ -lapachone with 5-FU; ⁇ -lapachone with methotrexate; ⁇ -lapachone with 5-fluorodeoxyuridine; or ⁇ -lapachone with cytarabine.
  • ⁇ -lapachone with gemcitabine is the most prefened combination.
  • Prefened combinations ofthe present invention also include reduced ⁇ -lapachone with gemcitabine; reduced ⁇ -lapachone with 5-FU; reduced ⁇ - lapachone with methotrexate; reduced ⁇ -lapachone with 5-fluorodeoxyuridine; or reduced ⁇ - lapachone with cytarabine.
  • ⁇ -lapachone, or derivatives or analogs thereof are not combined with cis-platinum.
  • ⁇ -lapachone is the prefened Gl/S-phase compound for use in the composition in accordance with the present invention
  • the invention is not limited in this respect, and ⁇ - lapachone derivatives or analogs, such as lapachol, and pharmaceutical compositions and formulations thereof are part ofthe present invention.
  • ⁇ -lapachone analogs include those recited in PCT International Application PCT/US93/07878 (WO 94/04145), which discloses compounds ofthe formula:
  • R and Ri are each independently hydrogen, substituted and unsubstituted aryl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkyl and substituted or unsubstituted alkoxy.
  • the alkyl groups preferably have from 1 to about 15 carbon atoms, more preferably from 1 to about 10 carbon atoms, still more preferably from 1 to about 6 carbon atoms.
  • the term alkyl unless otherwise modified refers to both cyclic and noncyclic groups, although of course cyclic groups will comprise at least three carbon ring members.
  • Straight or branched chain noncyclic alkyl groups are generally more prefened than cyclic groups.
  • Straight chain alkyl groups are generally more prefened than branched.
  • the alkenyl groups preferably have from 2 to about 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to 6 carbon atoms. Especially prefened alkenyl groups have 3
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • the substituted R and R ⁇ groups may be substituted at one or more available positions by one or more suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from six to ten carbon atoms, halogen such as fluoro, chloro and bromo, and N, O and S, including heteroalkyl, e.g., heteroalkyl having one or more hetero atom linkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms.
  • suitable groups such as, for example, alkyl groups such as alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups such as alkenyl groups having from 2 to 10 carbon atoms or 2
  • R and R ⁇ are each independently selected from hydrogen, hydroxy, sulfliydryl, halogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted aryl, unsubstituted aryl, substituted alkoxy, unsubstituted alkoxy, and salts thereof, where the dotted double bond between the ring carbons represents an optional ring double bond.
  • Additional ⁇ -lapachone analogs and derivatives are recited in PCT International Application PCT/US00/10169 (WOOO/61142), which disclose compounds ofthe structure:
  • R 5 and R 6 may be independently selected from hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkenyl, Ci- C 6 alkoxy, C ⁇ -C 6 alkoxycarbonyl, -(CH 2 ) n -phenyl; and R 7 is hydrogen, hydroxyl, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkenyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkoxycarbonyl, — (CH 2 ) n -amino, — (CH 2 ) n -aryl, ⁇ (CH ) n - heteroaryl, ⁇ (CH 2 ) n -heterocycle, or ⁇ (CH 2 ) n -phenyl, wherein n is an integer from 0 to 10.
  • R and R ⁇ are each independently selected from hydrogen, hydroxy, sulfliydryl, halogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted aryl, unsubstituted aryl, substituted alkoxy, unsubstituted alkoxy, and salts thereof.
  • the alkyl groups preferably have from 1 to about 15 carbon atoms, more preferably from 1 to about 10 carbon atoms, still more preferably from 1 to about 6 carbon atoms.
  • alkyl refers to both cyclic and noncyclic groups.
  • Straight or branched chain noncyclic alkyl groups are generally more prefened than cyclic groups.
  • Straight chain alkyl groups are generally more prefened than branched.
  • the alkenyl groups preferably have from 2 to about 15 carbon atoms, more preferably from 2 to about 10 carbon atoms, still more preferably from 2 to 6 carbon atoms.
  • Especially prefened alkenyl groups have 3 carbon atoms (i.e., 1-propenyl or 2- propenyl), with the allyl moiety being particularly prefened.
  • Phenyl and napthyl are generally prefened aryl groups.
  • Alkoxy groups include those alkoxy groups having one or more oxygen linkage and preferably have from 1 to 15 carbon atoms, more preferably from 1 to about 6 carbon atoms.
  • the substituted R and Ri groups may be substituted at one or more available positions by one or more suitable groups such as, for example, alkyl groups having from 1 to 10 carbon atoms or from 1 to 6 carbon atoms, alkenyl groups having from 2 to 10 carbon atoms or 2 to 6 carbon atoms, aryl groups having from six to ten carbon atoms, halogen such as fluoro, chloro and bromo, and N, O and S, including heteroalkyl, e.g., heteroalkyl having one or more hetero atom linkages (and thus including alkoxy, aminoalkyl and thioalkyl) and from 1 to 10 carbon atoms or from 1 to 6 carbon atoms; and where R 5 and R 6 may be independently selected from hydroxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkeny
  • Ri is (CH 2 ) n -R 2 , where n is an integer from 0-10 and R 2 is hydrogen, an alkyl, an aryl, a heteroaromatic, a heterocychc, an aliphatic, an alkoxy, an allyloxy, a hydroxyl, an amine, a thiol, an amide, or a halogen.
  • Analogs and derivatives also contemplated by the invention include 4-acetoxy- ⁇ - lapachone, 4-acetoxy-3-bromo- ⁇ -lapachone, 4-keto- ⁇ -lapachone, 7-hydroxy- ⁇ -lapachone, 7- methoxy- ⁇ -lapachone, 8-hydroxy- ⁇ -lapachone, 8-methoxy- ⁇ -lapachone, 8-chloro- ⁇ -lapachone, 9-chloro- ⁇ -lapachone, 8-methyl- ⁇ -lapachone and 8,9-dimethoxy- ⁇ -lapachone.
  • Preferred analogs and derivatives also contemplated by the invention include compounds ofthe following general formula VIII:
  • Ri-Ri are each, independently, selected from the group consisting of H, C ⁇ -C 6 alkyl, - C 6 alkenyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkoxycarbonyl, — (CH ) n -aryl, ⁇ (CH 2 ) n -heteroaryl, ⁇ (CH 2 ) n - heterocycle, or ⁇ (CH 2 ) n -phenyl; or Ri and R 2 combined are a single substituent selected from the above group, and R 3 and j combined are a single substituent selected from the above groups, in which case — is a double bond.
  • Prefened analogs and derivatives also contemplated by this invention include dunnione and 2-ethyl-6-hydroxynaphtho[2,3-b]-furan-4,5-dione.
  • Prefened analogs and derivatives also contemplated by the invention include compounds ofthe following general formula IX:
  • Formula IX where Ri is selected from H, CH 3 , OCH 3 and NO 2 .
  • Additional prefened ⁇ -lapachone analogs useful in the methods and kits ofthe invention are represented by Formula X (see also the co-owned PCT patent application entitled “NOVEL LAPACHONE COMPOUNDS AND METHODS OF USE THEREOF", PCT/US2003/037219, filed November 18, 2003, and claiming priority to U.S. provisional application no. 60/427,283, filed November 18, 2002):
  • R1-R6 are each, independently, selected from the group consisting of H, OH, substituted and unsubstituted C ⁇ -C 6 alkyl, substituted and unsubstituted C ⁇ -C 6 alkenyl, substituted and unsubstituted C ⁇ -C 6 alkoxy, substituted and unsubstituted C ⁇ -C 6 alkoxycarbonyl, substituted and unsubstituted C ⁇ -C 6 acyl, -(CH ) n -amino, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocycle, and -(CH 2 ) n -phenyl; or one of RI or R2 and one of R3 or R4; or one of R3 or R4 and one of R5 or R6 form a fused ring, wherein the ring has 4-8 ring members
  • RI and R2 are alkyl
  • R3-R6 are, independently, H, OH, halogen, alkyl, alkoxy, substituted or unsubstituted acyl, substituted alkenyl or substituted alkyl carbonyl
  • R7-R10 are hydrogen.
  • RI and R2 are each methyl and R3-R10 are each hydrogen.
  • R1-R4 are each hydrogen
  • R5 and R6 are each methyl and R7-R10 are each hydrogen.
  • R1-R4 are each, independently, selected from the group consisting of H, OH, substituted and unsubstituted C ⁇ -C 6 alkyl, substituted and unsubstituted C ⁇ -C 6 alkenyl, substituted and unsubstituted C ⁇ -C 6 alkoxy, substituted and unsubstituted Ci-Ce alkoxycarbonyl, substituted and unsubstituted C ⁇ -C 6 acyl, -(CH 2 ) n -amino, -(CH 2 ) n -aryl, -(CH 2 ) n -heterocycle, and -(CH 2 ) n -phenyl; or one of RI or R2 and one of R3 or R4 form a fused ring, wherein the ring has 4-8 ring members; R5-R8 are each, independently, hydrogen, hydroxyl, halogen, substitute
  • the Gl/S phase drug is selected from the group consisting of 3,4- dihydro-2,2-dimethyl-3-(3-methyl-2-butenyl)-2H-naphtho[ 1 ,2-b]pyran-5,6-dione, 3,4-dihydro- 2,2-dimethyl-2H-naphtho[l,2-b]thiopyran-5,6-dione and 3,4-dihydro-4,4-dimethyl-2H- naphtho[ 1 ,2-b]thiopyran-5,6-dione.
  • All stereoisomers ofthe compounds ofthe instant invention are contemplated, either in admixture or in pure or substantially pure form, including crystalline forms of reacemic mixtures and crystalline forms of individual isomers.
  • the definition ofthe compounds according to the invention embraces all possible stereoisomers (e.g., the R and S configurations for each asymmetric center) and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having a specified activity.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, separation by chiral column chromatography or supercritical fluid chromatography.
  • the individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization. Furthermore, all geometric isomers, such as E- and Z- configurations at a double bond, are within the scope ofthe invention unless otherwise stated. Certain compounds of this invention may exist in tautomeric forms. All such tautomeric forms ofthe compounds are considered to be within the scope of this invention unless otherwise stated.
  • the present invention also includes one or more regioisomeric mixtures of an analog or derivative of ⁇ -lapachone. In additional aspects, a compound or combination ofthe present invention may be administered in combination with a chemotherapeutic agent.
  • chemotherapeutic agent can be a taxane, an aromatase inhibitor, an anthracycline, a microtubule targeting drug, a topoisomerase poison drug, a targeted monoclonal or polyconal antibody, an inhibitor of a molecular target or enzyme (e.g., a kinase inhibitor), or a cytidine analogue drug.
  • the chemotherapeutic agent can be, but is not restricted to, tamoxifen, raloxifene, anastrozole, exemestane, letrozole, HERCEPTIN ® (trasruzumab), GLEEVEC ® (imatanib), TAXOL ® (paclitaxel), IRESSA ® (gefitinib), TARCEVATM (erlotinib), cyclophosphamide, lovastatin, minosine, araC, 5-fluorouracil (5-FU), methotrexate (MTX), TAXOTERE ® (docetaxel), ZOLADEX ® (goserelin), AVASTINTM (bevacizumab), vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin,
  • the chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor).
  • G-CSF granulocyte colony stimulating factor
  • ⁇ - lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof may be administered in combination with radiation therapy.
  • ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • CAF cyclophosphamide, adriamycin and 5-fluorouracil
  • AC adr
  • salt is a pharmaceutically acceptable salt and can include acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Na + , K + , Li + , alkali earth metal salts such as Mg or Ca, or organic amine salts.
  • the term "metabolite” means a product of metabolism of a compound of the present invention, or a pharmaceutically acceptable salt, analog or derivative thereof, that exhibits a similar activity in vivo to a compound ofthe present invention.
  • the tenn “prodrug” means a compound ofthe present invention covalently linked to one or more pro-moieties, such as an amino acid moiety or other water solubilizing moiety.
  • a compound ofthe present invention may be released from the pro-moiety via hydrolytic, oxidative, and/or enzymatic release mechanisms.
  • a prodrug composition ofthe present invention exhibits the added benefit of increased aqueous solubility, improved stability, and improved pharmacokinetic profiles.
  • the pro-moiety may be selected to obtain desired prodrug characteristics.
  • the pro-moiety e.g., an amino acid moiety or other water solubilizing moiety may be selected based on solubility, stability, bioavailability, and/or in vivo delivery or uptake.
  • a "subject” can be any mammal, e.g., a human, a primate, mouse, rat, dog, cat, cow, horse, pig, sheep, goat, camel.
  • the subject is a human.
  • a "subject in need thereof is a subject having a cell proliferative disorder, or a subject having an increased risk of developing a cell proliferative disorder relative to the population at large.
  • a subject in need thereof has a precancerous condition.
  • a subject in need thereof has cancer.
  • the subject may be suffering from a known (i.e., diagnosed) condition characterized by cell hyperproliferation (e.g., cancer).
  • a known (i.e., diagnosed) condition characterized by cell hyperproliferation e.g., cancer
  • cell proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • a cell proliferative disorder includes a non-cancerous condition, e.g., rheumatoid arthritis; inflammation; autoimmune disease; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram- negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjun
  • a cell proliferative disorder includes a precancer or a precancerous condition.
  • a cell proliferative disorder includes cancer.
  • a cell proliferative disorder includes a non-cancerous cell proliferative disorder.
  • Various cancers to be treated include but are not limited to breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal carcinoma, liver cancer, hepatoma, brain cancer, skin cancer, melanoma, multiple myeloma, chronic myelogenous leukemia, hematologic tumor, and lymphoid tumor, including metastatic lesions in other tissues or organs distant from the primary tumor site.
  • cancers to be treated include but are not limited to sarcoma, carcinoma, and adenocarcinoma.
  • a "precancer cell” or “precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition.
  • a "cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells.
  • cancer cells or precancerous cells are identified by histological typing or grading of a tissue sample (e.g., a biopsy sample).
  • cancer cells or precancerous cells are identified through the use of appropriate molecular markers.
  • a solid tumor is formed as a result of a cancer selected from the group consisting of breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal carcinoma, liver cancer, hepatoma, brain cancer, skin cancer, and melanoma.
  • a "cell proliferative disorder ofthe hematologic system” is a cell proliferative disorder involving cells ofthe hematologic system.
  • a cell proliferative disorder ofthe hematologic system includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
  • a cell proliferative disorder ofthe hematologic system includes hyperplasia, dysplasia, and metaplasia of cells ofthe hematologic system.
  • compositions ofthe present invention may be used to treat a cancer selected from the group consisting of a hematologic cancer ofthe present invention or a hematologic cell proliferative disorder ofthe present invention.
  • a hematologic cancer ofthe present invention i.e., a hematologic tumor
  • lymphoma including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin
  • leukemia including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia
  • myeloid neoplasms and mast cell neoplasms myeloid neoplasms and mast cell neoplasms.
  • a “cell proliferative disorder ofthe lung” is a cell proliferative disorder involving cells ofthe lung.
  • a cell proliferative disorder includes a pre-cancer or precancerous condition ofthe lung.
  • a cell proliferative disorder ofthe lung includes a non- cancerous cell proliferative disorder ofthe lung.
  • a cell proliferative disorder includes lung cancer, including metastatic lesions in other tissues or organs distant from the primary tumor site.
  • a "precancer cell” or “precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition.
  • a "cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells.
  • cancer cells or precancerous cells are identified by histological typing or grading of a tissue sample (e.g., a biopsy sample).
  • cancer cells or precancerous cells are identified through the use of appropriate molecular markers.
  • the cell proliferative disorder ofthe lung is lung cancer.
  • compositions ofthe present invention may be used to treat lung cancer or cell proliferative disorders ofthe lung.
  • lung cancer includes all forms of cancer ofthe lung.
  • lung cancer includes malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors.
  • lung cancer includes small cell lung cancer ("SCLC”), non-small cell lung cancer (“NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • squamous cell carcinoma adenocarcinoma
  • small cell carcinoma large cell carcinoma
  • adenosquamous cell carcinoma and mesothelioma.
  • lung cancer includes "scar carcinoma,” bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma.
  • lung cancer includes lung neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types).
  • lung cancer includes mixed small cell/large cell carcinoma.
  • cell proliferative disorders ofthe lung include all forms of cell proliferative disorders affecting lung cells.
  • cell proliferative disorders ofthe lung include lung cancer and precancerous conditions ofthe lung.
  • cell proliferative disorders ofthe lung include hyperplasia, metaplasia, and dysplasia ofthe lung.
  • cell proliferative disorders to be treated include sporadic and hereditary cell proliferative disorders ofthe lung.
  • cell proliferative disorders ofthe lung include benign tumors ofthe lung.
  • cell proliferative disorders ofthe lung include asbestos- induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia.
  • cell proliferative disorders ofthe lung include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia.
  • individuals exposed to inhaled injurious environmental agents such as cigarette smoke and asbestos may be at increased risk for developing cell proliferative disorders ofthe lung.
  • prior lung diseases that may predispose individuals to development of cell proliferative disorders ofthe lung include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.
  • a lung cancer that is to be treated has arisen in a subject equal to or older than 30 years old, or a subject younger than 30 years old.
  • a lung cancer that is to be treated has arisen in a subject equal to or older than 50 years old, or a subject younger than 50 years old. In one aspect, a lung cancer that is to be treated has arisen in a subject equal to or older than 70 years old, or a subject younger than 70 years old. In one aspect, a lung cancer that is to be treated has been typed to identify a familial or spontaneous mutation in ⁇ 53, Rb, CDKN2A (P 16INK4A), FHIT, myc, ras, TP73, MADH2, MADH4, PPP2Rlb, or PTEN. In another aspect, a lung cancer that is to be treated is associated with a GSTM1 null allele.
  • a lung cancer that is to be treated is associated with a mutation selected from the group consisting of del(3p), del(9p) and del(lp36).
  • a lung cancer that is to be treated is associated with elevated levels of CEA (carcinoembryonic antigen) or NSE (neuron- specific enolase), or an upregulation of one or more components of telomerase.
  • a lung cancer that is to be treated is associated with an increased level of a marker selected from the group consisting of MOC-1, MOC-21, MOC-31, MOC-32, and MOC-52.
  • a lung cancer that is to be treated includes a localized tumor ofthe lung.
  • a lung cancer that is to be treated includes a tumor ofthe lung that is associated with a negative regional lymph node biopsy. In one aspect, a lung cancer that is to be treated includes a tumor ofthe lung that is associated with a positive regional lymph node biopsy. In another aspect, a lung cancer that is to be treated includes a tumor ofthe lung that has been typed as having nodal negative status (e.g., node-negative) or nodal positive status (e.g., node-positive). In another aspect, a lung cancer that is to be treated includes a tumor ofthe lung that has metastasized to other locations in the body.
  • a lung cancer that is to be treated is classified as having metastasized to a location selected from the group consisting of lymph node, stomach, bile duct, lung, liver, bone, and brain.
  • a lung cancer that is to be treated is classified according to a characteristic selected from the group consisting of metastatic, limited stage, extensive stage, unresectable, resectable, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.
  • a lung cancer that is to be treated has been staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of Tis, TI, T2, T3,T4; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, NI, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) has been assigned a stage of MX, M0, or Ml.
  • AJCC American Joint Committee on Cancer
  • a lung cancer that is to be treated has been staged according to an American Joint Committee on Cancer (AJCC) classification as Stage 0, 1, IA, IB, II, IIA, JJB, III, IIIA, IID3, IIIC and IV lung cancer.
  • AJCC American Joint Committee on Cancer
  • a lung cancer that is to be treated has been assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a lung cancer that is to be treated includes a tumor that has been determined to be less than or equal to about 3 centimeters in diameter.
  • a lung cancer that is to be treated includes a tumor that has been determined to be from about 3 to about 5 centimeters in diameter.
  • a lung cancer that is to be treated includes a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. In another aspect, a lung cancer that is to be treated includes a tumor that has been determined to be greater than 5 centimeters in diameter. In another aspect, a lung cancer that is to be treated is classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. In another aspect, a lung cancer that is to be treated is classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells).
  • mitosis count e.g., amount of cell division
  • nuclear pleiomorphism e.g., change in cells
  • a lung cancer that is to be treated is classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a lung cancer that is to be treated is classified as having an abnormal karyotype, having an abnonnal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a lung cancer that is to be treated is classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a lung cancer that is to be treated is classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a "cell proliferative disorder ofthe colon” is a cell proliferative disorder involving cells ofthe colon.
  • a cell proliferative disorder includes a pre-cancer or precancerous condition ofthe colon.
  • a cell proliferative disorder ofthe colon includes a non- cancerous cell proliferative disorder ofthe colon.
  • a cell proliferative disorder includes colon cancer, including metastatic lesions in other tissues or organs distant from the primary tumor site.
  • a "precancer cell” or “precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition.
  • a “cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells.
  • cancer cells or precancerous cells are identified by histological typing or grading of a tissue sample (e.g., a biopsy sample).
  • cancer cells or precancerous cells are identified through the use of appropriate molecular markers.
  • the cell proliferative disorder ofthe colon is colon cancer.
  • compositions ofthe present invention may be used to treat colon cancer or cell proliferative disorders ofthe colon.
  • colon cancer includes all forms of cancer of the colon.
  • a colon cancer to be treated includes carcinoma, sarcoma, and adenocarcinoma.
  • colon cancer includes sporadic and hereditary colon cancers.
  • colon cancer includes malignant colon neoplasms, carcinoma in situ, leiomyosarcomas, typical carcinoid tumors, and atypical carcinoid tumors.
  • colon cancer includes adenocarcinoma, squamous cell carcinoma, signet ring cell adenocarcinoma and adenosquamous cell carcinoma.
  • colon cancer is associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • HNPCC hereditary nonpolyposis colorectal cancer
  • FAP familial adenomatous polyposis
  • Gardner's syndrome adenomatous polyposis
  • Turcot's syndrome and juvenile polyposis.
  • colon cancer is caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • HNPCC hereditary nonpolyposis colorectal cancer
  • FAP familial adenomatous polyposis
  • Gardner's syndrome adenomatous polyposis
  • Gardner's syndrome adenomatous polyposis
  • Turcot's syndrome a hereditary nonpolyposis colorectal cancer
  • cell proliferative disorders ofthe colon include all forms of cell proliferative disorders affecting colon cells.
  • cell proliferative disorders ofthe colon include colon cancer, precancerous conditions ofthe colon, adenomatous polyps ofthe colon and metachronous lesions ofthe colon.
  • a cell proliferative disorder ofthe colon includes adenoma, h one aspect, cell proliferative disorders ofthe colon are characterized by hyperplasia, metaplasia, and dysplasia ofthe colon.
  • prior colon diseases that may predispose individuals to development of cell proliferative disorders ofthe colon include prior colon cancer.
  • cunent disease that may predispose individuals to development of cell proliferative disorders ofthe colon include Crohn's disease and ulcerative colitis.
  • a cell proliferative disorder ofthe colon is associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • an individual has an elevated risk of developing a cell proliferative disorder ofthe colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • a colon cancer that is to be treated has arisen in a subject equal to or older than 30 years old, or a subject younger than 30 years old.
  • a colon cancer that is to be treated has arisen in a subject equal to or older than 50 years old, or a subject younger than 50 years old.
  • a colon cancer that is to be treated has arisen in a subject equal to or older than 70 years old, or a subject younger than 70 years old.
  • a colon cancer that is to be treated has been typed to identify a familial or spontaneous mutation in p53, Rb, myc or ras.
  • a colon cancer that is to be treated is associated with a mutation in a gene selected from the group consisting of MSH2, MSH6, MLH1, PMS1, PMS2, TGFBR2, BAX, and APC.
  • a colon cancer that is to be treated is associated with a mutation selected from the group consisting of de(lp),del(8p), del(8q21), del(17p), LOH17p, and chrmosome 18q allelic loss, hi one aspect, a colon cancer that is to be treated has been typed as having the replication enor phenotype RER+. In one aspect, a colon cancer that is to be treated has been typed as CpG island methylator phenotype positive (CJVIP+) or CpG island methylator phenotype negative (CIMP-). In one aspect, a colon cancer that is to be treated is associated with elevated levels of CEA (carcinoembryonic antigen).
  • CEA carcinoembryonic antigen
  • a colon cancer that is to be treated includes a localized tumor ofthe colon, hi one aspect, a colon cancer that is to be treated includes a tumor ofthe colon that is associated with a negative regional lymph node biopsy. In one aspect, a colon cancer that is to be treated includes a tumor ofthe colon that is associated with a positive regional lymph node biopsy. In another aspect, a colon cancer that is to be treated includes a tumor ofthe colon that has been typed as having nodal negative status (e.g., node-negative) or nodal positive status (e.g., node- positive), i another aspect, a colon cancer that is to be treated includes a tumor ofthe colon that has metastasized to other locations in the body.
  • nodal negative status e.g., node-negative
  • nodal positive status e.g., node- positive
  • a colon cancer that is to be treated is classified as having metastasized to a location selected from the group consisting of lymph node, stomach, bile duct, liver, bone, ovary, peritoneum and brain.
  • a colon cancer that is to be treated is classified according to a characteristic selected from the group consisting of metastatic, limited stage, extensive stage, unresectable, resectable, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.
  • a colon cancer that is to be treated has been staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of Tx, Tis, TI, T2, T3, T4; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, NI, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) has been assigned a stage of MX, M0, or Ml.
  • AJCC American Joint Committee on Cancer
  • a colon cancer that is to be treated has been staged according to an American Joint Committee on Cancer (AJCC) classification as Stage 0, 1, II, IIA, ID3, III, IIIA, IIIB, IIIC and IN colon cancer.
  • AJCC American Joint Committee on Cancer
  • a colon cancer that is to be treated has been assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a colon cancer that is to be treated has been assigned a grade according to the Dukes staging system of A, B, or C.
  • a colon cancer that is to be treated has been assigned a grade according to the Asfler-Coller staging system of A, BI, B2, B3 or Cl, C2, C3, or D.
  • a colon cancer that is to be treated includes a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. In another aspect, a colon cancer that is to be treated includes a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. In another aspect, a colon cancer that is to be treated includes a tumor that has been determined to be greater than or equal to about 2 centimeters in diameter. In another aspect, a colon cancer that is to be treated includes a tumor that has been determined to be greater than 5 centimeters in diameter. In another aspect, a colon cancer that is to be treated is classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
  • a colon cancer that is to be treated is classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells).
  • a colon cancer that is to be treated is classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a colon cancer that is to be treated is classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a colon cancer that is to be treated is classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy. In one aspect, a colon cancer that is to be treated is classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a "cell proliferative disorder ofthe breast” is a cell proliferative disorder involving cells ofthe breast. In one aspect, cell proliferative disorders ofthe breast include all forms of cell proliferative disorders affecting breast cells.
  • cell proliferative disorders ofthe breast include breast cancer, a precancer or precancerous condition ofthe breast, benign growths or lesions ofthe breast, and malignant growths or lesions ofthe breast, and metastatic lesions in tissue and organs in the body other than the breast.
  • cell proliferative disorders ofthe breast include hyperplasia, metaplasia, and dysplasia ofthe breast.
  • a cell proliferative disorder ofthe breast is a precancerous condition ofthe breast.
  • compositions ofthe present invention may be used to treat a precancerous condition ofthe breast.
  • a precancerous condition ofthe breast includes atypical hyperplasia ofthe breast, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0 growth or lesion ofthe breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ).
  • DCIS ductal carcinoma in situ
  • LCIS lobular carcinoma in situ
  • lobular neoplasia lobular neoplasia
  • stage 0 or grade 0 growth or lesion ofthe breast e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ
  • a precancerous condition ofthe breast has been staged according to the TNM classification scheme as accepted by the American Joint Committee on Cancer (AJCC), where the primary tumor (T) has been assigned a stage of TO or Tis; and where the regional lymph nodes (N) have been assigned a stage of NO; and where distant metastasis (M) has been assigned a stage of MO.
  • the cell proliferative disorder ofthe breast is breast cancer.
  • compositions ofthe present invention may be used to treat breast cancer.
  • breast cancer includes all forms of cancer ofthe breast.
  • breast cancer includes primary epithelial breast cancers.
  • breast cancer includes cancers in which the breast is involved by other tumors such as lymphoma, sarcoma or melanoma.
  • breast cancer includes carcinoma ofthe breast, ductal carcinoma ofthe breast, lobular carcinoma ofthe breast, undifferentiated carcinoma ofthe breast, cystosarcoma phyllodes ofthe breast, angiosarcoma ofthe breast, and primary lymphoma ofthe breast.
  • breast cancer includes Stage I, II, IIIA, IIIB, IIIC and IN breast cancer
  • ductal carcinoma ofthe breast includes invasive carcinoma, invasive carcinoma in situ with predominant intraductal component, inflammatory breast cancer, and a ductal carcinoma ofthe breast with a histo logic type selected from the group consisting of comedo, mucinous (colloid), medullary, medullary with lymphcytic infiltrate, papillary, scirrhous, and tubular.
  • lobular carcinoma ofthe breast includes invasive lobular carcinoma with predominant in situ component, invasive lobular carcinoma, and infiltrating lobular carcinoma.
  • breast cancer includes Paget's disease, Paget's disease with intraductal carcinoma, and Paget's disease with invasive ductal carcinoma.
  • breast cancer includes breast neoplasms having histologic and ultrastrucrual heterogeneity (e.g., mixed cell types).
  • a breast cancer that is to be treated has been typed to identify a familial or spontaneous mutation in BRCA1, BRCA2, or p53.
  • a breast cancer that is to be treated has been typed as having a HER2/neu gene amplification, as overexpressing HER2/neu, or as having a low, intermediate or high level of HER2/neu expression.
  • a breast cancer that is to be treated has been typed for a marker selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor- 2, Ki-67, CA15-3, CA 27-29, and c-Met.
  • a breast cancer that is to be treated has been typed as ER-unknown, ER-rich or ER-poor.
  • a breast cancer that is to be treated has been typed as ER-negative or ER-positive.
  • ER-typing of a breast cancer may be performed by any reproducible means. In a prefened aspect, ER-typing of a breast cancer may be performed as set forth in Onkologie 27: 175-179 (2004).
  • a breast cancer that is to be treated has been typed as PR-unknown, PR-rich or PR-poor. In another aspect, a breast cancer that is to be treated has been typed as PR-negative or PR-positive. In another aspect, a breast cancer that is to be treated has been typed as receptor positive or receptor negative. In one aspect, a breast cancer that is to be treated has been typed as being associated with elevated blood levels of CA 15-3, or CA 27-29, or both.
  • a "cell proliferative disorder ofthe pancreas" is a cell proliferative disorder involving cells ofthe pancreas.
  • a cell proliferative disorder includes a pre-cancer or precancerous condition ofthe pancreas, hi one aspect, a cell proliferative disorder ofthe pancreas includes a non-cancerous cell proliferative condition ofthe pancreas.
  • a cell proliferative disorder includes pancreatic cancer, including metastatic lesions in other tissues or organs distant from the primary tumor site, hi one aspect, a "precancer cell” or "precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition.
  • a "cancer cell” or “cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells.
  • cancer cells or precancerous cells are identified by histological typing or grading of a tissue sample (e.g., a biopsy sample), hi another aspect, cancer cells or precancerous cells are identified through the use of appropriate molecular markers.
  • the cell proliferative disorder ofthe pancreas is pancreatic cancer.
  • compositions ofthe present invention may be used to treat pancreatic cancer or cell proliferative disorders ofthe pancreas.
  • pancreatic cancer includes all forms of cancer ofthe pancreas.
  • a pancreatic cancer to be treated includes carcinoma, sarcoma, and adenocarcinoma.
  • a pancreatic cancer to be treated includes sporadic and hereditary pancreatic cancers.
  • a pancreatic cancer to be treated includes duct cell carcinoma, acinar cell carcinoma, papillary mucinous carcinoma, signet ring carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, mucinous carcinoma, giant cell carcinoma, small cell carcinoma, cystadenocarcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified pancreatic cancer, and pancreatoblastoma.
  • a pancreatic cancer to be treated includes mixed type pancreatic cancers (e.g., ductal-endocrine or acinar-endocrine).
  • a pancreatic cancer to be treated includes ductal adenocarcinoma, adenosquamous carcinoma, pleiomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, and small cell carcinoma.
  • cell proliferative disorders ofthe pancreas to be treated include all forms of cell proliferative disorders affecting pancreas cells.
  • cell proliferative disorders ofthe pancreas to be treated include pancreatic cancer, a precancer or precancerous condition of the pancreas, benign growths or lesions ofthe pancreas, and malignant growths or lesions ofthe pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas, hi another aspect, cell proliferative disorders ofthe pancreas to be treated include hyperplasia, metaplasia, and dysplasia ofthe pancreas.
  • cell proliferative disorders ofthe pancreas to be treated include mucinous cystadenoma, intraductal papillary neoplasm, serous cystadenoma, papillary-cystic neoplam, mucinous cystic tumor with dysplasia, intraductal papillary mucinous tumor with dysplasia, and pseudopapillary solid tumor.
  • cunent disease that may predispose individuals to development of cell proliferative disorders of the pancreas include diabetes mellitus or pancreatitis.
  • individuals are at an increased risk of developing a cell proliferative disorder ofthe pancreas, such as pancreatic cancer, due to a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP).
  • HNPCC hereditary nonpolyposis colorectal cancer
  • FAP familial adenomatous polyposis
  • individuals are at an increased risk of developing a cell proliferative disorder ofthe pancreas, such as pancreatic cancer, due to a mutation in a gene selected from the group consisting of MSH2, MSH6, MLH1, and APC.
  • a pancreatic cancer that is to be treated has arisen in a subject equal to or older than 30 years old, or a subject younger than 30 years old.
  • a pancreatic cancer that is to be treated has arisen in a subject equal to or older than 50 years old, or a subject younger than 50 years old. In one aspect, a pancreatic cancer that is to be treated has arisen in a subject equal to or older than 70 years old, or a subject younger than 70 years old. In one aspect, a pancreatic cancer that is to be treated has been typed to identify a familial or spontaneous mutation in p53, Rb, myc or ras.
  • a pancreatic cancer that is to be treated is associated with a mutation in a gene selected from the group consisting of K-Ras, p53, BRCA2, pl6 (CDKN2A), MADH4 (DPC4), STK11, MSH2, MSH6, MLH1, and APC.
  • a pancreatic cancer that is to be treated is associated with elevated levels of expression of a growth factor selected from the group consisting of EGF, TGF alpha, TGF beta 1-3, aFGF, and bTGF.
  • a pancreatic cancer that is to be treated is associated with elevated levels in blood of CEA (carcinoembryonic antigen).
  • a pancreatic cancer that is to be treated is associated with increased levels in blood or increased cellular expression of tumor marker carbohydrate antigen 19-9 (CA 19-9).
  • a pancreatic cancer that is to be treated includes a localized tumor ofthe pancreas.
  • a pancreatic cancer that is to be treated includes a tumor ofthe pancreas that is associated with a negative regional lymph node biopsy.
  • a pancreatic cancer that is to be treated includes a tumor ofthe pancreas that is associated with a positive regional lymph node biopsy, hi another aspect, a pancreatic cancer that is to be treated includes a tumor ofthe pancreas that has been typed as having nodal negative status (e.g., node-negative) or nodal positive status (e.g., node-positive). In another aspect, a pancreatic cancer that is to be treated includes a tumor ofthe pancreas that has metastasized to other locations in the body.
  • a pancreatic cancer that is to be treated is classified as having metastasized to a location selected from the group consisting of lymph node, stomach, bile duct, liver, bone, ovary, peritoneum and brain.
  • a pancreatic cancer that is to be treated is classified according to a characteristic selected from the group consisting of metastatic, limited stage, extensive stage, unresectable, resectable, locally advanced, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recunent, and inoperable.
  • a pancreatic cancer that is to be treated has been staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of Tx, TI, T2, T3, T4; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, NI; and where distant metastasis (M) has been assigned a stage of MX, M0, or Ml .
  • AJCC American Joint Committee on Cancer
  • a pancreatic cancer that is to be treated has been staged according to an American Joint Committee on Cancer (AJCC) classification as Stage 0, 1, IA, IB, II, IIA, IIB, III, and IN pancreatic cancer.
  • a pancreatic cancer that is to be treated has been assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • Grade GX e.g., grade cannot be assessed
  • Grade 1 Grade 2
  • Grade 3 Grade 4
  • a pancreatic cancer that is to be treated includes a tumor that has been determined to be less than or equal to about 2 centimeters in diameter.
  • a pancreatic cancer that is to be treated includes a tumor that has been determined to be from about 2 to about 5 centimeters in diameter.
  • a pancreatic cancer that is to be treated includes a tumor that has been determined to be greater than or equal to about 2 centimeters in diameter.
  • a pancreatic cancer that is to be treated includes a tumor that has been determined to be greater than 5 centimeters in diameter.
  • a pancreatic cancer that is to be treated is classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
  • a pancreatic cancer that is to be treated is classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells), hi another aspect, a pancreatic cancer that is to be treated is classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a pancreatic cancer that is to be treated is classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a pancreatic cancer that is to be treated is classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a pancreatic cancer that is to be treated is classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a “cell proliferative disorder ofthe prostate” is a cell proliferative disorder involving cells ofthe prostate.
  • cell proliferative disorders ofthe prostate include all forms of cell proliferative disorders affecting prostate cells.
  • cell proliferative disorders ofthe prostate include prostate cancer, a precancer or precancerous condition ofthe prostate, benign growths or lesions ofthe prostate, and malignant growths or lesions ofthe prostate, and metastatic lesions in tissue and organs in the body other than the prostate.
  • cell proliferative disorders ofthe prostate include hyperplasia, metaplasia, and dysplasia ofthe prostate.
  • a "cell proliferative disorder ofthe skin” is a cell proliferative disorder involving cells of the skin.
  • cell proliferative disorders ofthe skin include all fonns of cell proliferative disorders affecting skin cells, hi one aspect, cell proliferative disorders ofthe skin include a precancer or precancerous condition ofthe skin, benign growths or lesions ofthe skin, melanoma, malignant melanoma and other malignant growths or lesions ofthe skin, and metastatic lesions in tissue and organs in the body other than the skin. In another aspect, cell proliferative disorders ofthe skin include hyperplasia, metaplasia, and dysplasia ofthe skin.
  • a "cell proliferative disorder ofthe ovary" is a cell proliferative disorder involving cells ofthe ovary.
  • cell proliferative disorders ofthe ovary include all forms of cell proliferative disorders affecting cells ofthe ovary.
  • cell proliferative disorders of the ovary include a precancer or precancerous condition ofthe ovary, benign growths or lesions ofthe ovary, ovarian cancer, malignant growths or lesions ofthe ovary, and metastatic lesions in tissue and organs in the body other than the ovary.
  • cell proliferative disorders ofthe skin include hyperplasia, metaplasia, and dysplasia of cells ofthe ovary.
  • a cancer that is to be treated has been staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, TI, Tlmic, Tis, Tla, Tib, Tic, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, Nl, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) has been assigned a stage of MX, MO, or Ml.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated has been staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage II, Stage IIA, Stage IIB,
  • a cancer that is to be treated has been assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a cancer that is to be treated has been staged according to an AJCC pathologic classification (p ⁇ ) of p ⁇ X, p ⁇ O, P ⁇ O (I-), P ⁇ O (I+), P ⁇ O (mol-), P ⁇ O (mol+), P ⁇ 1, P ⁇ 1(mi), P ⁇ 1a, P ⁇ lb, P ⁇ 1c, p ⁇ 2, pN2a, pN2b, ⁇ N3, pN3a, pN3b, or ⁇ N3c.
  • a cancer that is to be treated includes a tumor that has been determined to be less than or equal to about 2 centimeters in diameter.
  • a cancer that is to be treated includes a tumor that has been determined to be from about 2 to about 5 centimeters in diameter. In another aspect, a cancer that is to be treated includes a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. In another aspect, a cancer that is to be treated includes a tumor that has been determined to be greater than 5 centimeters in diameter. In another aspect, a cancer that is to be treated is classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
  • a cancer that is to be treated is classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells), h another aspect, a cancer that is to be treated is classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a cancer that is to be treated is classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance, hi one aspect, a cancer that is to be treated is classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a cancer that is to be treated is classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a cancer that is to be treated is evaluated by DNA cytometry, flow cytometry, or image cytometry.
  • a cancer that is to be treated has been typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division), hi one aspect, a cancer that is to be treated has been typed as having a low S-phase fraction or a high S-phase fraction.
  • a "normal cell” is a cell that cannot be classified as part of a "cell proliferative disorder.” In one aspect, a normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. Preferably, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms. As used herein, "contacting a cell” refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a combination ofthe present invention to prevent the onset ofthe symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder.
  • treating a cancer ofthe present invention results in a decrease in number of cancerous cells.
  • number of cancerous cells is reduced by 5% or greater relative to number prior to treatment; more preferably, number of cancerous cells is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%).
  • Number of cancerous cells may be measured by any reproducible means of measurement.
  • number of cancerous cells may be measured by counting cancerous cells at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • number of cancerous cells is measured by fluorescence activated cell sorting (FACS).
  • number of cancerous cells is measured by immunofluorescence microscopy.
  • treating a cancer ofthe present invention results in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be refened to as "tumor regression."
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10%) or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. In a preferred aspect, size of a tumor may be measured as a diameter ofthe tumor. In another aspect, treating a cancer ofthe present invention results in a reduction in tumor volume.
  • tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20%o or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • treating a cancer ofthe present invention results in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10%) or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40%o or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • Number of tumors may be measured by any reproducible means of measurement. In a prefened aspect, number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In a prefened aspect, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • treating a cancer ofthe present invention results in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20%> or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%>.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • treating a cancer ofthe present invention results in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival iollowmg initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a cancer ofthe present invention results in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a cancer ofthe present invention results in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • an increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • an increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • treating a cancer ofthe present invention results in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone.
  • treating cancer results in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • treating cancer results a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound ofthe present invention, or a phannaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, hi another preferred aspect, a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. In another prefened aspect, a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound. In another aspect, treating a cancer ofthe present invention results in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%>; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%>; and most preferably, reduced by at least 75%>.
  • Tumor growth rate may be measured by any reproducible means of measurement. In a prefened aspect, tumor growth rate is measured according to a change in tumor diameter per unit time. hi another aspect, treating a cancer ofthe present invention results in a decrease in tumor regrowth.
  • tumor regrowth is less than 5%>; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%o; and most preferably, less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement.
  • tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment.
  • a decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • preventing cancer metastases results in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5%> or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30%) or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement. In a preferred aspect, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • treating or preventing a cell proliferative disorder ofthe present invention results in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%>; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • treating or preventing a cell proliferative disorder ofthe present invention results in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%>; more preferably, by at least 50%o; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells is equivalent to the mitotic index.
  • treating or preventing a cell proliferative disorder ofthe present invention results in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%o; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%o; and most preferably, reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement. In a prefened aspect, size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • treating or preventing a cell proliferative disorder ofthe present invention results in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%>; more preferably, reduced by at least 30%>; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%o.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • an abnonnal cellular morphology is measured by microscopy, e.g., using an inverted tissue culture microscope.
  • an abnormal cellular mo ⁇ hology takes the form of nuclear pleiomorphism.
  • activating refers to placing a composition of matter (e.g., protein or nucleic acid) in a state suitable for canying out a desired biological function.
  • a composition of matter capable of being activated also has an unactivated state.
  • an activated composition of matter may have an inhibitory or stimulatory biological function, or both.
  • elevation refers to an increase in a desired biological activity of a composition of matter (e.g., a protein or a nucleic acid).
  • elevation may occur through an increase in concentration of a composition of matter.
  • selective means tending to occur at a higher frequency in one population than in another population, hi one aspect, the compared populations are cell populations.
  • a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof acts selectively on a cancer or precancerous cell but not on a normal cell.
  • a compound ofthe present invention acts selectively to modulate one molecular target (e.g., E2F-1) but does not significantly modulate another molecular target (e.g., Protein Kinase C).
  • the invention provides a method for selectively inhibiting the activity of an enzyme, such as a kinase.
  • an enzyme such as a kinase.
  • an event occurs selectively in population A relative to population B if it occurs greater than two times more frequently in population A as compared to population B. More preferably, an event occurs selectively if it occurs greater than five times more frequently in population A.
  • an event occurs selectively if it occurs greater than ten times more frequently in population A; more preferably, greater than fifty times; even more preferably, greater than 100 times; and most preferably, greater than 1000 times more frequently in population A as compared to population B.
  • cell death would be said to occur selectively in cancer cells if it occuned greater than twice as frequently in cancer cells as compared to normal cells.
  • a compound ofthe present invention or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof modulates the activity of a molecular target (e.g., E2F-1).
  • modulating refers to stimulating or inhibiting an activity of a molecular target.
  • a compound ofthe present invention modulates the activity of a molecular target if it stimulates or inhibits the activity ofthe molecular target by at least 10% relative to the activity ofthe molecular target under the same conditions but lacking only the presence of said compound. More preferably, a compound of the present invention modulates the activity of a molecular target if it stimulates or inhibits the activity ofthe molecular target by at least 25%, at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity ofthe molecular target under the same conditions but lacking only the presence of said compound.
  • the activity of a molecular target may be measured by any reproducible means.
  • the activity of a molecular target may be measured in vitro or in vivo.
  • the activity of a molecular target may be measured in vitro by an enzymatic activity assay or a DNA binding assay, or the activity of a molecular target may be measured in vivo by assaying for expression of a reporter gene.
  • a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof does not significantly modulate the activity of a molecular target if the addition ofthe compound stimulates or inhibits the activity ofthe molecular target by less than 10% relative to the activity ofthe molecular target under the same conditions but lacking only the presence of said compound.
  • a compound ofthe present invention demonstrates a minimum of a four fold differential, preferably a ten fold differential, more preferably a fifty fold differential, in the dosage required to achieve a biological effect.
  • a compound ofthe present invention demonstrates this differential across the range of inhibition, and the differential is exemplified at the IC 50 , i.e., a 50% inhibition, for a molecular target of interest.
  • administering ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to a cell or a subject in need thereof results in modulation (i.e., stimulation or inhibition) of an activity of a member ofthe E2F family of transcnption factors (e.g., E2F-1, E2F-2, or E2F-3).
  • an activity of a member ofthe E2F family of transcription factors refers to any biological function or activity that is carried out by an E2F family member.
  • a function of E2F-1 includes binding of E2F-1 to its cognate DNA sequences.
  • Other functions of E2F-1 include migrating to the cell nucleus and activating transcription.
  • treating cancer or a cell proliferative disorder results in cell death, and preferably, cell death results in a decrease of at least 10% in number of cells in a population.
  • cell death means a decrease of at least 20%; more preferably, a decrease of at least 30%; more preferably, a decrease of at least 40%; more preferably, a decrease of at least 50%; most preferably, a decrease of at least 75%.
  • Number of cells in a population may be measured by any reproducible means. In one aspect, number of cells in a population is measured by fluorescence activated cell sorting (FACS). In another aspect, number of cells in a population is measured by immunofluorescence microscopy. In another aspect, number of cells in a population is measured by light microscopy. In another aspect, methods of measuring cell death are as shown in Li et al, (2003) Proc Natl Acad Sci USA. 100(5): 2674-8.
  • cell death occurs by apoptosis.
  • an effective amount of a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof is not significantly cytotoxic to normal cells.
  • a therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration ofthe compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • a therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration ofthe compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • cell death occurs by apoptosis.
  • contacting a cell with a combination ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof induces or activates cell death selectively in cancer cells.
  • administering to a subject in need thereof a combination ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof induces or activates cell death selectively in cancer cells.
  • contacting a cell with a combination ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • administering to a subject in need thereof a combination ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • the present invention relates to a method of treating or preventing cancer by administering a combinationof the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof to a subject in need thereof, where administration ofthe combination ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof results in one or more ofthe following: accumulation of cells in Gl and/or S phase ofthe cell cycle, cytotoxicity via cell death in cancer cells without a significant amount of cell death in normal cells, antitumor activity in animals with a therapeutic index of at least 2, and activation of a cell cycle checkpoint.
  • therapeutic index is the maximum tolerated dose divided by the efficacious dose.
  • stimulation of unscheduled expression of a checkpoint molecule by ⁇ - lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof triggers cell death in cells with defective checkpoints, a hallmark of cancer and pre-cancer cells.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof stimulates unscheduled expression ofthe checkpoint molecule E2F.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of an E2F checkpoint pathway.
  • E2F pathway activity is increased by more than 10%>; more than 25%>; more than 50%; more than 2-fold; more than 5-fold; and most preferably, by more than 10-fold.
  • E2F activity is increased by more than 10%; more than 25%; more than 50%>; more than 2-fold; more than 5-fold; and most preferably, by more than 10-fold.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in elevation of an E2F transcription factor.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in elevation of an E2F transcription factor.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in elevation of an E2F transcription factor selectively in cancer cells but not in normal cells.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in elevation of an E2F transcription factor selectively in cancer cells but not in normal cells.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof stimulates unscheduled activation of an E2F transcription factor.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof stimulates unscheduled activation of an E2F transcription factor.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof stimulates unscheduled activation of an E2F transcription factor selectively in cancer cells but not in normal cells.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof stimulates unscheduled activation of an E2F transcription factor selectively in cancer cells but not in normal cells.
  • checkpoint molecule In normal cells with their intact regulatory mechanisms, imposed expression of a checkpoint molecule (e.g., as induced by contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof) results in an expression pattern that is not reported to be of substantial consequence.
  • cancer and pre-cancer cells have defective mechanisms, which result in unchecked or persistent expression, or both, of unscheduled checkpoint molecules, e.g., E2F, leading to selective cell death in cancer and pre-cancer cells.
  • the present invention includes and provides for the unchecked or persistent expression, or both, of unscheduled checkpoint molecules by the administration of ⁇ - lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoints.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoints.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoint pathways.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoint pathways.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoint regulators.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof results in activation of one or more cell cycle checkpoint regulators.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof induces or activates cell death selectively in cancer cells.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof induces or activates cell death selectively in cancer cells.
  • contacting a cell with ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • administering to a subject in need thereof ⁇ -lapachone, or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • ⁇ -lapachone or a pharmaceutically acceptable salt, metabolite, analog or derivative thereof.
  • These texts include Ausubel et al, Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al, Molecular Cloning, A Laboratory Manual (3d ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al, Current Protocols in Immunology, John Wiley &
  • a compound of the present invention can be incorporated into pharmaceutical compositions suitable for administration.
  • Such compositions typically comprise the compound (i.e. including the active compound), and a pharmaceutically acceptable excipient or carrier.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field. Prefened examples of such carriers or diluents include, but are not limited to, water, saline, ringer's solutions, dextrose solution, and 5%> human serum albumin.
  • Pharmaceutically acceptable carriers include solid carriers such as lactose, tena alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time-delay material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like.
  • Other fillers, excipients, flavorants, and other additives such as are known in the art may also be included in a pharmaceutical composition according to this invention.
  • compositions of this invention which are provided as part ofthe combination therapies may exist in the dosage form as a solid, semi-solid, or liquid such as, e.g., suspensions, aerosols or the like. Preferably the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.
  • compositions may also include, depending on the formulation desired, pharmaceutically-acceptable, nontoxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • diluents are selected so as not to affect the biological activity ofthe combination. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank's solution.
  • a preferred carrier for the solubilization of ⁇ -lapachone is hydroxypropyl beta cyclodextrin, a water solubilizing carrier molecule.
  • water-solubilizing agents for combining with ⁇ -lapachone and/or an S-phase compound, such as Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol 400, propylene glycol and Trappsol, are contemplated.
  • the invention is not limited to water-solubilizing agents, and oil- based solubilizing agents such as lipiodol and peanut oil, may also be used.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • Effective amounts of such diluent or carrier will be those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility of components, or biological activity, and the like.
  • Liposome formulations are also contemplated by the present invention, and have been described See, e.g., U.S. Pat. No. 5,424,073.
  • the Gl/S phase drugs or compounds, or derivatives or analogs thereof, and the S phase drugs or compounds, or derivatives or analogs thereof, described herein include their pharmacologically acceptable salts, preferably sodium; analogs containing halogen substitutions, preferably chlorine or fluorine; analogs containing ammonium or substituted ammonium salts, preferably secondary or tertiary ammonium salts; analogs containing alkyl, alkenyl, aryl or their alkyl, alkenyl, aryl, halo, alkoxy, alkenyloxy substituted derivatives, preferably methyl, methoxy, ethoxy, or phenylacetate; and natural analogs such as naphthyl acetate.
  • Gl/S phase compounds or derivatives or analogs thereof, and the S phase compounds or derivatives or analogs thereof, described herein may be conjugated to a water-soluble polymer or may be derivatized with water-soluble chelating agents or radionuclides.
  • water soluble polymers are, but not limited to: polyglutamic acid polymer, copolymers with polycaprolactone, polyglycolic acid, polyactic acid, polyacrylic acid, poly (2-hydroxyethyl 1-glutamine), carboxymethyl dextran, hyaluronic acid, human serum albumin, polyalginic acid or a combination thereof.
  • water-soluble chelating agents are, but not limited to: DIP A (diethylenetriaminepentaacetic acid), EDTA, DTTP, DOTA or their water-soluble salts, etc.
  • radionuclides include, but not limited to: ⁇ n rn, 90 Y, 166 Ho, 68 Ga, 99w Tc, and the like. Due to the water insolubility of ⁇ -lapachone, pharmaceutical carriers or solubilizing agents may be used to provide sufficient quantities of ⁇ -lapachone for use in the treatment methods ofthe present invention. See, e.g., U.S. Patent Publication 20030091639 to Jiang et al, and U.S.
  • Patent Publication 20040001871 to Boothman et al. This publication describes the use of complexing agents such as cyclodextrins, including hydroxypropyl beta-cyclodextrin (HPBCD), to permit the solubilization of ⁇ -lapachone at levels sufficient for administration. See also U.S. Patent Publication 20040001871 to Boothman et al.
  • complexing agents such as cyclodextrins, including hydroxypropyl beta-cyclodextrin (HPBCD)
  • the Gl/S phase drug, or a derivative or analog thereof is administered with a pharmaceutically acceptable water solubilizing carrier molecule selected from the group consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or derivatives or analogs thereof, beta- cyclodextrin or derivatives or analogs thereof, and gamma-cyclodextrin or derivatives or analogs thereof.
  • a pharmaceutically acceptable water solubilizing carrier molecule selected from the group consisting of Poloxamer, Povidone K17, Povidone K12, Tween 80, ethanol, Cremophor/ethanol, polyethylene glycol (PEG) 400, propylene glycol, Trappsol, alpha-cyclodextrin or derivatives or analogs thereof, beta- cyclodextrin or derivatives or analogs thereof, and
  • a compound ofthe present invention or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered in a suitable dosage form prepared by combining a therapeutically effective amount (e.g., an efficacious level sufficient to achieve the desired therapeutic effect through inhibition of tumor growth, killing of tumor cells, treatment or prevention of cell proliferative disorders, etc.) of a compound ofthe present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, (as an active ingredient) with standard pharmaceutical carriers or diluents according to conventional procedures (i.e., by producing a pharmaceutical composition ofthe invention). These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to attain the desired preparation.
  • a therapeutically effective amount e.g., an efficacious level sufficient to achieve the desired therapeutic effect through inhibition of tumor growth, killing of tumor cells, treatment or prevention of cell proliferative disorders, etc.
  • standard pharmaceutical carriers or diluents i.e.
  • a pharmaceutical composition ofthe invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,, inhalation), transdermal (topical), and transmucosal administration.
  • intravenous administration is prefened as discussed above, the invention is not intended to be limited in this respect, and the compounds can be administered by any means known in the art.
  • Such modes include oral, rectal, nasal, topical (including buccal and sublingual) or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • oral administration is generally prefened.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition ofthe invention can be administered to a subject in many ofthe well-known methods cunently used for chemotherapeutic treatment.
  • a compound ofthe invention may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects.
  • the state ofthe disease condition e.g., cancer, precancer, and the like
  • the term "therapeutically effective amount,” as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent ofthe condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment ofthe clinician.
  • the disease or condition to be treated is cancer.
  • the disease or condition to be treated is a cell proliferative disorder.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% ofthe population) and LD 50 (the dose lethal to 50%) ofthe population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED 5 Q/LD 50 .
  • Pharmaceutical compositions that exhibit large therapeutic indices are prefened.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity ofthe patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity ofthe disease state, general health ofthe subject, age, weight, and gender ofthe subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate ofthe particular formulation.
  • the pharmaceutical compositions containing active compounds ofthe present invention may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing ofthe active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N. J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition.
  • Prolonged abso ⁇ tion ofthe injectable compositions can be brought about by including in the composition an agent which delays abso ⁇ tion, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by inco ⁇ orating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by inco ⁇ orating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the pu ⁇ ose of oral therapeutic administration, the active compound can be inco ⁇ orated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • compositions can be included as part ofthe composition.
  • the tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid,
  • Primogel, or corn starch a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • the compounds are delivered in the fonn of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penevers appropriate to the barrier to be permeated are used in the formulation.
  • Such penevers are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds are prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Co ⁇ oration and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms ofthe invention are dictated by and directly dependent on the unique characteristics ofthe active compound and the particular therapeutic effect to be achieved.
  • the dosages ofthe pharmaceutical compositions used in accordance with the invention vary depending on the agent, the age, weight, and clinical condition ofthe recipient patient, and the experience and judgment ofthe clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth ofthe tumors and also preferably causing complete regression ofthe cancer.
  • Dosages can range from about 0.01 mg/kg per day to about 3000 mg/kg per day. In prefened aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day.
  • the dose will be in the range of about 0.1 mg/day to about 70 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m 2 , and age in years).
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression.
  • the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the S phase compound, such as an antimetabolite drug may be administered in any manner found appropriate by a clinician in generally accepted efficacious dose ranges, such as those described in the Physician 's Desk Reference, 59 th Edition, Thomson PDR (2005)("PDR").
  • the S phase drug or compound, such as gemcitabine is administered intravenously at dosages from about 10 mg/m 2 to about 10,000 mg/m 2 , preferably from about 100 mg/m 2 to about 2000 mg/m , and most preferably about 500 to about 1500 mg/m .
  • the S phase drug is administered intravenously at a dosage from approximately 100 mg/m 2 to about 2000 mg/m 2 .
  • the S phase drug is administered intravenously at a dosage of approximately 1000 mg/m 2 . Dosage can be repeated, e.g., once weekly, preferably for about 1 to 6 weeks. It is preferred that dosages be administered over a time period of about 30 minutes to about 6 hours, and typically over a period of about 3 hours.
  • the S phase drug such as an antimetabolite drug
  • a Gl/S phase drug such as ⁇ -lapachone or a derivative or analog thereof
  • the amounts will preferably be reduced from that normally administered. It is prefened, for example, that the S-phase drug be administered at the same time or after the ⁇ -lapachone has administered to the patient.
  • the S-phase drug is advantageously administered about 24 hours after the ⁇ -lapachone has been administered.
  • the combination therapy agents described herein may be administered singly and sequentially, or in a cocktail or combination containing both agents or one ofthe agents with other therapeutic agents, including but not limited to, immunosuppressive agents, potentiators and side-effect relieving agents.
  • the therapeutic combination if administered sequentially, may be more effective when the Gl/S phase drug component (e.g., ⁇ -lapachone) is administered prior to the S phase drug, e.g., gemcitabine.
  • a dose ofthe Gl/S phase drug component is administered at least one hour (more preferably at least 2 hours, 4 hours, 8 hours, 12 hours, or 24 hours) prior to administration of a dose ofthe S phase drug, e.g., gemcitabine.
  • a dose ofthe Gl/S phase drug component is administered at least one hour (more preferably at least 2 hours, 4 hours, 8 hours, 12 hours, or 24 hours) following administration of a dose ofthe S phase drug, e.g., gemcitabine.
  • the therapeutic agents will preferably be administered intravenously or otherwise systemically by injection intramuscularly, subcutaneously, intrathecally or intraperitoneally.
  • the S phase drug is administered simultaneously with or following administration ofthe Gl/S phase drug.
  • the S phase drug is administered following administration ofthe Gl/S phase drug.
  • the S drug is administered within 24 hours after the Gl/S phase drug is administered.
  • the other component ofthe combination therapy for combination with the S phase drug or compound is the Gl/S phase drug, which is preferably ⁇ -lapachone or a derivative or analog thereof.
  • ⁇ -lapachone has been shown to have a variety of pharmacological effects, ⁇ -lapachone has been shown to be a DNA repair inhibitor which sensitizes cells to DNA damaging agents (Boorstein, R.J., et al, (1984) Biochem. Biophys. Res. Commun., 118:828-834; Boothman, D.A., et al, (1989) J. Cancer Res., 49:605-612).
  • ⁇ -lapachone is generally well-tolerated in dogs, rats, and mice.
  • the present invention provides a method of treating cancer or a precancerous condition or preventing cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising ⁇ -lapachone, or a derivative or analog thereof, or pharmaceutically acceptable salt thereof, or a metabolite thereof, and a pharmaceutically acceptable canier such that the composition maintains a plasma concentration of about 0.15 ⁇ M to about 50 ⁇ M and treats the cancer or precancerous condition or prevents the cancer.
  • the plasma concentration can be about 0.1 ⁇ M to about 100 ⁇ M, about 0.125 ⁇ M to about 75 ⁇ M; about 0.15 ⁇ M to about 50 ⁇ M; about 0.175 ⁇ M to about 30 ⁇ M; and about 0.2 ⁇ M to about 20 ⁇ M.
  • the pharmaceutical composition can maintain a suitable plasma concentration for at least a month, at least a week, at least 24 hours, at least 12 hrs, at least 6 hrs, at least 1 hour, h a further aspect, a suitable plasma concentration ofthe pharmaceutical composition can be maintained indefinitely.
  • the subject can be exposed to the pharmaceutical composition in a AUC (area under the curve) range of about 0.5 ⁇ M-hr to about 100 ⁇ M-hr, about 0.5 ⁇ M-hr to about 50 ⁇ M-hr, about 1 ⁇ M-hr to about 25 ⁇ M-hr, about 1 ⁇ M-hr to about 10 ⁇ M-hr; about 1.25 ⁇ M-hr to about 6.75 ⁇ M-hr, about 1.5 ⁇ M-hr to about 6.5 ⁇ M-hr.
  • AUC area under the curve
  • the pharmaceutical composition can be administered at a dosage from about 2 mg/m 2 to 5000 mg/m 2 per day, more preferably from about 20 mg/m 2 to 2000 mg/m 2 per day, more preferably from about 20 mg/m 2 to 500 mg/m 2 per day, most preferably from about 30 to 300 mg/m 2 per day.
  • 2 mg/m 2 to 5000 mg/m 2 per day is the administered dosage for a human.
  • the pharmaceutical composition can be administered at a dosage from about 10 to 1,000,000 ⁇ g per kilogram body weight of recipient per day; preferably about 100 to 500,000 ⁇ g per kilogram body weight of recipient per day, more preferably from about 1000 to 250,000 ⁇ g per kilogram body weight of recipient per day, most preferably from about 10,000 to 150,000 ⁇ g per kilogram body weight of recipient per day.
  • One of ordinary skill in the art can determine the appropriate dosage amount in mg/m 2 per day or ⁇ g per kilogram body weight of recipient per day depending on subject to which the pharmaceutical composition is to be administered. As with the use of other chemotherapeutic drugs, the individual patient will be monitored in a manner deemed appropriate by the treating physician.
  • Dosages can also be reduced if severe neutropenia or severe peripheral neuropathy occurs, or if a grade 2 or higher level of mucositis is observed, using the Common Toxicity Criteria ofthe National Cancer Institute.
  • a Gl/S phase compound such as ⁇ -lapachone
  • the normal dose of such compound individually is utilized as set forth above.
  • a lower dosage ⁇ preferably 75 %> or less ofthe individual amount, more preferably 50%> or less, still more preferably 40% or less.
  • effective amount refers to an amount effective to treat the disease condition in combination with any other active agent in a combination regimen according to the invention.
  • the dosages ofthe agents used in accordance with the invention vary depending on the agent, the age, weight, and clinical condition ofthe recipient patient, and the experience and judgment ofthe clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth ofthe tumors and also preferably causing complete regression ofthe cancer.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • Regression of a tumor in a patient is typically measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • a decrease in tumor size or burden of at least 20%, more preferably 50%, 80%, 90%, 95% or 99% is prefened.
  • This invention further includes compositions comprising a dose of a Gl/S-phase drag
  • compositions may optionally include a pharmceutically acceptable solvent or carrier.
  • the Gl/S- phase drug and S-phase drug are present in an effective amount in combination.
  • a kit ofthe present invention comprises a) a first container comprising a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, b) a second container comprising a therapeutically effective amount of an S phase drug, (e.g., gemcitabine) or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and c) instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the S phase drag, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to treat a subject.
  • an S phase drug e.g., gemcitabine
  • a kit ofthe present invention comprises instructions for using the ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the S phase drug, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, to treat a cell proliferative disorder, such as cancer.
  • a kit ofthe present invention further comprises one or more additional doses of a therapeutically effective amount of ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • kits ofthe present invention further comprises one or more additional doses of a therapeutically effective amount of an S phase drug, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof.
  • a kit ofthe present invention comprises ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, and the S phase drag, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, in separate containers.
  • a kit ofthe present invention comprises ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, and the S phase drag, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, in a single container.
  • a kit ofthe present invention comprises ⁇ -lapachone, or a phannaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, and the S phase drug, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, in combination with a pharmaceutically acceptable carrier (e.g., for co-administration via a single pill or single intravenous formulation).
  • a kit ofthe present invention comprises instructions for administering ⁇ -lapachone, or a pharmaceutically acceptable salt, prodrag, metabolite, analog or derivative thereof, by a route of administration selected from the group consisting of orally, intravenously, intramuscularly, and by injection.
  • a kit ofthe present invention comprises instructions for administering the S phase drag, or a phannaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, by a route of administration selected from the group consisting of orally, intravenously, intramuscularly, and by injection.
  • a kit ofthe present invention comprises a dose of a Gl/S-phase drag (such as ⁇ -lapachone or a derivative or analog thereof as provided above) and a dose of a Gl/S-phase drug (such as ⁇ -lapachone or a derivative or analog thereof as provided above), e.g., at the doses provided above.
  • a dose of drug may be contained in an individual vial.
  • the kit contains instructions describing the use ofthe drags in combination for the treatment of cancer.
  • the therapeutically effective amount ofthe Gl/S phase drag, or a derivative or analog thereof is contained in a first vial, and the S phase drag is contained in a second vial, the contents ofthe first and second vials being administered to the patient simultaneously or sequentially.
  • ⁇ -lapachone administered in monotherapy, or in combination with gemcitabine potently reduces mean tumor volume in a human pancreatic cancer xenograft mouse model.
  • ⁇ -lapachone alone, and in combination with gemcitabine shows striking efficacy in a pancreatic cancer xenograft model.
  • Human pancreatic cancer Panc-1 cells (2xl0 6 ) are implanted subcutaneously into male athymic nude (Ncr) mice. Following establishment of tumor nodules (about 50 mm ), the ammals are randomized into four groups of five animals per group.
  • mice are treated intraperitoneally with one of four treatments: ⁇ -lapachone at 40 mg/kg in 40% hydroxypropy- ⁇ -cyclodextran; gemcitabine (Gemzar®) at 120 mg/kg (in PBS); ⁇ - lapachone (40mg/kg) + gemcitabine (120mg/kg); or vehicle control.
  • the mice receive a total of ten treatments, administered every three days (on study day 5, 8, 11, 14, 17, 20, 31, 34, 37, and 40).
  • the combination therapy group receives ⁇ -lapachone and gemcitabine on the same day in each treatment. Following freatment, the animals are observed for an additional 19 days. Tumors are measured throughout the treatment and post-treatment periods.
  • Example 2 ⁇ -lapachone administered in monotherapy, or in combination with gemcitabine (GEMZAR ® ), potently reduces mean tumor volume in a human lung cancer xenograft mouse model.
  • the anti-tumor activity of ⁇ -lapachone is examined using a human lung cancer xenograft model. Briefly, athymic female nude mice (Ncr) are inoculated subcutaneously with 4xl0 6
  • A549 human lung cancer cells and the tumors are allowed to grow to approximately 50mm 3 in size.
  • the animals are randomized into five groups of seven animals per group, and treated intraperitoneally every three days with one ofthe following five regimens: ⁇ -lapachone at
  • HPBCD hydroxypropy- ⁇ -cyclodextran
  • ⁇ -lapachone at 60mg/kg in 40% HPBCD
  • gemcitabine GEMZAR ®
  • the combination therapy group receives treatments with ⁇ -lapachone and gemcitabine at the indicated concentrations on the same day, every three days. Mice receive a total of eight treatments.
  • Mean tumor volume is analyzed; data points in Figure 2 represent the arithmetic mean +/- SEM of five tumors. As shown in Figure 2, treatment with either ⁇ -lapachone (60mg/kg) or gemcitabine

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Abstract

Des cancers et/ou des tumeurs malignes peuvent être traités par administration d'un médicament en phase G1/S, de préférence un β-lapachone, ou un sel pharmaceutiquement acceptable, un promédicament, un métabolite, un analogue ou un dérivé de celui-ci, combiné avec un médicament en phase S, avantageusement de la gemcitabine. Cette combinaison d'un médicament en phase G1/S avec un médicament en phase S permet d'obtenir un traitement incroyablement efficace du cancer. Cette invention porte sur des procédés de traitement de cancers par administration d'une combinaison d'un médicament en phase G1/S et d'un médicament en phase S, sur des compositions pharmaceutiques contenant la combinaison de médicaments utilisés dans ces procédés, ainsi que sur des kits pharmaceutiques.
EP05713938A 2004-02-23 2005-02-23 Combinaisons de beta-lapachone et de medicament en phase s pour le traitement du cancer Withdrawn EP1727536A1 (fr)

Applications Claiming Priority (4)

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US54728704P 2004-02-23 2004-02-23
US11/060,747 US20050192360A1 (en) 1999-04-14 2005-02-18 Method of treatment of pancreatic cancer
US11/068,459 US20050197406A1 (en) 1999-04-14 2005-02-18 Method of treatment of lung cancer
PCT/US2005/005620 WO2005082354A1 (fr) 2004-02-23 2005-02-23 Combinaisons de beta-lapachone et de medicament en phase s pour le traitement du cancer

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US20050187288A1 (en) * 2004-02-20 2005-08-25 Chiang Li Beta-lapachone and methods of treating cancer
WO2005082359A2 (fr) * 2004-02-20 2005-09-09 Arqule, Inc. Procede de traitement du cancer du pancreas
KR101752697B1 (ko) * 2015-04-17 2017-07-03 (주)나디안바이오 나프토퀴논계 화합물을 유효성분으로 포함하는 췌장염 예방 및 치료용 조성물
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AU2002226650A1 (en) * 2001-01-18 2002-07-30 Arnold Hoffman Redox therapy for tumors
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