WO2010132817A1 - Carcinoma diagnosis and treatments, based on odc1 genotype - Google Patents
Carcinoma diagnosis and treatments, based on odc1 genotype Download PDFInfo
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- WO2010132817A1 WO2010132817A1 PCT/US2010/034974 US2010034974W WO2010132817A1 WO 2010132817 A1 WO2010132817 A1 WO 2010132817A1 US 2010034974 W US2010034974 W US 2010034974W WO 2010132817 A1 WO2010132817 A1 WO 2010132817A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
- G01N33/57419—Specifically defined cancers of colon
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/112—Disease subtyping, staging or classification
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- CA78134 HAC
- CA78285 HAC
- CA95060 EWG
- the present invention relates generally to the fields of cancer biology and medicine. More particularly, it concerns methods for the diagnosis, prevention and treatment of carcinomas and risk factors thereof.
- the reported minor A-allele frequency is approximately 25% and despite differences across race/ethnicity, ODCl genotype distribution is in Hardy- Weinberg equilibrium within each race (O'Brien et al, 2004; ZeIl et al, 2009). Individuals homozygous for the ODCl minor A-allele have reduced risk of adenoma recurrence compared to those with the major G-allele (Martinez et al, 2003; Hubner et al, 2008).
- ODCl A-allele (AA or GA genotype, but not GG genotype) and reported aspirin usage have been associated with reduced colon polyp recurrence (Martinez et al, 2003; Barry et al, 2006; Hubner et al, 2008), and a statistically significant 50% reduced risk of advanced adenomas (Barry et al, 2006).
- ODCl genotype differentially affects adenoma recurrence, tissue polyamine responses, toxicity profiles and how it may be used to determine the suitability of preventative and curative treatments would be a major advantage.
- a method for the preventative or curative treatment of carcinoma in a patient comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) if the results indicate that the patient's genotype at position +316 of at least one allele of the ODCl promoter gene is G, administering to the patient effective amounts of a pharmaceutical therapy comprising:
- a first agent that inhibits ornithine decarboxylase (ODC) within the patient
- ODC ornithine decarboxylase
- a second agent that modulates the polyamine pathway to reduce overall polyamine content within the patient when combined with the first agent
- the second agent also increases the expression of spermidine/spermine //-acetyltransferase within the patient.
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GA.
- the pharmaceutical therapy further comprises increasing the dosage of the first or the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test. In some embodiments, the pharmaceutical therapy further comprises increasing the dosage of the first and the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test.
- the first agent is ⁇ -difluoromethylornithine (DFMO).
- the second agent is a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID). In some embodiments, the non-aspirin containing NSAID is a selective COX-2 inhibitor.
- the non-aspirin containing NSAID is sulindac or celecoxib. In some embodiments, the non-aspirin containing NSAID is sulindac.
- a method for the treatment of colorectal carcinoma risk factors in a patient comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) if the results indicate that the patient's genotype at position +316 of at least one allele of the ODCl promoter gene is G, administering to the patient effective amounts of a pharmaceutical therapy comprising:
- a second agent that modulates the polyamine pathway to reduce overall polyamine content within the patient when combined with the first agent, wherein the method prevents the formation of new aberrant crypt foci, new adenomatous polyps or new adenomas with displasia in the patient.
- the second agent also increases the expression of spermidine/spermine //-acetyltransferase within the patient.
- the method prevents the formation of new aberrant crypt foci in the patient.
- the method prevents the formation of new adenomatous polyps in the patient.
- the method prevents the formation of new adenomas with displasia in the patient.
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GA.
- the pharmaceutical therapy further comprises increasing the dosage of the first or the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test. In some embodiments, the pharmaceutical therapy further comprises increasing the dosage of the first and the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test.
- the first agent is ⁇ -difluoromethylornithine (DFMO).
- the second agent is a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID). In some embodiments, the non-aspirin containing NSAID is a selective COX-2 inhibitor.
- the non-aspirin containing NSAID is sulindac or celecoxib. In some embodiments, the non-aspirin containing NSAID is sulindac.
- a method for evaluating the suitability of a patient for preventative or curative treatment of carcinoma comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) if the results indicate that the patient's genotype at position +316 of at least one allele of the ODCl promoter gene is G, identifying the patient as suitable for treatment by a pharmaceutical therapy, said therapy comprising combined effective amounts of a first agent that inhibits ornithine decarboxylase (ODC) within the patient; and a second agent that modulates the polyamine pathway to reduce overall polyamine content within the patient when combined with the first agent.
- ODC ornithine decarboxylase
- the second agent also increases the expression of spermidine/spermine ⁇ -acetyltransferase within the patient.
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG.
- the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GA.
- the pharmaceutical therapy further comprises increasing the dosage of the first or the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test.
- the pharmaceutical therapy further comprises increasing the dosage of the first and the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test.
- the first agent is ⁇ -difluoromethylornithine (DFMO).
- the second agent is a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID).
- NSAID non-steroidal anti-inflammatory drug
- the non-aspirin containing NSAID is a selective COX-2 inhibitor.
- the non-aspirin containing NSAID is sulindac or celecoxib.
- the non-aspirin containing NSAID is sulindac.
- a method of rendering a carcinoma tumor in a patient resectable comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) if the results indicate that the patient's genotype at position +316 of at least one allele of the ODCl promoter gene is G, administering to the patient effective amounts of a pharmaceutical therapy comprising:
- a first agent that inhibits ornithine decarboxylase (ODC) within the patient (i) a second agent that increases the expression of spermidine/spermine //-acetyltransferase within the patient.
- ODC ornithine decarboxylase
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GA.
- the pharmaceutical therapy further comprises increasing the dosage of the first or the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test. In some embodiments, the pharmaceutical therapy further comprises increasing the dosage of the first and the second agent if the patient was already being treated with the pharmaceutical therapy, but at a lower dosage, prior to obtaining to the results of the test.
- the first agent is ⁇ -difluoromethylornithine (DFMO).
- the second agent is a non-aspirin containing non-steroidal antiinflammatory drug (NSAID).
- NSAID non-steroidal antiinflammatory drug
- the non-aspirin containing NSAID is a selective COX-2 inhibitor.
- the non-aspirin containing NSAID is sulindac or celecoxib.
- the non-aspirin containing NSAID is sulindac.
- a method for preventing the development or recurrence of a carcinoma in a patient at risk therefor comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) administering to the patient combined effective amounts of ⁇ -difluoromethylornithine (DFMO) and a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID) if the results indicate that the patient's genotype at position +316 of at least one allele of the ODCl promoter gene is G.
- DFMO ⁇ -difluoromethylornithine
- NSAID non-steroidal anti-inflammatory drug
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GA.
- a method for treating a patient at risk for development or recurrence of carcinoma with ⁇ -difluoromethylornithine (DFMO) and a non- aspirin containing non-steroidal anti-inflammatory drug (NSAID), comprising administering to the patient effective amounts of ⁇ -difluoromethylornithine (DFMO) and a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID), wherein the patient has been identified as having a G at position +316 of at least one ODCl promoter gene allele.
- DFMO ⁇ -difluoromethylornithine
- NSAID non-aspirin containing non-steroidal anti-inflammatory drug
- the genotype identified at position +316 of both of the patient's ODCl promoter gene alleles is GG. In some embodiments, the genotype identified at position +316 of both of the patient's ODCl promoter gene alleles is GA.
- a method for treating a carcinoma in a patient comprising: a) obtaining results from a test that determines the patient's genotype at position +316 of at least one ODCl promoter gene allele; and b) administering to the patient combined effective amounts of ⁇ -difluoromethylornithine (DFMO) and a non-aspirin containing non-steroidal anti-inflammatory drug (NSAID) if the results indicate that the patient's genotype at position +316 of the ODCl promoter gene of at least one allele is G.
- DFMO ⁇ -difluoromethylornithine
- NSAID non-steroidal anti-inflammatory drug
- the results are obtained by receiving a report containing said genotype or taking a patient history that reveals the results.
- the test determines the nucleotide base at position +316 of one allele of the ODCl promoter gene of the patient. In some embodiments, the test determines the nucleotide bases at position +316 of both alleles of the ODCl promoter gene of the patient. In some embodiments, the results indicate that the patient's genotype at position +316 of both alleles of the ODCl promoter gene is GG. In some embodiments, the results indicate that the patient's genotype at position
- the non-aspirin containing NSAID is a selective COX-2 inhibitor.
- the non-aspirin containing NSAID is sulindac or celecoxib.
- the non-aspirin containing NSAID is sulindac.
- DFMO and sulindac are administered systemically.
- DFMO and sulindac are administered by distinct routes.
- the DFMO or the non-aspirin containing NSAID is administered orally, intraarterially or intravenously.
- the DFMO is administered orally.
- the effective amount of DFMO is 500 mg/day.
- the DFMO is administered intravenously. In some embodiments, the effective amount of DFMO is from about 0.05 to about 5.0 g/m /day. In some embodiments, the DFMO and the non-aspirin containing NSAID is formulated for oral administration. In some embodiments, the DFMO and the non-aspirin containing NSAID is formulated as a hard or soft capsule or a tablet. In some embodiments, the DFMO and the non-aspirin containing NSAID is administered every 12 hours. In some embodiments, the DFMO and the non-aspirin containing NSAID is administered every 24 hours. In some embodiments, the effective amount of sulindac is from about 10 to about 1500 mg/day.
- the effective amount of sulindac is from about 10 to about 400 mg/day. In some embodiments, the effective amount of sulindac is 150 mg/day. In some embodiments, DFMO is administered prior to sulindac. In some embodiments, DFMO is administered after sulindac. In some embodiments, DFMO is administered before and after sulindac. In some embodiments, DFMO is administered concurrently with sulindac. In some embodiments, DFMO is administered at least a second time. In some embodiments, sulindac is administered at least a second time.
- the patient has a solid tumor, and said method further comprises resection of said solid tumor.
- DFMO and sulindac are administered prior to said resection.
- DFMO and sulindac are administered after said resection.
- the carcinoma is colorectal cancer, breast cancer, pancreatic cancer, brain cancer, lung cancer, stomach cancer, a blood cancer, skin cancer, testicular cancer, prostate cancer, ovarian cancer, liver cancer or esophageal cancer, cervical cancer, head and neck cancer, non-melanoma skin cancer, neuroblastoma and glioblastoma.
- the carcinoma is colorectal cancer.
- the colorectal cancer is stage I.
- the colorectal cancer is stage II.
- the colorectal cancer is stage III.
- the colorectal cancer is stage IV.
- the method prevents the formation of new advanced colorectal neoplasms within the patient. In some embodiments, the method prevents ototoxicity or the risk thereof within the patient. In some embodiments, the method prevents the formation of new right- sided advanced colorectal neoplasms. In some embodiments, the method prevents the formation of new left-sided advanced colorectal neoplasms. In variations on any of the above embodiments, the patient has been identified as having one or more adenomatous polyps in the colon, rectum or appendix. In some embodiments, the patient has been identified as having one or more advanced colorectal neoplasms.
- the patient has been identified as having one or more leftside advanced colorectal neoplasms. In some embodiments, the patient has been identified as having one or more right-sided advanced colorectal neoplasms. In some embodiments, the patient has been diagnosed with familial adenomatous polyposis. In some embodiments, the patient has been diagnosed with Lynch syndrome. In some embodiments, the patient has been diagnosed with familial colorectal cancer type X. In some embodiments, the patient satisfies the Amsterdam Criteria or the Amsterdam Criteria II. In some embodiments, the patient has a history of resection of one or more colorectal adenomas.
- the patient has an intraepithelial neoplasia or a precancerous lesion associated ODC hyperactivity. In some embodiments, the patient has an intraepithelial neoplasia or a precancerous lesion and elevated cellular polyamine levels.
- the patient is human.
- IC 50 refers to an inhibitory dose which is 50% of the maximum response obtained.
- patient or subject refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, juveniles, infants and fetuses. "Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
- Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
- Effective amount means that amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
- Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
- the above definitions supersede any conflicting definition in any of the reference that is incorporated by reference herein.
- FIG. 1 Differential Effects of Polyamine Regulation by MADl and c-MYC.
- FIG. 2 Colorectal Cancer-Specific Survival Rate Estimates.
- This figure shows Kaplan-Meier colorectal cancer-specific survival rate estimates for cases with stage III colorectal cancer, stratified by ODCl +316 genotype. Included are cases from the University of California Irvine Gene-Environment Study of Familial Colorectal Cancer diagnosed during the period 1994-1996 with follow-up through March 2008: ODCl GG (64 cases, 15 colorectal cancer-specific deaths), ODCl GA/AA (62 cases, 25 colorectal cancer-specific deaths).
- FIGS. 3A & B Location and Analysis of the ODCl promoter SNP.
- FIG. A shows the A, location of the ODCl promoter SNP.
- the SNP under investigation in this study is 316 nucleotides 3' of the ODCl transcription start site (*). This SNP resides between two consensus E-boxes as shown by the underlined sequences, and affects a Pstl restriction site (box) (SEQ ID NO:5).
- FIG. 3B shows a restriction fragment length polymorphism analysis of ODCl SNP. The DNA was obtained from two cell types, and the region surrounding the ODCl SNP site was sequenced.
- Colon-derived HT29 cells were found to be heterozygous GA, whereas HCTl 16 cells were found to be homozygous GG, at the ODCl SNP locus.
- a 350-bp PCR product of this region was obtained from each cell type and subjected to digestion with Pstl. Evidence of an A-allele was indicated by restriction products ⁇ 350 bp.
- FIGS. 4A & B E-Box Expression and Immunoprecipitation Analysis. Location of the ODCl promoter SNP.
- FIG. 4A shows E-box protein expression in colon-derived cells. Expression of proteins to be evaluated for binding to the +316 ODCl SNP was assessed by Western blot analysis. Extracts of both HT29 and HCTl 16 cells were evaluated for c- MYC, MADl, and MAD4; ⁇ -actin was used as a loading control.
- FIG. 4B shows documentation for the allele-specif ⁇ c transcription factor binding by chromatin immunoprecipitation analysis, which was conducted as described in the examples section below.
- HT29 cells were a source of ODCl A-alleles, as these cells are heterozygous GA at this site.
- HCTl 16 cells were used as a source of ODCl G-alleles.
- FIGS. 5A & B Effects of c-MYC and MADl expression on ODCl Activity.
- FIG. 5A shows the effect of c-MYC expression on ODCl allele-specif ⁇ c promoter activity in HT29 colon-derived cells. Promoter activity was measured after transfection with ODCl promoter reporter plasmids co-trans fected with pcDNA 3.0 plasmid or CMV-MFC expression vector. Promoter constructs differ by the presence of the first E-box element, located in -485 to -480 bp ("wt E-box 1" for the wild-type sequence or "mut E-box 1" for a mutant sequence).
- FIG. 6 Reduction in Adenomatous Polyps. This figure shows the percent recurrence of adenomatous polyps of patients were treated with DFMO and Sulindac compared with placebo. There was a 70% reduction in total adenoma, a 92% reduction in advanced adenoma, and 95% reduction in multiple adenoma.
- FIG. 7 Pharmacogenomic Benefit/Risk Analysis Based on +316 ODCl Genotype. This figure compares reduction in % recurrence of adenomas at the end of 3 years versus placebo, with % ototoxicity for treatment and placebo groups as a function of the patient's +316 ODCl genotype. Ototoxicity was determined using audiometric testing.
- FIG. 8A-C Pharmacogenomic Benefit/Risk Analysis Based on +316 ODCl
- FIG. 9 Average Number of Tumors by Size in Colon of Mm/+ Mice. This figure shows the average number of tumors by size in the colon of the three treatment groups compared to untreated controls. Mice, purchased from The Jackson Laboratory (Bar Harbor, Me.), were bred crossing C57BL/6J- Apc Mml+ males and C57/BL6 females.
- Heterozygous Min mice (Apc Mm /Apc + ): (heterozygous for a nonsense mutation at codon 850 of Ape) were identified by genotyping at weaning by an allele specific PCR assay using tail-tip DNA. Homozygous (Apc + IApc + ) litter mates served as controls.
- One treatment consisted of supplementing drinking water with 2% DFMO (Merrell Dow Research Inst.) on the 8th day of study.
- DFMO Merrell Dow Research Inst.
- sulindac 167 ppm of sulindac (Harlen Teklad) was added to AIN-93G mouse diet on the 21st day of the study.
- the third treatment was a combination of DFMO and sulindac.
- mice After 114 days, the mice were sacrificed through CO 2 asphyxiation. The small intestine and colon segments were removed from mice and dissected lengthwise, mounted and fixed in 70% ethanol, and placed at 4 0 C for tumor scoring. Representative tissues were also taken for histopathology evaluation.
- FIG. 10 Average Number of Tumors by Size in the Small Intestine of Min/+
- mice This figure shows the average number of tumors by size in the small intestine of the three treatment groups compared to untreated controls. For experimental details, see FIG. 9 description above.
- FIG. 11 Number of High Grade Adenomas as a Function of Therapy in Minl+ Mice. This figure shows how the number of high grade adenomas various depending on therapy type. For experimental details, see FIG. 9 description above.
- methods comprise predicting the suitability, efficacy, toxicity and/or dosage of anti-carcinoma combination therapies comprising ornithine decarboxylase (ODC) inhibitor and a spermidine/spermine ⁇ -acetyltransferase expression agonist based at least in part on the patient's ODCl promoter genotype.
- ODC ornithine decarboxylase
- the present invention also involves the delivery of therapeutic compounds to individuals exhibiting pre-cancerous symptoms to prevent the onset of cancer and/or to prevent the onset of cancer risk factors, such as the formation of new aberrant crypt foci, the formation of new adenomatous polyps or new adenomas with dysplasia.
- Cells of this category include polyps and other precancerous lesions, premalignancies, preneoplastic or other aberrant phenotype indicating probable progression to a cancerous state, based at least in part on the patient's ODCl promoter genotype.
- Polyamines are small ubiquitous molecules involved in various processes, including transcription, RNA stabilization, ion channel gating and others (Wallace, 2000).
- Ornithine decarboxylase (ODC) the first enzyme in polyamine synthesis, is essential for normal development and tissue repair in mammals but is down-regulated in most adult tissues (Gerner and Meyskens, 2004). Multiple abnormalities in the control of polyamine metabolism and transport result in increased polyamine levels that can promote tumorigenesis in several tissues (Thomas and Thomas, 2003).
- FAP familial adenomatous polyposis
- APC adenomatous polyposis coli
- Wild type APC expression leads to decreased expression of ODC, while mutant APC leads to increased expression of ODC.
- the mechanism of APC-dependent regulation of ODC involves E-box transcription factors, including the transcriptional activator c-MYC and the transcriptional repressor MADl (Fultz and Gerner, 2002; Martinez et al, 2003).
- c-MYC was shown by others to regulate ODC transcription (Bellofernandez et al, 1993).
- Several genes involved in polyamine metabolism are essential genes for optimal growth in most organisms, and are down-regulated in non-proliferating and/or adult cells and tissues (Gerner and Meyskens, 2004).
- the polyamines influence specific cellular phenotypes, in part, by affecting patterns of gene expression, as reviewed elsewhere (Childs et al, 2003).
- ODC activity i.e., the rate- limiting enzyme of polyamine synthesis
- reduction of cellular polyamine levels has demonstrated remarkable efficacy in preventing recurrence of colorectal polyps in humans.
- Epidemiologic and experimental results from the present research demonstrate conditional regulation of polyamine homeostasis by genetic polymorphism in ODC, and suggest a model in which the +316 ODC SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. This information may be used for determining colon cancer prognosis.
- tertiary prevention management strategies By identifying patients at increased risk for cancer progression/recurrence, early implementation of tertiary prevention management strategies can be instituted. Additionally, this research may be used to identify high-risk but otherwise optimally-treated locoregional colorectal cancer patients that would benefit from tertiary cancer prevention therapies.
- the excess polyamine problem may be compounded by the fact that polyamines, e.g., putrescine is present in many common foods, such as orange juice, which contains approximately 400 ppm putrescine.
- a high polyamine diet is contraindicatory, and for some of the embodiments provided herein such a diet is to be avoided.
- Familial Adenomatous Polyposis Familial Adenomatous Polyposis (FAP), an inherited polyposis syndrome, is the result of germ- line mutation of the adenomatous polyposis coli (APC) tumor suppressor gene (Su et al., 1992). This autosomal-dominant condition with variable expression is associated with the development of hundreds of colonic adenomas, which uniformly progress to adenocarcinoma by forty years of age, two decades earlier than the mean age diagnosis for sporadic colon cancer (Bussey, 1990).
- APC adenomatous polyposis coli
- Min multiple intestinal neoplasia
- FAP enzyme- activated irreversible inhibitor
- the Min mouse which shares a mutated APCI ape genotype with FAP, serves as a useful experimental animal model for human FAP patients (Lipkin, 1997).
- the Min mouse can develop greater than 100 gastrointestinal adenomas/adenocarcinomas throughout the gastrointestinal tract by 120 days of life leading to GI bleeding, obstruction and death.
- ODC ornithine decarboxylase
- SNP single nucleotide polymorphism in intron-1 of the human ODCl gene affects ODCl transcription (Guo et al, 2000), and has been investigated as a genetic marker for colorectal adenoma (CRA) risk (Martinez et al, 2003; Barry et al, 2006; Hubner et al, 2008).
- the reported minor A-allele frequency is approximately 25% and despite differences across race/ethnicity, ODCl genotype distribution is in Hardy- Weinberg equilibrium within each race (O'Brien et al, 2004; ZeIl et al., 2009).
- ODCl minor A-allele Individuals homozygous for the ODCl minor A-allele have reduced risk of adenoma recurrence compared to those with the major G- allele (Martinez et al, 2003; Hubner et al, 2008). Furthermore, the ODCl A-allele (AA or GA genotype, but not GG genotype) and reported aspirin usage have been associated with reduced colon polyp recurrence (Martinez et al, 2003; Barry et al, 2006; Hubner et al, 2008), and a statistically significant 50% reduced risk of advanced adenomas (Barry et al, 2006).
- FIG. 2A shows that a polymerase chain reaction (PCR) product made from human colon HT29 cells was partially sensitive to Pstl cutting, suggesting that these cells contained at least one ODC A-allele.
- PCR polymerase chain reaction
- E-box binding proteins including the transcriptional activator c-MYC and several transcriptional repressors in HT29 and HCTl 16 cells ⁇ e.g. MADl and MAD4
- Western blotting FIG. 3A
- Chromatin immunoprecipitation (CHIP) analysis of the region surrounding +316 of the ODC promoter was conducted, using antibodies directed against these proteins.
- FIG. 3B ODC promoter-specific PCR products were synthesized from HT29 DNA obtained after immunoprecipitation of chromatin with antibodies directed against c-MYC, MADl or MAD4.
- ODC allele-specific promoter activity was assessed.
- the hypothesis that +316 ODC SNP influenced ODC expression in a manner dependant on the expression of E-box activators and repressors was tested as follows. Transient co-transfection of colon cancer-derived HT29 cells was accomplished with ODC allele-specific promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MADl (FIGS. 4A & B).
- the standard error bars shown reflect the variability in triplicate measurements within a single representative experiment, which has been replicated.
- the allele-specific promoter-reporters used in these experiments included all three E-boxes shown in FIG. 2A. As shown in FIG.
- DFMO also know as eflornithine, has the following chemical designation; 2-(difluoromethyl)-(i/-ornithine. It is an enzyme-activated irreversible inhibitor of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine biosynthetic pathway.
- ODC ornithine decarboxylase
- the compound is effective in preventing cancer formation in many organ systems, inhibiting cancer growth, and reducing tumor size. It also has synergistic action with other antineoplastic agents.
- DFMO and its use in the treatment of benign prostatic hypertrophy are described in two patents, U.S. Pat. Nos. 4,413,141, and 4,330,559.
- U.S. Pat. No. 4,413,141 describes DFMO as being a powerful inhibitor of ODC, both in vitro and in vivo.
- Administration of DFMO causes a decrease in putrescine and spermidine concentrations in cells in which these polyamines are normally actively produced. Additionally, DFMO has been shown to be capable of slowing neoplastic cell proliferation when tested in standard tumor models.
- U.S. Pat. No. 4,330,559 describes the use of DFMO and DFMO derivatives for the treatment of benign prostatic hypertrophy.
- Benign prostatic hypertrophy like many disease states characterized by rapid cell proliferation, is accompanied by abnormal elevation of polyamine concentrations.
- the treatment described within this reference can be administered to a patient either orally, or parenterally.
- DFMO can potentially be given continuously with significant anti-tumor effects.
- This drug is relatively non-toxic at low doses of 0.4 g/m /day to humans while producing inhibition of putrescine synthesis in tumors. Studies in a rat-tumor model demonstrate that
- DFMO infusion can produce a 90% decrease in tumor putrescine levels without suppressing peripheral platelet counts.
- DFMO may significantly inhibit ODC activity of the bone marrow precursors of megakaryocytes. DFMO may inhibit proliferative repair processes, such as epithelial wound healing.
- a phase III clinical trial assessed the recurrence of adenomatous polyps after treatment for 36 months with difluoromethylornithine (DFMO) plus sulindac or matched placebos.
- Temporary hearing loss is a known toxicity of treatment with DFMO, thus a comprehensive approach was developed to analyze serial air conduction audiograms.
- the generalized estimating equation method estimated the mean difference between treatment arms with regard to change in air conduction pure tone thresholds while accounting for within-subject correlation due to repeated measurements at frequencies.
- NSAIDs are anti-inflammatory agents that are not steroids. In addition to antiinflammatory actions, they have analgesic, antipyretic, and platelet-inhibitory actions. They are used primarily in the treatment of chronic arthritic conditions and certain soft tissue disorders associated with pain and inflammation. They act by blocking the synthesis of prostaglandins by inhibiting cyclooxygenase, which converts arachidonic acid to cyclic endoperoxides, precursors of prostaglandins. Inhibition of prostaglandin synthesis accounts for their analgesic, antipyretic, and platelet-inhibitory actions; other mechanisms may contribute to their anti-inflammatory effects. Certain NSAIDs also may inhibit lipoxygenase enzymes or phospholipase C or may modulate T-cell function. (AMA Drug Evaluations Annual, 1814-5, 1994).
- NSAIDs nonsteroidal anti-inflammatory drugs
- aspirin, ibuprofen, piroxicam Reddy et al, 1990; Singh et al, 1994
- indomethacin Naarisawa, 1981
- sulindac sulindac
- NSAIDs appear to inhibit carcinogenesis via the induction of apoptosis in tumor cells (Bedi et al, 1995; Lupulescu, 1996; Piazza et al, 1995; Piazza et al, 1997b).
- a number of studies suggest that the chemopreventive properties of the NSAIDs, including the induction of apoptosis, is a function of their ability to inhibit prostaglandin synthesis (reviewed in DuBois et al, 1996; Lupulescu, 1996; Vane and Botting, 1997).
- NSAIDs may act through both prostaglandin- dependent and -independent mechanisms (Alberts et al, 1995; Piazza et al, 1997a; Thompson et al., 1995; Hanif, 1996).
- Sulindac sulfone a metabolite of the NSAID sulindac, lacks COX-inhibitory activity yet induces apoptosis in tumor cells (Piazza et al., 1995; Piazza et al., 1997b) and inhibits tumor development in several rodent models of carcinogenesis (Thompson et al, 1995; Piazza et al, 1995, 1997a).
- Several NSAIDs have been examined for their effects in human clinical trials.
- a phase Ha trial (one month) of ibuprofen was completed and even at the dose of 300 mg/day, a significant decrease in prostaglandin E 2 (PGE 2 ) levels in flat mucosa was seen.
- PGE 2 prostaglandin E 2
- a dose of 300 mg of ibuprofen is very low (therapeutic doses range from 1200-3000 mg/day or more), and toxicity is unlikely to be seen, even over the long-term.
- ibuprofen is less effective than other NSAIDs.
- Sulindac is a non-steroidal, anti-inflammatory indene derivative with the following chemical designation; (Z)-5-fluoro-2-methyl-l-((4 (methylsulfinyl)phenyl)methylene) IH- indene-3 -acetic acid (Physician's Desk Reference, 1999).
- the sulfmyl moiety is converted in vzVo by reversible reduction to a sulfide metabolite and by irreversible oxidation to a sulfone metabolite (exisulind). See U.S. Patent 6,258,845, which is incorporated herein by reference in its entirety.
- Sulindac which also inhibits Ki-ras activation, is metabolized to two different molecules which differ in their ability to inhibit COX, yet both are able to exert chemopreventive effects via the induction of apoptosis.
- Sulindac sulfone lacks COX- inhibitory activity, and most likely facilitates the induction of apoptosis in a manner independent of prostaglandin synthesis. Available evidence indicates that the sulfide derivative is at least one of the biologically active compounds. Based on this, sulindac may be considered a prodrug.
- Sulindac (Clinoril®) is available, for example, as 150 mg and 200 mg tablets. The most common dosage for adults is 150 to 200 mg twice a day, with a maximal daily dose of 400 mg. After oral administration, about 90% of the drug is absorbed. Peak plasma levels are achieved in about 2 hours in fasting patients and 3 to 4 hours when administered with food. The mean half-life of sulindac is 7.8 hours: the mean half-life of the sulfide metabolite is 16.4 hours.
- U.S. Pat. Nos. 3,647,858 and 3,654,349 cover preparations of sulindac, both are incorporate by reference herein in their entireties.
- Sulindac is indicated for the acute and long-term relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gout, and acute painful shoulder.
- the analgesic and antiinflammatory effects exerted by sulindac (400 mg per day) are comparable to those achieved by aspirin (4 g per day), ibuprofen (1200 mg per day), indometacin (125 mg per day), and phenylbutazone (400 to 600 mg per day).
- Side effects of sulindac include mild gastrointestinal effects in nearly 20% of patients, with abdominal pain and nausea being the most frequent complaints.
- CNS side effects are seen in up to 10% of patients, with drowsiness, headache, and nervousness being those most frequently reported. Skin rash and pruritus occur in 5% of patients.
- Chronic treatment with sulindac can lead to serious gastrointestinal toxicity such as bleeding, ulceration, and perforation.
- sulindac for chemoprevention of cancers, and in particular colorectal polyps.
- Doses of sulindac claimed in U.S. Pat. No. 5,814,625 range from 10 mg to 1500 mg per day, with preferred doses of 50 mg to 500 mg per day.
- the biggest problem with the use of sulindac as a single agent in chemoprevention is its well-known toxicities and moderately high risk of intolerance.
- the elderly appear to be especially vulnerable, as the incidence of side effects is higher in those over the age of 60. It is noted that this age group is most likely to develop colorectal cancer, and therefore, most likely to benefit from chemoprevention.
- NCI National Cancer Institute
- NCI National Cancer Institute
- NCI National Cancer Institute
- NCI National Cancer Institute
- Phases Phase I / Phase II
- NCI National Cancer Institute
- NCI National Cancer Institute
- Drug estramustine phosphate sodium
- NCI National Cancer Institute
- NCI National Cancer Institute
- Phase II Phase II / Phase III
- NCI National Cancer Institute
- a non-steroidal anti-inflammatory agent that is well established in the treatment of rheumatoid arthritis and osteoarthritis with the following chemical designation; 4-hydroxy-2- methyl- ⁇ /-2-pyridyl-2H-l,2-benzothiazine-3-carboxamide 1,1 -dioxide. Its usefulness also has been demonstrated in the treatment of musculoskeletal disorders, dysmenorrhea, and postoperative pain. Its long half-life enables it to be administered once daily. The drug has been shown to be effective if administered rectally. Gastrointestinal complaints are the most frequently reported side effects.
- Piroxicam has been shown to be effective chemoprevention agent in animal models (Pollard and Luckert, 1989; Reddy et al., 1987), although it demonstrated side effects in a recent lib trial. A large meta-analysis of the side effects of the NSAIDs also indicates that piroxicam has more side effects than other NSAIDs (Lanza et al., 1995). Sulindac has been shown to produce regression of adenomas in Familial Adenomatous Polyposis (FAP) patients (Muscat et al., 1994), although at least one study in sporadic adenomas has shown no such effect (Ladenheim et al. , 1995).
- FAP Familial Adenomatous Polyposis
- Combinations of NSAIDs are also used for various purposes. By using lower doses of two or more NSAIDs, it is possible to reduce the side effects or toxicities associated with higher doses of individual NSAIDs.
- sulindac may be used together with celecoxib.
- the one or both of the NSAIDS are selective COX-2 inhibitors.
- NSAIDS that back be used either alone or in combination include, but are not limited to, the following: ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, diclofenac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib rofecoxib valdecoxib parecoxib, lumiracoxib, or etoricoxib.
- Min multiple intestinal neoplasia
- FAP multiple intestinal neoplasia
- the Min mouse can develop greater than 100 gastrointestinal adenomas/adenocarcinomas throughout the gastrointestinal tract by 120 days of life leading to GI bleeding, obstruction and death.
- a combination therapy of DFMO and sulindac was shown to be effective in reducing adenomas in these mice (US Patent No. 6,258,845; Gerner and Meyskens, 2004).
- FIGS. 9 & 10 show the results of treating Min mice with either DFMO alone, sulindac alone, or a combination of DFMO and sulindac on tumor formation in either the colon or small intestine.
- FIG. 9 shows the average number of tumors by size in the colon of the three treatment groups compared to untreated controls.
- FIG. 10 shows the average number of tumors by size in the small intestine of the three treatment groups compared to untreated controls.
- FIG. 11 shows how the number of high grade adenomas various depending on therapy, single or combination. VII. Efficacy of Polyamine-Inhibitory Therapy Based On Patient Profile
- DFMO oral difluoromethylornithine
- sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site.
- DFMO oral difluoromethylornithine
- the DSMB monitored all safety and efficacy endpoints. As discussed in greater detail in the Examples, section this study involves analysis of patient data from the multicenter phase III colon adenoma prevention trial. See also (Meyskens et ah, 2008), which is incorporated herein by reference in its entirety.
- CRC colorectal cancer
- ODCl genotype distribution was: 126 GG (55%), 87 GA (38%), and 15 AA (7%). Baseline clinical characteristics revealed differences, as shown in Table 1. In regression models with predictors age, gender, race, aspirin use, treatment, ODCl genotype, and treatment, treatment was the only factor associated with differences in adenoma recurrence, tissue polyamine response, and ototoxicity.
- ODCl genotype was not significantly associated with a tissue putrescine response or spermidine spermine ratio response in the full regression models (data not shown).
- the relative risk (RR) for adenoma recurrence related to treatment after adjustment in the full regression model was 0.39 (95% CI 0.24-0.66).
- HR ODC GG hazards ratio
- ODC GA HR 1.73
- CRC-specific survival analysis revealed that the ODC +316 SNP was an independent predictor of CRC-specific survival, after adjustment for the above clinical variables.
- the ODC +316 genotype distribution differed across ethnicity.
- the observed mortality risk other than by chance, likely reflects differences based on ODC genotype, however the risk may be restricted to a particular ethnic group.
- multivariate analyses were conducted among Caucasian colon cancer cases, to assess genotype-specific mortality risk within this single ethnic group.
- the ODC +316 SNP was an independent predictor of CRC-specific survival among Caucasian colon cancer cases after adjustment for the aforementioned relevant clinical variables.
- HR ODC GG genotype cases
- HR adjusted CRC- SS hazards ratio
- the ODC +316 SNP flanked by two E-boxes, predicts ODC promoter activity.
- the E-box activator c-MYC and repressors MADl and MAD4 preferentially bind to minor A-, compared to major G-, alleles in cultured cells.
- wild type APC a gene expressed in normal colonic mucosa, suppresses c-MYC, and increases MADl, expression
- wild type APC can regulate ODC promoter activity in a manner dependent on the +316 SNP (Martinez et al., 2003). Wild type APC is expressed in the apparently normal colonic mucosa of individuals not afflicted with FAP, while the majority of sporadic colon adenomas show evidence of mutated or deleted APC (Iwamoto et al., 2000).
- MYC is expressed at low levels in normal intestinal mucosa but is increased in intestinal adenomas of ⁇ PC ⁇ 1 " ⁇ mice.
- Conditional knockout of intestinal epithelial MYC expression suppresses intestinal tumorigenesis in ⁇ pC ⁇ 1 " ⁇ mice (Ignatenko et al., 2006).
- Previous work by our group (Martinez et al., 2003) and others (Hubner et al., 2008) demonstrated a protective role for the ODC A-allele, especially in aspirin users, against recurrence of colon polyps in clinical prevention trials.
- the ODC A-allele was associated with poor survival.
- TGF- ⁇ transforming growth factor- beta
- ODC overexpression promotes the formation of human colorectal adenomas
- ODC overexpression causes enhanced proliferation and is associated with improved response to anti-proliferative treatments.
- that study did not include stratification by ODC genotype, so it is not known if these effects are independent of ODC genotype.
- the observed associations of the ODC +316 SNP with CRC-specific mortality were limited to colon cancer cases. Among colon cancer cases, particularly strong effects were observed for Caucasians. Similar to other reports, the ODC +316 SNP allele frequency differs considerably by ethnicity (O'Brien et al, 2004). When the inventors limited the survival analysis to Caucasians only (i.e., the only ethnic group with adequate power for such analyses), the associations of the ODC +316 SNP were significant, and of greater magnitude than the estimates observed for the entire cohort.
- the inventors have observed clinical consequences of the ODC +316 SNP on CRC-specific mortality among colon cancer cases. Additionally, the inventors have further established the functional significance of the ODC +316 SNP in the c-MYC- and MADl -dependent transcription of this gene in human colon cancer cells. Together, these experimental and epidemiologic findings suggest roles for the ODC +316 SNP in progression of colon cancer that are distinct from its previously reported role in progression to colon adenomas. These findings may be used to assess risk of colon cancer progression and may be used to direct patient-specific pharmaco genetic management, surveillance monitoring, and inform novel targeted approaches to secondary and tertiary colon cancer prevention.
- the genotype at the +316 position of the ODCl promoter gene of patient can determined using the methods provided below, including the specific methods described in the Examples section. These methods can be further modified and optimized using the principles and techniques of molecular biology as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Small et al, (2002), which is incorporated herein by reference. General methods employed for the identification of single nucleotide polymorphisms (SNPs) are provided below. The reference of Kwok and Chen (2003) and Kwok (2001) provide overviews of some of these methods; both of these references are specifically incorporated by reference.
- SNPs relating to ODCl can be characterized by the use of any of these methods or suitable modification thereof.
- Such methods include the direct or indirect sequencing of the site, the use of restriction enzymes where the respective alleles of the site create or destroy a restriction site, the use of allele-specific hybridization probes, the use of antibodies that are specific for the proteins encoded by the different alleles of the polymorphism, or any other biochemical interpretation.
- a commonly used method of characterizing a polymorphism is direct DNA sequencing of the genetic locus that flanks and includes the polymorphism. Such analysis can be accomplished using either the "dideoxy-mediated chain termination method,” also known as the “Sanger Method” (Sanger et al, 1975) or the “chemical degradation method,” also known as the “Maxam-Gilbert method” (Maxam et al, 1977). Sequencing in combination with genomic sequence-specific amplification technologies, such as the polymerase chain reaction may be utilized to facilitate the recovery of the desired genes (Mullis et al, 1986; European Patent Application 50,424; European Patent Application. 84,796, European Patent Application 258,017, European Patent Application. 237,362; European Patent Application. 201,184; U.S. Patents 4,683,202; 4,582,788; and 4,683,194), all of the above incorporated herein by reference.
- Patent. 4,656,127 A primer complementary to an allelic sequence immediately 3'-to the polymorphic site is hybridized to the DNA under investigation. If the polymorphic site on the
- DNA contains a nucleotide that is complementary to the particular exonucleotide -resistant nucleotide derivative present, then that derivative will be incorporated by a polymerase onto the end of the hybridized primer. Such incorporation makes the primer resistant to exonuclease cleavage and thereby permits its detection. As the identity of the exonucleotide- resistant derivative is known one can determine the specific nucleotide present in the polymorphic site of the DNA.
- French Patent 2,650,840 and PCT Application WO91/02087 discuss a solution-based method for determining the identity of the nucleotide of a polymorphic site. According to these methods, a primer complementary to allelic sequences immediately 3 '-to a polymorphic site is used. The identity of the nucleotide of that site is determined using labeled dideoxynucleotide derivatives which are incorporated at the end of the primer if complementary to the nucleotide of the polymorphic site.
- PCT Application WO92/15712 describes a method that uses mixtures of labeled terminators and a primer that is complementary to the sequence 3' to a polymorphic site.
- the labeled terminator that is incorporated is complementary to the nucleotide present in the polymorphic site of the target molecule being evaluated and is thus identified.
- the primer or the target molecule is immobilized to a solid phase.
- OLA Oligonucleotide Ligation Assay
- Two oligonucleotides capable of hybridizing to abutting sequences of a single strand of a target DNA are used.
- One of these oligonucleotides is biotinylated while the other is detectably labeled. If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate. Ligation permits the recovery of the labeled oligonucleotide by using avidin.
- Other nucleic acid detection assays, based on this method, combined with PCR have also been described (Nickerson et al., 1990). Here PCR is used to achieve the exponential amplification of target DNA, which is then detected using the OLA.
- U.S. Patent 5,952,174 describes a method that also involves two primers capable of hybridizing to abutting sequences of a target molecule.
- the hybridized product is formed on a solid support to which the target is immobilized.
- the hybridization occurs such that the primers are separated from one another by a space of a single nucleotide.
- Incubating this hybridized product in the presence of a polymerase, a ligase, and a nucleoside triphosphate mixture containing at least one deoxynucleoside triphosphate allows the ligation of any pair of abutting hybridized oligonucleotides.
- Invasive cleavage reactions can be used to evaluate cellular DNA for a particular polymorphism.
- a technology called INVADER® employs such reactions (e.g., de Arruda et al, 2002; Stevens et al, 2003, which are incorporated by reference).
- upstream oligo an oligonucleotide upstream of the target site
- probe a probe oligonucleotide covering the target site
- target a single-stranded DNA with the the target site
- the upstream oligo and probe do not overlap but they contain contiguous sequences.
- the probe contains a donor fluorophore, such as fluoroscein, and an acceptor dye, such as Dabcyl.
- a donor fluorophore such as fluoroscein
- an acceptor dye such as Dabcyl
- the nucleotide at the 3' terminal end of the upstream oligo overlaps ("invades") the first base pair of a probe-target duplex. Then the probe is cleaved by a structure-specific 5' nuclease causing separation of the fluorophore/quencher pair, which increases the amount of fluorescence that can be detected. See Lu et al., 2004.
- the assay is conducted on a solid-surface or in an array format.
- extended haplotypes may be determined at any given locus in a population, which allows one to identify exactly which SNPs will be redundant and which will be essential in association studies.
- the latter is referred to as 'haplotype tag SNPs (htSNPs)', markers that capture the haplotypes of a gene or a region of linkage disequilibrium.
- htSNPs 'haplotype tag SNPs
- the VDA-assay utilizes PCR amplification of genomic segments by long PCR methods using TaKaRa LA Taq reagents and other standard reaction conditions. The long amplification can amplify DNA sizes of about 2,000-12,000 bp.
- Hybridization of products to variant detector array (VDA) can be performed by a Affymetrix High Throughput Screening Center and analyzed with computerized software.
- Chip Assay uses PCR amplification of genomic segments by standard or long PCR protocols. Hybridization products are analyzed by VDA, Halushka et al. (1999), incorporated herein by reference. SNPs are generally classified as “Certain” or “Likely” based on computer analysis of hybridization patterns. By comparison to alternative detection methods such as nucleotide sequencing, “Certain” SNPs have been confirmed 100% of the time; and “Likely” SNPs have been confirmed 73% of the time by this method.
- individual exons or overlapping fragments of large exons are PCR-amplif ⁇ ed.
- Primers are designed from published or database sequences and PCR- amplif ⁇ cation of genomic DNA is performed using the following conditions: 200 ng DNA template, 0.5 ⁇ M each primer, 80 ⁇ M each of dCTP, dATP, dTTP and dGTP, 5% formamide, 1.5mM MgCl 2 , 0.5 U of Taq polymerase and 0.1 volume of the Taq buffer.
- PCR-SSCP PCR-single strand conformation polymorphism
- DEMIGLACE In a method called CGAP-GAI (DEMIGLACE), sequence and alignment data (from a PHRAP. ace file), quality scores for the sequence base calls (from PHRED quality files), distance information (from PHYLIP dnadist and neighbour programs) and base-calling data (from PHRED '-d' switch) are loaded into memory. Sequences are aligned and examined for each vertical chunk ('slice') of the resulting assembly for disagreement. Any such slice is considered a candidate SNP (DEMIGLACE). A number of filters are used by DEMIGLACE to eliminate slices that are not likely to represent true polymorphisms.
- filters that: (i) exclude sequences in any given slice from SNP consideration where neighboring sequence quality scores drop 40% or more; (ii) exclude calls in which peak amplitude is below the fifteenth percentile of all base calls for that nucleotide type; (iii) disqualify regions of a sequence having a high number of disagreements with the consensus from participating in SNP calculations; (iv) removed from consideration any base call with an alternative call in which the peak takes up 25% or more of the area of the called peak; (v) exclude variations that occur in only one read direction.
- PHRED quality scores were converted into probability- of-error values for each nucleotide in the slice. Standard Baysian methods are used to calculate the posterior probability that there is evidence of nucleotide heterogeneity at a given location.
- CU-RDF PCR amplification is performed from DNA isolated from blood using specific primers for each SNP, and after typical cleanup protocols to remove unused primers and free nucleotides, direct sequencing using the same or nested primers.
- DEBNICK DEBNICK
- EST sequences is performed and confirmed by fluorescent-based DNA sequencing.
- DEBNICK METHOD-C
- ERO ERO
- new primers sets are designed for electronically published STSs and used to amplify DNA from 10 different mouse strains.
- the amplification product from each strain is then gel purified and sequenced using a standard dideoxy, cycle sequencing technique with 33 P-labeled terminators. All the ddATP terminated reactions are then loaded in adjacent lanes of a sequencing gel followed by all of the ddGTP reactions and so on. SNPs are identified by visually scanning the radiographs.
- ERO RESEQ-HT
- new primers sets are designed for electronically published murine DNA sequences and used to amplify DNA from 10 different mouse strains.
- the amplification product from each strain is prepared for sequencing by treating with Exonuclease I and Shrimp Alkaline Phosphatase. Sequencing is performed using ABI Prism Big Dye Terminator Ready Reaction Kit (Perkin-Elmer) and sequence samples are run on the 3700 DNA Analyzer (96 Capillary Sequencer).
- FGU-CBT (SCA2-SNP) identifies a method where the region containing the SNP were PCR amplified using the primers SCA2-FP3 and SCA2-RP3. Approximately 100 ng of genomic DNA is amplified in a 50 ml reaction volume containing a final concentration of 5 mM Tris, 25 mM KCl, 0.75 mM MgCl 2 , 0.05% gelatin, 20 pmol of each primer and 0.5U of Taq DNA polymerase.
- Samples are denatured, annealed and extended and the PCR product is purified from a band cut out of the agarose gel using, for example, the QIAquick gel extraction kit (Qiagen) and is sequenced using dye terminator chemistry on an ABI Prism 377 automated DNA sequencer with the PCR primers.
- QIAquick gel extraction kit Qiagen
- JBLACK SEQ/RESTRICT
- two independent PCR reactions are performed with genomic DNA. Products from the first reaction are analyzed by sequencing, indicating a unique Fspl restriction site. The mutation is confirmed in the product of the second PCR reaction by digesting with Fsp I.
- SNPs are identified by comparing high quality genomic sequence data from four randomly chosen individuals by direct DNA sequencing of PCR products with dye-terminator chemistry (see Kwok et al, 1996).
- SNPs are identified by comparing high quality genomic sequence data from overlapping large-insert clones such as bacterial artificial chromosomes (BACs) or Pl -based artificial chromosomes (PACs). An STS containing this SNP is then developed and the existence of the SNP in various populations is confirmed by pooled DNA sequencing (see Taillon-Miller et al, 1998).
- SNPs are identified by comparing high quality genomic sequence data from overlapping large-insert clones BACs or PACs.
- the SNPs found by this approach represent DNA sequence variations between the two donor chromosomes but the allele frequencies in the general population have not yet been determined.
- SNPs are identified by comparing high quality genomic sequence data from a homozygous DNA sample and one or more pooled DNA samples by direct DNA sequencing of PCR products with dye -terminator chemistry.
- the STSs used are developed from sequence data found in publicly available databases.
- these STSs are amplified by PCR against a complete hydatidiform mole (CHM) that has been shown to be homozygous at all loci and a pool of DNA samples from 80 CEPH parents (see Kwok et al, 1994).
- CHM complete hydatidiform mole
- KWOK OverlapSnpDetectionWithPolyBayes
- SNPs are discovered by automated computer analysis of overlapping regions of large-insert human genomic clone sequences. For data acquisition, clone sequences are obtained directly from large-scale sequencing centers. This is necessary because base quality sequences are not present/available through GenBank. Raw data processing involves analyzed of clone sequences and accompanying base quality information for consistency.
- SNP detection Overlapping pairs of clone sequence are analyzed for candidate SNP sites with the 'POLYBAYES' SNP detection software. Sequence differences between the pair of sequences are scored for the probability of representing true sequence variation as opposed to sequencing error. This process requires the presence of base quality values for both sequences. High-scoring candidates are extracted. The search is restricted to substitution-type single base pair variations. Confidence score of candidate SNP is computed by the POLYBAYES software.
- TaqMan assay In method identified by KWOK (TaqMan assay), the TaqMan assay is used to determine genotypes for 90 random individuals.
- PCR products are post- labeled with fluorescent dyes and analyzed by an automated capillary electrophoresis system under SSCP conditions (PLACE-SSCP).
- PLACE-SSCP automated capillary electrophoresis system under SSCP conditions
- PCR primers are tagged to have 5'-ATT or 5'-GTT at their ends for post-labeling of both strands.
- Samples of DNA (10 ng/ul) are amplified in reaction mixtures containing the buffer (1OmM Tris-HCl, pH 8.3 or 9.3, 5OmM KCl, 2.OmM MgCl 2 ), 0.25 ⁇ M of each primer, 200 ⁇ M of each dNTP, and 0.025 units/ ⁇ l of Taq DNA polymerase premixed with anti-Taq antibody.
- the two strands of PCR products are differentially labeled with nucleotides modified with RI lO and R6G by an exchange reaction of Klenow fragment of DNA polymerase I.
- the reaction is stopped by adding EDTA, and unincorporated nucleotides are dephosphorylated by adding calf intestinal alkaline phosphatase.
- SSCP For the SSCP: an aliquot of fluorescently labeled PCR products and TAMRA-labeled internal markers are added to deionized formamide, and denatured. Electrophoresis is performed in a capillary using an ABI Prism 310 Genetic Analyzer. Genescan softwares (P-E Biosystems) are used for data collection and data processing. DNA of individuals (two to eleven) including those who showed different genotypes on SSCP are subjected for direct sequencing using big-dye terminator chemistry, on ABI Prism 310 sequencers. Multiple sequence trace files obtained from ABI Prism 310 are processed and aligned by Phred/Phrap and viewed using Consed viewer. SNPs are identified by PolyPhred software and visual inspection.
- KYUGEN In yet another method identified as KYUGEN (Method2), individuals with different genotypes are searched by denaturing HPLC (DHPLC) or PLACE-SSCP (Inazuka et al, 1997) and their sequences are determined to identify SNPs. PCR is performed with primers tagged with 5'-ATT or 5'-GTT at their ends for post-labeling of both strands. DHPLC analysis is carried out using the WAVE DNA fragment analysis system (Transgenomic). PCR products are injected into DNASep column, and separated under the conditions determined using WAVEMaker program (Transgenomic).
- the reaction is stopped by adding EDTA, and unincorporated nucleotides are dephosphorylated by adding calf intestinal alkaline phosphatase.
- SSCP followed by electrophoresis is performed in a capillary using an ABI Prism 310 Genetic Analyzer. Genescan softwares (P-E Biosystems). DNA of individuals including those who showed different genotypes on DHPLC or SSCP are subjected for direct sequencing using big-dye terminator chemistry, on ABI Prism 310 sequencer.
- SNPs are identified by PolyPhred software and visual inspection. Trace chromatogram data of EST sequences in Unigene are processed with PHRED. To identify likely SNPs, single base mismatches are reported from multiple sequence alignments produced by the programs PHRAP, BRO and POA for each Unigene cluster. BRO corrected possible misreported EST orientations, while POA identified and analyzed non-linear alignment structures indicative of gene mixing/chimeras that might produce spurious SNPs.
- Bayesian inference is used to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing; sequencing error rates; context-sensitivity; cDNA library origin, etc.
- the therapeutic compounds of the present disclosure may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, intraperitoneal, etc.).
- the active compounds may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. They may also be administered by continuous perfusion/infusion of a disease or wound site.
- the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
- suitable diluents include saline and aqueous buffer solutions.
- Liposomes include water-in- oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al, 1984).
- the therapeutic compound may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally.
- Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
- 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.
- the composition must be sterile and must be fluid to the extent that easy syringability 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 (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the 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, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
- Sterile injectable solutions can be prepared by incorporating the therapeutic 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 incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
- the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
- the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
- Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
- the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.
- Active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient.
- the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in humans, such as the model systems shown in the examples and drawings.
- the actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.
- An effective amount typically will vary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 10.0 mg/kg to about 150 mg/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above).
- Other suitable dose ranges include 1 mg to
- 10000 mg per day 100 mg to 10000 mg per day, 500 mg to 10000 mg per day, and 500 mg to
- the amount is less than 10,000 mg per day with a range of 750 mg to 9000 mg per day.
- the effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day or less than 10 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 200 mg/kg/day.
- the unit dosage may be an amount that reduces blood glucose by at least 40% as compared to an untreated subject.
- the unit dosage is an amount that reduces blood glucose to a level that is ⁇ 10% of the blood glucose level of a non-diabetic subject.
- a dose may also comprise from about 1 micro- gram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
- a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc. can be administered, based on the numbers described above.
- a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a compound of the present disclosure.
- the compound of the present disclosure may comprise between about 2% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.
- Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agent is administered once a day.
- the agent(s) may be administered on a routine schedule.
- a routine schedule refers to a predetermined designated period of time.
- the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
- the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks therebetween.
- the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
- the invention provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake.
- the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
- Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a compound of this invention, and the other includes the second agent(s).
- the therapy may precede or follow the other agent treatment by intervals ranging from minutes to months.
- A represents the first agent (e.g., DFMO) and "B” represents a secondary agent (e.g., sulindac), non- limiting examples of which are described below:
- CRC-Specific Survival Experimental Design The study included 440 incident CRC cases from the population-based UC Irvine Gene -Environment Study of Familial CRC (diagnosed 1994- 1996 with follow-up through March 2008). The primary outcome was CRC-specific survival (CRC-SS) dependent on ODC genotype (GG vs. AA/GA). In human colon cancer cell lines, ODC allele-specific binding of E-box transcription factors was determined via western blotting and chromatin immunoprecipitation (CHIP) assays. ODC allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MADl.
- Tumor, node, metastasis (TNM) staging determination was derived from existing AJCC codes where available and conversion of extent of disease codes, as previously reported (Le et al., 2008).
- Family history of cancer in a first-degree relative was ascertained by self-reporting during a telephone interview conducted at enrollment (ZeIl et al., 2008; Ziogas and Anton-Culver, 2003).
- the median time from CRC diagnosis until study entry i.e., date of family history interview was 16 months (95% CI 12-23 months).
- DNA extraction and ODC +316 SNP genotyping DNA was extracted from 2.0 mL red blood cell clot samples using the QIAGEN QIAamp DNA Midi or Mini Kits, (Qiagen) following the manufacturer's instructions. Genotyping of the ODC +316 SNP was conducted using oligonucleotide primers designed to amplify a 172-bp fragment containing the polymorphic base at +316 (Applied Biosystems, Foster City, CA). Allele-specif ⁇ c TaqMan probes were synthesized with different 5 ' labels (6-carboxyflourescein or VIC) and the same 3' quencher dye (6-carboxytetramethylrhodamine) (23).
- Each PCR reaction (5 ⁇ L total) contained 10 ng of participant DNA, 30 pmol of each primer, 12.5 pmol of each TaqMan probe, and Ix TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA), as previously reported (Martinez et ah, 2003; Guo et ah, 2000).
- Cox proportional hazards modeling was performed for all CRC cases, colon cancer cases, and rectal cancer cases using time since diagnosis to profile the adjusted risk of overall and CRC-specific death based on ODC genotype.
- ODC genotype GG, GA, or AA
- the effects of ODC genotype (GG, GA, or AA) on survival were analyzed in the Cox models with adjustment for the following covariates: age, gender, ethnicity, family history of CRC, TNM stage at diagnosis, tumor site within the colon, histologic subtype, treatment with surgery, radiation therapy, and chemotherapy. Each variable in the model was coded using dummy variables. All analyses were conducted using SAS 9.2 statistical software (SAS Institute, Cary, NC). Statistical significance was assumed for a 2-tailed P value ⁇ 0.05.
- the human colon cancer cell lines HT29 and HCTl 16 were maintained in McCoy's 5 A medium (Invitrogen, Carlsbad, CA). All media used were supplemented with 10% FBS plus 1% penicillin/streptomycin solution (Invitrogen, Carlsbad, CA). Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2.
- Genotyping assay DNA samples from HT29 and HCTl 16 cells were subjected to a PCR-RFLP procedure to detect the polymorphic Pstl site. Sequences were amplified by PCR, using the following primers: 5'- TCTGCGCTTCCCCATGGGGCT-3' (SEQ ID NO:1) and 5'-TTTCCCAACCCTTCG-3' (SEQ ID NO:2). Each reaction contained - 1 ⁇ l DNA, 4 pmol of each primer, 12.5 ⁇ l 2x PCR PreMixes buffer "G” (EPICENTRE Biotechnologies, Madison, WI) and 0.5 unit of Taq DNA polymerase, in a final volume of 25 ⁇ l. The expected size of the PCR product was 351 bp.
- Chemiluminescent detection was conducted using ECL Western Detection reagent (Amersham Biosciences, Piscataway, NJ) and exposed on Biomax XAR film (Kodak). Chromatin immunoprecipitation (CHIP). CHIP assays were performed using a commercial kit, as recommended by the manufacturer (Upstate Biotech, Lake Placid, NY, USA). Briefly, cells were treated with 1% formaldehyde to crosslink DNA and proteins, and DNA-protein complexes were disrupted by sonication to lengths between 200 to 1000 bp. Lysates were diluted 10-fold with immunoprecipitation (IP) dilution buffer containing protease inhibitors.
- IP immunoprecipitation
- Antibodies for c-MYC, MADl and MAD4 were used to precipitate chromatin, while additional sample was left as a minus-antibody (-Ab) control. Samples were immunoprecipitated overnight at 4oC with rotation. Immune complexes were obtained by adding 60ul of salmon sperm DNA/protein A Agarose slurry and incubating for an hour at 4oC with rotation followed by gentle centrifugation (1000 rpm, 1 min). Protein A agarose pellets were washed with low salt buffer, high salt buffer, LiCl buffer and TE buffer.
- Quantitative real-time PCR was performed using TaqMan gene expression assays kit (Applied Biosystems, Foster City, CA) on an ABI7700 sequence detection system. Details for the computation of relative binding can be found on the manufacturer's web site (http://www.appliedbiosystems.com/).
- Transient transfections were preformed using LipofectAMINE reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's protocol, as detailed in the supplementary file.
- HCTl 16 and HT29 cells were transfected with 1 ⁇ g of pGL3-ODC/A or pGL3-ODC/G plasmids (Martinez et al, 2003) along with 0.01 ⁇ g of Renilla-TK plasmid.
- the Renilla-TK plasmid was purchased from Promega (Madison, WI) and used as a transfection efficiency control in all promoter-reporter transfection experiments.
- ODC pGL3 -plasmids were co-transfected with either pcDNA 3.0 or QMS -c-MYC expression vector (OriGene, Rockville, MD).
- MADl the ODC plasmids were co-transfected with either pcDNA 3.1 or pcDNA- MADl.
- ODC promoter reporter constructs were prepared which contain the first 1.6 Kb of the ODC gene cloned into a pGL3 vector. The constructs included E-box 1 (-485 to -480 bp) intact (wt E-box 1) or deleted (mut E-box 1).
- both variants of the +316 ODC SNP were used, creating a total of 4 different constructs.
- cells were supplemented with complete medium containing 20% FBS and left to grow overnight. The next day after transfection 20% FBS- containing complete medium was replaced with 10% FB S -containing medium.
- 48 hours after transfection cells were washed with PBS and lysed in Passive Lysis Buffer from the Dual Luciferase Assay kit (Promega, Madison, WI). Dual luciferase activities were measured using a Turner Designs TD-20/20 luminometer, as described by the manufacturer, and presented as relative luciferase units (RLU) . Experiments were preformed in triplicates and repeated at least 2 times.
- RLU relative luciferase units
- two-sample t-tests were used to compare promoter activity between cells co-trans fected with pcDNA3.0 plasmid versus those transfected with the CMV -c-MYC expression vector.
- two-sample t-tests were used to compare the effect of promoter activity in promoter constructs co-transfected with pcDNA3.1 plasmid versus those transfected with pcDNA-M4Di plasmid.
- Statistical significance was assumed for a 2-tailed P value ⁇ 0.05.
- DSMB Data Safety Monitoring Board
- ODCl (rs2302615) genotyping was conducted on patient-derived genomic DNA using allele-specific TaqMan probes as described previously (Guo et ah, 2000). Rectal tissue polyamine content was determined as described previously (Meyskens et ah, 1998; Seiler and Knodgen, 1980), using 3 of 8 randomly selected rectal mucosal biopsy specimens. Tissue polyamine response was performed for response values ranging from 25% to 45%.
- ODCl genotype was analyzed under a dominant model: AA/GA vs. GG patients. Wilcoxon Rank Sums tests were performed on non-normally distributed continuous variables across two genotype groups. Chi-square tests or Fisher's Exact Test were utilized to assess the association between baseline categorical variables and genotype group. Log binomial regression was performed on the primary outcome (adenoma recurrence) with predictors: treatment group, age, gender, race (Caucasian vs. other), aspirin usage, ODCl genotype (in the dominant model), and a term representing the treatment by genotype interaction.
- ODCl genotype distribution was: 126 GG (55%), 87 GA (38%), and 15 AA (7%). Baseline clinical characteristics revealed differences, as shown in Table 1.
- the relative risk (RR) for adenoma recurrence related to treatment after adjustment in the full regression model was 0.39 (95% CI 0.24-0.66).
- RR relative risk
- ⁇ Cardiovascular events included coronary artery disease, myocardial infarction, cerebrovascular accident, congestive heart failure, and chest pain.
- ⁇ ' ' Gastrointestinal events included gastrointestinal bleeding (from any region) such as rectal bleeding, upper gastrointestinal bleeding, hematochezia, or occult blood in the stool.
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EP10775626.4A EP2430452B1 (en) | 2009-05-14 | 2010-05-14 | Carcinoma diagnosis and treatments, based on odc1 genotype |
SI201030738T SI2430452T1 (en) | 2009-05-14 | 2010-05-14 | Carcinoma diagnosis and treatments, based on odc1 genotype |
DK10775626.4T DK2430452T3 (en) | 2009-05-14 | 2010-05-14 | CARCINOM DIAGNOSIS AND TREATMENTS BASED ON ODC1 GENOTYPE |
CN201080031983.5A CN102483415B (en) | 2009-05-14 | 2010-05-14 | Based on the genotypic cancerous diagnose of ODC1 and treatment |
PL10775626T PL2430452T3 (en) | 2009-05-14 | 2010-05-14 | Carcinoma diagnosis and treatments, based on odc1 genotype |
CA2761946A CA2761946A1 (en) | 2009-05-14 | 2010-05-14 | Carcinoma diagnosis and treatment, based on odc1 genotype |
AU2010248803A AU2010248803B2 (en) | 2009-05-14 | 2010-05-14 | Carcinoma diagnosis and treatments, based on ODC1 genotype |
ES10775626.4T ES2507145T3 (en) | 2009-05-14 | 2010-05-14 | Diagnosis and treatment of carcinoma, based on the genotype of ODC1 |
JP2012511052A JP6083860B2 (en) | 2009-05-14 | 2010-05-14 | Cancer diagnosis and treatment based on the genotype of ODC1 |
IL216369A IL216369B (en) | 2009-05-14 | 2011-11-14 | Alpha-difluoromethylornithine for carcinoma diagnosis and treatment of patients with odc1 genotype |
HK12111787.0A HK1171082A1 (en) | 2009-05-14 | 2012-11-19 | Carcinoma diagnosis and treatments, based on odci genotype odc1 |
HRP20140887AT HRP20140887T1 (en) | 2009-05-14 | 2014-09-17 | Carcinoma diagnosis and treatments, based on odc1 genotype |
SM201400177T SMT201400177B (en) | 2009-05-14 | 2014-11-21 | Diagnosis and treatment of carcinoma based on the odc1 genotype |
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JP (2) | JP6083860B2 (en) |
CN (1) | CN102483415B (en) |
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US9121852B2 (en) | 2009-05-14 | 2015-09-01 | Arizona Board Of Regents On Behalf Of University Of Arizona | Carcinoma diagnosis and treatment, based on ODC1 genotype |
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PL2430452T3 (en) | 2014-12-31 |
US8329636B2 (en) | 2012-12-11 |
JP2016074672A (en) | 2016-05-12 |
US20100317708A1 (en) | 2010-12-16 |
CA2761946A1 (en) | 2010-11-18 |
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AU2010248803B2 (en) | 2014-05-29 |
EP2430452A4 (en) | 2013-03-06 |
AU2010248803A1 (en) | 2011-12-01 |
US9121852B2 (en) | 2015-09-01 |
HRP20140887T1 (en) | 2014-11-21 |
PT2430452E (en) | 2014-09-30 |
CN102483415A (en) | 2012-05-30 |
EP2430452A1 (en) | 2012-03-21 |
SI2430452T1 (en) | 2014-11-28 |
IL216369B (en) | 2018-07-31 |
JP2012526852A (en) | 2012-11-01 |
EP2430452B1 (en) | 2014-06-25 |
CN102483415B (en) | 2015-09-09 |
ES2507145T3 (en) | 2014-10-14 |
US9937141B2 (en) | 2018-04-10 |
JP6083860B2 (en) | 2017-02-22 |
IL216369A0 (en) | 2012-01-31 |
US20190038584A1 (en) | 2019-02-07 |
HK1171082A1 (en) | 2013-03-15 |
US20160213634A1 (en) | 2016-07-28 |
SMT201400177B (en) | 2015-01-15 |
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