Functional enhancers at the gene-poor 8q24 cancer-linked locus.

PLoS Genet. 2009 Aug;5(8):e1000597

Authors: Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff P, Oh W, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman M, Tanay A, Coetzee GA

Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

PMID: 19680443 [PubMed - in process]

Read Full Article pubmed: colon cancer

S-1: a new oral fluoropyrimidine in the treatment of patients with advanced non-small-cell lung cancer.

Clin Lung Cancer. 2009 Jul;10(4):290-4

Authors: Okamoto I, Fukuoka M

S-1 (also known as TS-1; Taiho Pharmaceutical Co. Ltd.; Tokyo, Japan) is a new oral fluoropyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1. Single-agent S-1 has demonstrated marked activity against non-small-cell lung cancer (NSCLC) as well as a broad array of other solid tumors, including gastric, colorectal, breast, cervical, and pancreatic cancers. This comprehensive review summarizes the results of previous clinical studies and describes ongoing clinical trials of S-1 in advanced NSCLC. S-1 combined with platinum compounds, irinotecan, and gemcitabine has produced promising results in terms of feasibility, safety, and effectiveness. Available data have stimulated further research, including phase III trials for the first-line treatment of advanced NSCLC.

Malignant pleural mesothelioma: medical treatment update.

Clin Lung Cancer. 2009 Mar;10(2):112-7

Authors: Vorobiof DA, Mafafo K

Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available.

Influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival.

Can J Surg. 2009 Aug;52(4):E79-E86

Authors: Simunovic M, Rempel E, Thériault ME, Baxter NN, Virnig BA, Meropol NJ, Levine MN

BACKGROUND: There has been minimal research on the influence of delays for cancer treatments on patient outcomes. We measured the influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival.

METHODS: We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare databases (1993-1996) to identify patients who underwent nonemergent colon cancer surgery. We assessed 2 time intervals: surgeon consult to hospital admission for surgery and first diagnostic test for colon cancer to hospital admission. Follow-up data were available to the end of 2003. We selected the time intervals to create patient groups with clinical relevance and they did not extend past 120 days.

RESULTS: We identified 7989 patients who underwent nonemergent colon cancer surgery. Median delays from surgeon consult to admission and from first diagnostic test to admission were 7 and 17 days, respectively. The odds of operative mortality were similar if the consult-to-admission interval was 22 days or more versus 1-7 days (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.6-1.8, p = 0.91) or if the test-to-admission interval was 43 days or more versus 1-14 days (OR 0.8, 95% CI 0.4-1.5, p = 0.51), respectively. For these same respective interval comparisons, disease-specific survival was not influenced by the consult-to-admission wait (hazard ratio [HR] 1.0, 95% CI 0.9-1.2, p = 0.91) or the test-to-admission wait (HR 1.0, 95% CI 0.8-1.1, p = 0.63). The risk of death was slightly greater if the consult-to-admission interval was 22 or more days versus 1-7 days (HR 1.1, 95% CI 1.0-1.2, p = 0.013) and if the test-to-admission interval was 43 days or more versus 1-14 days (HR 1.2, 95% CI 1.1-1.3, p = 0.003). CONCLUSION: It is unlikely that delays to nonemergent colon cancer surgery longer than 3 weeks from initial surgical consult or longer than 6 weeks from first diagnostic test negatively impact operative mortality, disease-specific survival or overall survival.

PMID: 19680502 [PubMed - as supplied by publisher]

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Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy.

PLoS One. 2009;4(5):e5735

Authors: Lubin M, Lubin A

BACKGROUND: The gene for methylthioadenosine phosphorylase (MTAP) lies on 9p21, close to the gene CDKN2A that encodes the tumor suppressor proteins p16 and p14ARF. MTAP and CDKN2A are homozygously co-deleted, with a frequency of 35 to 70%, in lung and pancreatic cancer, glioblastoma, osteosarcoma, soft-tissue sarcoma, mesothelioma, and T-cell acute lymphoblastic leukemia. In normal cells, but not in tumor cells lacking MTAP, MTAP cleaves the natural substrate, 5'-deoxy-5'-methylthioadenosine (MTA), to adenine and 5-methylthioribose-1-phosphate (MTR-1-P), which are then converted to adenine nucleotides and methionine. This distinct difference between normal MTAP-positive cells and tumor MTAP-negative cells led to several proposals for therapy. We offer a novel strategy in which both MTA and a toxic adenine analog, such as 2,6-diaminopurine (DAP), 6-methylpurine (MeP), or 2-fluoroadenine (F-Ade), are administered. In MTAP-positive cells, abundant adenine, generated from supplied MTA, competitively blocks the conversion of an analog, by adenine phosphoribosyltransferase (APRT), to its active nucleotide form. In MTAP-negative tumor cells, the supplied MTA cannot generate adenine; hence conversion of the analog is not blocked.

PRINCIPAL FINDINGS: We show that this combination treatment--adenine analog plus MTA--kills MTAP-negative A549 lung tumor cells, while MTAP-positive human fibroblasts (HF) are protected. In co-cultures of the breast tumor cell line, MCF-7, and HF cells, MCF-7 is inhibited or killed, while HF cells proliferate robustly. 5-Fluorouracil (5-FU) and 6-thioguanine (6-TG) may also be used with our strategy. Though neither analog is activated by APRT, in MTAP-positive cells, adenine produced from supplied MTA blocks conversion of 5-FU and 6-TG to their toxic nucleotide forms by competing for 5-phosphoribosyl-1-pyrophosphate (PRPP). The combination of MTA with 5-FU or 6-TG, in the treatment of MTAP-negative tumors, may produce a significantly improved therapeutic index.

CONCLUSION: We describe a selective strategy to kill tumor cells lacking MTAP.

PMID: 19478948 [PubMed - indexed for MEDLINE]

Read Full Article pubmed: mesothelioma

Related Articles The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews.

BMC Cancer. 2009 Jul 29;9(1):256

Authors: Lee PN, Hamling J

ABSTRACT:BACKGROUND: Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60-80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.

Three Epigenetic Drugs Up-regulate Homeobox Gene Rhox5 in Cancer Cells through Overlapping and Distinct Molecular Mechanisms.

Mol Pharmacol. 2009 Aug 13;

Authors: Li Q, Bartlett DL, Gorry MC, O'Malley ME, Guo ZS

Epigenetic therapy of cancer utilizing inhibitors of DNA methyltransferases (DNMT) or/and histone deacetylases (HDAC) have shown promising results in preclinical models and are being investigated in clinical trials. Homeodomain proteins play important roles in normal development and carcinogenesis. In this study, we demonstrated for the first time that an epigenetic drug could upregulate homeobox genes in the Rhox family, including murine Rhox5, Rhox6, Rhox9 and human RhoxF1, RhoxF2 in breast, colon and other types of cancer cells. We examined the molecular mechanisms underlining selective induction of Rhox5 in cancer cells by three epigenetic drugs, 5-aza-2'-deoxycytidine (DAC; decitabine), arsenic trioxide (ATO) and MS-275 (entinostat). DAC induced Rhox5 mRNA expression from both distal and proximal promoters, while MS-275 and ATO induced gene expression from the distal promoter (Pd) only. DAC and ATO inhibited both DNMT1 and DNMT3B protein expression, while MS-275 significantly reduced DNMT3B protein. In contrast to DAC, neither MS-275 nor ATO induced DNA demethylation on the Pd region. All three drugs led to enhanced acetylation of histones H3 and H4 at the promoter region. The occupancy of the activating histone mark dimethylated lysine 4 of H3 (H3K4Me2) at Pd was enhanced by DAC and MS-275, but not ATO. Based on the fact that they modulate gene expression with different potencies through shared and distinct epigenetic mechanisms, these epigenetic drugs may possess great potential in different applications for epigenetic therapy of cancer and other diseases.

PMID: 19679824 [PubMed - as supplied by publisher]

Read Full Article pubmed: colon cancer