The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons

Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/ checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs

Oxaliplatin in the treatment of colorectal cancer

Significant advances in the treatment of colorectal cancer have been observed over the past several years. With the introduction of oxaliplatin combined with infusional 5-fluorouracil and leucovorin, survival for patients with metastatic colorectal cancer has nearly doubled. The incorporation of biologic agents that target angiogenesis (bevacizumab) and tumor growth pathways (cetuximab, panitumimab) extends survival even further, in addition to increasing response rates in patients with metastatic disease. The benefit of these newer drugs is also being realized in the adjuvant setting, where the addition of oxaliplatin to infusional 5-fluorouracil and leucovorin has led to improvements in 3-year disease-free survival. Future challenges with the use of oxaliplatin include defining strategies to optimize its use while avoiding treatment-limiting neurotoxicity and identification of markers predictive of response. © 2007 Informa UK Ltd

Pathogenesis and risk factors of small bowel adenocarcinoma: a colorectal cancer sibling?

Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features. The purpose of this article is to review pathogenesis and risks factors of SBA to better understand its molecular features as well as its resemblances and dissimilarities with colorectal cancer (CRC). Better understanding of sporadic and hereditary genetic pathways potentially involved will undoubtedly lead to better prevention and therapeutic management of this rare but aggressive disease.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

Medical management of pancreatic neuroendocrine tumors

BACKGROUND: Pancreatic neuroendocrine tumors (PNET) are rare malignancies frequently diagnosed at a late stage, with symptoms related to bulky disease. Hormonal secretion, when responsible for symptoms, permits, on the other hand, early diagnosis of the disease. Surgery remains the cornerstone of therapeutic management. However, due to advanced disease, many patients are not candidates for aggressive surgical therapy. Tumor growth control and symptom management are thus achieved through medical approaches, including somatostatin (SST) analogs, chemotherapy, interferon, and more recently, targeted therapy. The purpose of this review is to collect, examine, and analyze data available in the literature regarding contemporary therapeutic management of PNET, with emphasis on medical approaches. It also offers perspectives on the future of molecular targeted therapies in these neoplasms. However, we point out that much of the literature published to date includes noncomparative studies (mainly phase II studies), leading to thorny interpretation of the results. METHODS: A systematic search of all the literature in English regarding PNET was performed, based on a MEDLINE search (Pubmed) carried out from January 1970 to May 2005. RESULTS: Approximately 40 trials, including over 1,000 patients, have been retrieved from our MEDLINE search. SST analogs and interferon therapies do allow control over hormone secretion and subsequent symptoms in the majority of treated subjects, but offer a poor tumor growth control rate. Chemotherapies, although more efficient in reducing tumor burden, are often toxic. New approaches such as immunotherapy and targeted therapies are still under investigation. CONCLUSIONS: Whether alone or in combination with surgery, conventional medical therapies represent a crucial aspect of PNET management. Hopefully, in the near future, a new era of antitumoral agents, such as targeted therapies, will strengthen our therapeutic arsenal, either alone or combined with other therapies. © 2008 by Am. Coll. of Gastroenterology.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors constitute a heterogeneous group of neoplasms that are often associated with typical symptoms due to excessive and uncontrolled release of diverse hormones. Because these tumors are usually slow growing, surgery is the cornerstone of treatment. However, these rare tumors can present with rapid progression that requires aggressive systemic therapy or diffuse metastatic disease not amenable to surgical palliation. For most patients, medical approaches are necessary at some point in the course of their disease, especially since most tumors are at an advanced stage at the time of diagnosis. Most gastroenteropancreatic neuroendocrine tumors express high levels of somatostatin receptors, which are bound by somatostatin or its synthetic analogues. These agents, alone or combined with other therapies, such as Interferon or radioisotopes, are therefore used frequently to control hormone-related symptoms and, for some patients, the growth of the disease Itself. This article reviews the evidence for the use of somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors based on a MEDLINE search of literature published from January 1970 to July 2003.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Development of Rational Drug Combinations with Investigational Targeted Agents

This manuscript explores specific examples and criteria in which an alternative regulatory process to the existing combination rule would be appropriate and feasible and thus could be adopted by developers