Chemoprevention strategies for pancreatic cancer.

Pancreatic cancer has a poor prognosis and is often diagnosed at an advanced stage, which makes it difficult to treat. The low survival rate of patients with pancreatic cancer points towards an increased need for novel therapeutic and chemopreventive strategies and also early detection of this disease. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Synthetic and natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have demonstrated various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example, curcumin or resveratrol) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example, gemcitabine or erlotinib), which suggests that chemopreventive agents could potentially be used as potentiators of standard chemotherapy. Few clinical trials of pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead.

Sensitivity of breast cancer cell lines to recombinant thiaminase I.

PURPOSE: We have previously shown that the expression of the thiamine transporter THTR2 is decreased sevenfold in breast cancer, which may leave breast cancer cells vulnerable to acute thiamine starvation. This concept was supported by the observation that MDA231 breast cancer xenografts demonstrated growth inhibition in mice fed a thiamine-free diet. METHODS: We purified recombinant Bacillus thiaminolyticus thiaminase I enzyme, which digests thiamine, to study acute thiamine starvation in breast cancer. RESULTS: Thiaminase I enzyme was cytotoxic in six breast cancer cell lines with IC(50)s ranging from 0.012 to 0.022 U/ml. The growth inhibitory effects of the combination of thiaminase I with either doxorubicin or paclitaxel were also examined. Over a wide range of drug concentrations, thiaminase 1 was consistently synergistic or additive with doxorubicin and paclitaxel in MCF-7, ZR75, HS578T and T47D cell lines, with most combinations having a calculated combination index (CI) of less than 0.8, indicating synergy. Although thiaminase I exposure did not stimulate the energy-sensing signaling kinases AKT, AMPK and GSK-3beta in MCF-7, ZR75, HS578T and T47D cell lines, thiaminase I exposure did stimulate expression of the ER stress response protein GRP78. In summary, thiaminase I is cytotoxic in breast cancer cell lines and triggers the unfolded protein response. CONCLUSION: These findings suggest that THTR2 down-regulation in breast tumors may present a nutritional vulnerability that could be exploited by thiaminase I enzyme therapy.

Antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds.

OBJECTIVES: The objective of this work was to investigate the antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds. METHODS: The following tests were used: ulcers induced by ethanol, indometacin and HCl/ethanol, and pleurisy induced by carrageenan in Swiss albino rats. The rats were treated by the oral route with essential oil of P. emarginatus seeds. KEY FINDINGS: The essential oil at 100, 300 and 500 mg/kg exhibited significant protection against ulcers induced by ethanol, indometacin and HCl/ethanol (P < 0.001). The essential oil caused a marked reduction in the exudate volume and inhibited leucocyte and neutrophil influx (P < 0.05) in carrageenan-induced pleurisy. Moreover, the essential oil significantly decreased nitric oxide (NO) and interleukin-1 (IL-1) levels, without affecting tumour necrosis factor-alpha production. CONCLUSIONS: The results demonstrated the marked antiulcerogenic and anti-inflammatory effects of the essential oil from P. emarginatus, which are, at least in part, a consequence of NO and IL-1 modulation. P. emarginatus or its constituents might represent new therapeutic options to treat gastric ulcers and inflammatory diseases.

Farnesyltransferase inhibitors as anticancer agents: critical crossroads.

Farnesyltransferase (FT) inhibitors were originally designed as anticancer agents, and were thought to act by inhibiting the farnesylation of mutant Ras proteins. However, these compounds were subsequently demonstrated to have antitumor effects even in the absence of Ras mutations and it has now become clear that other protein targets are involved. This article discusses the preclinical and clinical development of FT inhibitors. To date, tipifarnib (Zarnestra; Janssen Pharmaceutica NV) and lonafarnib (Sarasar; Schering-Plough Research Institute) are the only two FT inhibitors to have been evaluated in phase III clinical trials. The clinical results of these two compounds are presented below, with emphasis on ways of enhancing the possibility of a successful FT inhibitor anticancer drug. Details of new FT inhibitors disclosed since the beginning of 2003 are also included.

New cytotoxic and molecular-targeted therapies of head and neck tumors.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on novel medical treatments for head and neck cancer. RECENT FINDINGS: Despite the continuing introduction of new cytotoxic agents, such as antimetabolites (capecitabine, pemetrexed), and topoisomerase I inhibitors, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor is an appealing target for novel therapies in head and neck cancer. Several rational approaches have been designed to abrogate epidermal growth factor receptor function, among which the development of small molecules, such as gefitinib or erlotinib, that inhibit tyrosine kinase activity, therefore abrogating the receptor's catalytic activity, autophosphorylation, and its engagement with signal transducers. The development of monoclonal antibodies, such as cetuximab, directed against the receptor's extracellular domain and competing for the binding of receptor ligands is another antireceptor strategy, because it induces epidermal growth factor receptor downregulation from the tumor cell surface. Gefitinib has been evaluated in a phase II study in head and neck cancer, at a dose of 500 mg/day. In this study, a 53% disease control rate was achieved, with a low toxicity. Currently, a phase II study at a dose of 250 mg/day is ongoing. A phase II study of erlotinib in advanced head and neck cancer has provided similar results to those of gefitinib, with a 46% control rate and an acceptable toxicity. Phase I studies of cetuximab have been carried out in advanced head and neck cancer, mainly combining the drug with chemotherapy or radiotherapy. Three phase II studies have evaluated the combination of cetuximab with platinum-based chemotherapy in pretreated patients with recurrent/metastatic head and neck cancer, with a control rate ranging from 29 to 66%. A phase III placebo-controlled trial has shown that the addition of cetuximab to cisplatin does not significantly improve median progression-free survival, despite a difference in the response rate between the two arms. Other molecular-targeted approaches in head and neck cancer include farnesyl transferase inhibitors, cell cycle regulators, and gene therapy. SUMMARY: Novel targeted therapies are highly appealing in advanced head and neck cancer, and the most clever way to use them is a matter of intense investigation.