Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.
Inflammation and Methylation ChangesChanges in the genome which result in cancer promotion remain a complex interplay of aberrant methylation in the setting of a multitude of epigenetic changes. The events leading to these disruptions in methylation have been postulated; though remain to be fully elucidated. A causal relationship between inflammation and cancer has long been accepted in multiple tumor types, most prominently colon cancer; an association supported by the evidence that non-steroidal anti-inflammatory medications can potentially stop the development of colon cancer. Investigations in patients with ulcerative colitis who have a predisposition to the development of colon cancer have established a potential link between inflammation and cancer by the demonstration of hypermethylated gene promoters in early dysplastic lesions. 1 The mechanisms responsible for the contribution of inflammation to cancer remain to be fully understood. Mutagenesis resulting from the production of halogenated nucleotide precursors in activated neutrophils and eosinophils with subsequent incorporation into DNA has been demonstrated in vitro. 2,3 The link between inflammation-induced halogenated nucleotides and aberrant methylation stems from the demonstration that methyl-binding proteins cannot distinguish between methylated cytosine residues and chlorinated or brominated cytosine nucleotides. Furthermore, DNMT1 also could not distinguish between 5-methylcytosine and some 5-halocytosine products which could potentially result in mistaken methylation at sites of inflammation. 4 These halogenated cytosine residues were not recognized by DNA repair enzymes suggesting the possibility of accumulation of heritable changes within the genome.Infection with Helicobacter pylori has been implicated in the development of gastric cancer with a relative risk increase of 2.2-to 6 fold when infection is detected. 5-8 The mechanism of cancer development in this setting has been attributed to inflammation leading to cell proliferation resulting in a propensity for gene mutation. Aberrant methylation due to H. pylori infection has been suggested as an additional mechanism bridging the gap between inflammation and cancer. In a series of 154 healthy volunteers and 72 patients with gastric cancer, methylation of 8 regions of 7 CpG islands was assessed. 14 Among the healthy volunteers, the extent of DNA methylation was 5.4-to 303-times higher in the H. pylori positive cases compared to the H. pylori negative cases (p<0.0001) suggesting an increase in methylation levels due to the presence of H. pylori. However, the comparison of methylation levels between healthy volunteers and patients with gastric cancer stratified by H. pylori status
The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans.
Mitosis is a complex process resulting in division of a cell into two daughter cells, and its failure often results in the death of the daughter cells (via apoptotic, necrotic, or proliferative/senescent death). Many chemicals that inhibit the mitotic process (anti-mitotic drugs) have proven effective for killing cancer cells in vitro and in clinical settings. Among the most studied anti-mitotic drugs are plant-origin natural products including taxanes (e.g. paclitaxel, docetaxel) and vinca alkaloids (e.g. vincristine, vinblastine), whose validated target is the spindle microtubules. With the success of these agents, efforts have been made to develop other spindle poisons as well as to improve efficacy of existing spindle poisons with structural modifications. Novel drugs and natural products that inhibit other proteins involved in mitosis (nonmicrotubule targets) have been sought in hopes of expanding available cancer-directed therapies. Recently, significant advances have been made in the understanding of mitotic mechanisms in tumor cells as well as in normal epithelial cells. These advances help us to identify and develop potential natural agents for the prevention and treatment of cancer. This review will focus on natural products that target mitotic process and/or proteins involved in mitotic progression.
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