No abstract

Truly elderly people comprise an increasingly large fraction of the population and consume a disproportionate amount of drugs. Over the last 25 years a number of different studies have illustrated that advancing age is associated with adverse drug reactions (ADRs). Advancing age is also associated with polypharmacy and multiple pathology, and this complex inter-relationship makes it difficult to conclude that age itself is a causative factor for ADRs. ADRs resulting in hospital admission have been the subject of study for many years, but it has not been consistently demonstrated that advancing age is a predisposing factor. Early studies used the method of intensive inpatient monitoring and identified digoxin, diuretics, aspirin, psychotropics and cytotoxics as drugs of concern. Smaller more recent studies have used more sophisticated statistical techniques to identify predisposing factors. Nonsteroidal anti-inflammatory drugs have been added to the list of drugs that may cause ADR-related hospital admission. Polypharmacy, and altered pharmacokinetics and pharmacodynamics are possible causative factors; however, variable compliance and multiple pathology may cause difficulties with attributing causality. Some basic guidelines for sensible prescribing would almost certainly result in fewer ADRs in the elderly, including those ADRs severe enough to result in hospital admission.

No abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) including sulindac have shown potent chemopreventive and tumor regressive effects against colorectal cancer, the second leading cause of cancer death in the United States. However, the mechanisms by which sulindac inhibits tumor cell growth are not completely understood. We previously reported that sulindac metabolites inhibit the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ ERK) signaling cascade in colorectal cancer cell lines at doses that induce apoptosis, and inhibition of MEK/ERK activity with U0126 is sufficient to induce apoptotic cell death. To determine whether inhibition of MEK/ ERK activity is necessary for sulindac-induced apoptosis of human colon cancer cells, stable transfectants were created that express an activated MEK1 gene in HT29 cells. HT29-MEK1(R4F) clones displayed a 10-to 20-fold increase in MEK1 activity compared with control HT29-pCEP4 clones. When compared with control HT29-pCEP4 clones, HT29-MEK1(R4F) clones were resistant to both apoptosis and inhibition of ERK1/2 phosphorylation induced by sulindac metabolites. These results suggest that inhibition of MEK/ERK signaling is necessary for the induction of apoptosis by sulindac metabolites.

Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal antiinflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP -dependent protein kinase (PKG); (b) activate c-jun NH 2 -terminal kinase (JNK); (c) inhibit extracellular signal -regulated kinase 1/2 (ERK1/2); and (d) decrease B-catenin protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if PKG, ERK1/2, JNK, and B-catenin are independent targets for sulindac in vitro. Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or B-catenin protein expression. Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate B-catenin protein expression. Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and B-catenin. These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and death rate from colorectal cancer. [Mol Cancer Ther 2006;5(3):746 -54]