ABSTRACT
We previously showed that adhesion of myeloma cells to fibronectin (FN) by means of beta1 integrins causes resistance to certain cytotoxic drugs. The study described here found that adhesion of U937 human histiocytic lymphoma cells to FN provides a survival advantage with respect to damage induced by the topoisomerase (topo) II inhibitors mitoxantrone, doxorubicin, and etoposide. Apoptosis induced by a topo II inhibitor is thought to be initiated by DNA damage. The neutral comet assay was used to determine whether initial drug-induced DNA damage correlated with cellular-adhesion-mediated drug resistance. Cellular adhesion by means of beta1 integrins resulted in a 40% to 60% reduction in mitoxantrone- and etoposide-induced DNA double-strand breaks. When the mechanisms regulating the initial drug-induced DNA damage were examined, a beta1 integrin-mediated reduction in drug-induced DNA double-strand breaks was found to correlate with reduced topo II activity and decreased salt-extractable nuclear topo IIbeta protein levels. Confocal studies showed changes in the nuclear localization of topo IIbeta; however, alterations in the nuclear-to-cytoplasmic ratio of topo IIbeta in FN-adhered cells were not significantly different. Furthermore, after a high level of salt extraction of nuclear proteins, higher levels of topo IIbeta-associated DNA binding were observed in FN-adhered cells than in cells in suspension. Together, these data suggest that topo IIbeta is more tightly bound to the nucleus of FN-adhered cells. Thus, FN adhesion by means of beta1 integrins appears to protect U937 cells from initial drug-induced DNA damage by reducing topo II activity secondarily to alterations in the nuclear distribution of topo IIbeta.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Adhesion , DNA Damage , Drug Resistance, Neoplasm , Integrin beta1/physiology , Apoptosis , Cell Nucleus/metabolism , Cell Survival/drug effects , Comet Assay , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins , Doxorubicin/pharmacology , Etoposide/pharmacology , Fibronectins/metabolism , Humans , Mitoxantrone/pharmacology , Receptors, Fibronectin/physiology , Topoisomerase II Inhibitors , U937 CellsABSTRACT
Nonsteroidal antiinflammatory drug associated gastric ulcerations are often prepyloric and painless; when recurrent, such ulcers may lead to pyloric scarring and gastric outlet obstruction. We performed a retrospective case control study to seek an association between gastric outlet obstruction and nonsteroidal antiinflammatory drug use. The use of nonsteroidal antiinflammatory drugs in cases with gastric outlet obstruction was compared to an age- and sex-matched outpatient control group undergoing endoscopy. The proportion of drug use by patients with gastric outlet obstruction, seven of nine, was significantly higher than the proportion in controls, 29 of 90. The duration of nonsteroidal antiinflammatory drug use was also significantly longer in patients with gastric outlet obstruction than in control patients. Chronic nonsteroidal antiinflammatory drug use is associated with gastric outlet obstruction.
