Weak base drug-induced endolysosome iron dyshomeostasis controls the generation of reactive oxygen species, mitochondrial depolarization, and cytotoxicity.

Objectives: Approximately 75 % of marketed drugs have the physicochemical property of being weak bases. Weak-base drugs with relatively high pKa values enter acidic organelles including endosomes and lysosomes (endolysosomes), reside in and de-acidify endolysosomes, and induce cytotoxicity. Divalent cations within endolysosomes, including iron, are released upon endolysosome de-acidification. Endolysosomes are "master regulators of iron homeostasis", and neurodegeneration is linked to ferrous iron (Fe2+)-induced reactive oxygen species (ROS) generation via Fenton chemistry. Because endolysosome de-acidification-induced lysosome-stress responses release endolysosome Fe2+, it was crucial to determine the mechanisms by which a functionally and structurally diverse group of weak base drugs including atropine, azithromycin, fluoxetine, metoprolol, and tamoxifen influence endolysosomes and cause cell death. Methods: Using U87MG astrocytoma and SH-SY5Y neuroblastoma cells, we conducted concentration-response relationships for 5 weak-base drugs to determine EC50 values. From these curves, we chose pharmacologically and therapeutically relevant concentrations to determine if weak-base drugs induced lysosome-stress responses by de-acidifying endolysosomes, releasing endolysosome Fe2+ in sufficient levels to increase cytosolic and mitochondria Fe2+ and ROS levels and cell death. Results: Atropine (anticholinergic), azithromycin (antibiotic), fluoxetine (antidepressant), metoprolol (beta-adrenergic), and tamoxifen (anti-estrogen) at pharmacologically and therapeutically relevant concentrations (1) de-acidified endolysosomes, (2) decreased Fe2+ levels in endolysosomes, (3) increased Fe2+ and ROS levels in cytosol and mitochondria, (4) induced mitochondrial membrane potential depolarization, and (5) increased cell death; effects prevented by the endocytosed iron-chelator deferoxamine. Conclusions: Weak-base pharmaceuticals induce lysosome-stress responses that may affect their safety profiles; a better understanding of weak-base drugs on Fe2+ interorganellar signaling may improve pharmacotherapeutics.

Observations of aggressive, small, flat, and depressed colon cancer. Report of three cases.

Three cases of small, flat, and depressed colon cancers are reported. One lesion is less than 1 cm in diameter with lymphatic invasion in the submucosa; the other measures 0.8 cm in the longest dimension and penetrates through the muscular layers to the subserosa. The third one, 1.2 cm in diameter, has had liver metastasis. The endoscopic appearances of two lesions with a resected specimen are presented in color to demonstrate some difficulties in visualizing these lesions for endoscopists. The biologic aggressiveness of these three lesions appears due to their rapid growth, which is expressed by a high mitotic rate of the cancer cells. Their histogenesis is considered to derive from (1) flat adenoma, from (2) serrated adenoma, and (3) from hyperplastic epithelium (or de novo in origin), respectively.

The spread of upper gastrointestinal endoscopy in Japan and the United States. An international comparative analysis of technology diffusion.

The use of upper gastrointestinal (GI) fiberoptic endoscopy has spread at different times and rates in Japan than in the United States. Factors that explain this disparity and its effects on patient outcomes are reported. This essay outlines Japanese data in gastroenterology, giving an account of the resources and time that were spent on the development of upper GI endoscopy in Japan. It also draws implications for the assessment of endoscopy for populations at high risk for gastric cancer.

Fast-growing cancer of the colon and rectum.

Recently, the existence of a flat, colorectal cancer has been proposed. This cancer is completely different in appearance from ordinary polyp cancer and is believed to invade deeply into the submucosa, even in its early stages. Its characteristics are quite different from cancers that follow the adenoma-cancer sequence, and it requires a greater search to detect. The authors observed four cases of fast-growing cancer that were relatively flat in appearance, contained no adenomatous component, and were invasive, even in their early stages.

Gardner syndrome: study and follow-up of a family.

A study is in progress of a family (Family P) with Gardner syndrome (familial adenomatous polyposis with extraintestinal manifestations-FAPG). Occult bone lesions of the jaws and ocular fundus lesions were found in a number of affected and at-risk relatives. In some, these "markers" were found early in life before the appearance of colonic polyps. Family P is remarkable for differences in expression of the gene manifested by differences in the age-at-onset of polyps of the colon, in number and size of polyps, and in occurrence of desmoids. These differences may explain why some at-risk relatives wisely followed medical surveillance plans while others, who lacked symptoms, failed to do so. Others without medical guidance undertook their own independent "treatment." As knowledge about extracolonic lesions has increased and surgical treatment for FAPG improved from the time the first affected member of Family P received her diagnosis in 1953, the outlook for survival has also improved. Family communication and that among professionals treating families with FAPG may be improved as worldwide Polyposis Registries increase in number. The risk of postsurgical extraintestinal complications is reason enough to urge life-long medical surveillance for all at-risk relatives.

Effect of sodium amylosulfate (Depepsen) on the healing of duodenal ulcer.

Thirty-five patients with active duodenal ulceration were included in a double blind randomized trial, the antiulcer agent sodium amylosulfate (Depepsen), being compared with placebo. Diagnosis and healing were determined by duodenoscopy. Results showed, in the whole series, 13 of 18 patients treated with Depepsen healed, whereas 10 of 17 healed on placebo (P = 0.04). In the group of 23 outpatients, 6 of 11 healed on Depepsen, and 5 of 12 healed on placebo (P = 0.55). It was concluded that Depepsen did not accelerate the healing of duodenal ulcer.