Anthrapyrazole anticancer agents. Synthesis and structure-activity relationships against murine leukemias.

Chromophore modification of the anthracenediones related to mitoxantrone in an attempt to provide agents with diminished or no cardiotoxicity has resulted in a novel class of DNA binders, the anthrapyrazoles. Their synthesis was carried out by a two-stage condensation sequence starting from requisite 1,4- or 1,5-dichloro-9,10-anthracenedione precursors. Reaction with a monoalkylhydrazine gave a chloroanthrapyrazole intermediate whose subsequent condensation with primary or secondary alkylamines provided the target "two-armed" anthrapyrazoles. A-ring 7,10-dihydroxy anthrapyrazoles were derived from amine condensation with intermediate 5-chloro-7,10-dihydroxyanthrapyrazoles or, alternatively, from intermediate 5-chloro-7,10-bis(benzyloxy)anthrapyrazoles followed by hydrogenolysis of the benzyl protecting groups to provide the target compounds. Potent in vitro activity was demonstrated against murine L1210 leukemia in vitro (IC50 = 10(-7)-10(-8) M) as well as against P388 leukemia in vivo over a wide range of structural variants. In general, activity against the P388 line was maximized by basic side chains at N-2 and C-5, two to three carbon spacers between proximal and distal nitrogens of the side chain, and A-ring hydroxylation. Besides having curative activity against the P388 line, the more active compounds were curative against murine B-16 melanoma in vivo. On the basis of their exceptional in vivo anticancer activity, A-ring dihydroxy compounds 71 and 74 reported in this study have been selected for development toward clinical trials.

Effects of 24 hours of aspirin, Bufferin, paracetamol and placebo on normal human gastroduodenal mucosa.

Aspirin causes gastroduodenal erosions and/or ulcers in man when taken for prolonged periods. The effects of shorter periods of aspirin, Bufferin, or paracetamol (acetaminophen) intake as used for self-medication are unknown. In a four way, crossover, blinded endoscopic study, we compared the effects of aspirin, Bufferin, paracetamol, and placebo, two tablets four times a day for 24 hours, on the gastroduodenal mucosa of 10 normal volunteers. Both regular aspirin and bufferin produced multiple gastric (p less than 0.005) and duodenal erosions (p less than 0.05, compared with baseline and placebo studies). Paracetamol did not cause significant gastric or duodenal mucosal damage. Two subjects developed duodenal ulcer-like lesions in the course of the study. We conclude that the use of unbuffered aspirin and Bufferin, but not paracetamol, in recommended doses for one day causes significant gastroduodenal mucosal damage.

Does aspirin prolong bleeding from gastric biopsies in man?

Aspirin prolongs skin bleeding time in man by inducing abnormal platelet function. Prolongation of gastric bleeding time has been postulated as a mechanism for gastric hemorrhage after aspirin in man. To determine whether endoscopic gastric biopsy is safe in patients taking aspirin, we studied the effects of acute and chronic aspirin use on gastric bleeding time in four groups of subjects. Gastric bleeding time was assessed directly following endoscopic biopsy. Skin bleeding time was done by the Mielke method. Control subjects (group I) were studied twice at one-week intervals to determine reproducibility of the gastric bleeding time technique. The effect of aspirin on gastric and skin bleeding time when given to normal volunteers for 24 hours (group II) and for two weeks (group III) and to rheumatic disease patients on a chronic basis (group IV) was also studied. In normal volunteers given aspirin for 24 hours or two weeks, gastric bleeding time was not affected in spite of skin bleeding time being significantly prolonged over baseline. Gastric bleeding time was less then skin bleeding time in all groups including patients with rheumatoid arthritis (p less than 0.05). We conclude that aspirin ingestion does not prolong gastric bleeding time in man and that gastric biopsy is not contraindicated on th basis of recent aspirin ingestion.

Effect of aspirin on the human stomach in normals: endoscopic comparison of damage produced one hour, 24 hours, and 2 weeks after administration.

We studied the effects of regular aspirin on the human stomach by endoscopy in 15 volunteers divided equally into three groups. Each had a normal baseline endoscopy. In Group I, two aspirin or placebo tablets were administered suspended in 100 cc of water and endoscopic assessment made over on hour, at four hours, and 24 hours. In Group II, in a two way cross-over, blinded study we compared the effects of 24 hours' ingestion of 3.25 g of aspirin and placebo. Group III subjects received aspirin, two tablets four times daily for two weeks. In Group I, multiple petechiae (p less than 0.05) developed in the fundus and antrum by one hour and were still visible at 24 hours in 80%. In Group II, aspirin produced multiple antral erosions (p less than 0.05 vs. placebo) in all subjects and duodenal erosions in half. Antral and duodenal petechiae were common. In Group III, all subjects developed antral erosions (p less than 0.05 vs. control) and 50% duodenal erosions but only on subject developed petechiae. Acute aspirin administration appears to cause predominantly petechial hemorrhage in the fundus and antrum while longer term administration causes antral and duodenal erosions. Regular aspirin in recommended doses for one hour, 24 hours and two weeks produces endoscopically visible gastroduodenal damage in the majority of normal subjects.

Comparison of the effects of regular and enteric-coated aspirin on gastroduodenal mucosa of man.

To determine whether the topical or systemic effects of aspirin are of greater importance in the production of gastroduodenal mucosal damage, the effects of regular and enteric-coated aspirin were compared in 9 healthy volunteers in a 2-week crossover endoscopic study. All subjects developed multiple gastric erosions while taking regular aspirin; 2 subjects developed one gastric erosion each while taking enteric-coated aspirin. 5 subjects developed duodenal erosions while taking regular aspirin, whereas none developed an erosion while taking enteric-coated aspirin. Mean fasting salicylate levels were similar in the two groups. It is concluded that regular aspirin causes a greater amount of gastroduodenal mucosal damage than does enteric-coated aspirin despite similar serum-salicylate levels. This suggests that the topical effects of aspirin are of greater importance than the systemic effects in the production of gastroduodenal mucosal damage in healthy subjects.