Treatment of Crohn's Disease with 6-Mercaptopurine

Present, Daniel H.; Korelitz, Burton I.; Wisch, Nathaniel; Glass, Joseph L.; Sachar, David B.; Pasternack, Bernard S.

doi:10.1056/nejm198005013021801

Cited by 959 publications

(139 citation statements)

References 20 publications

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“…This co ntrasts, however, with the use of prednisone and 6-mercaptopurine where the mean onset of response is longer and the relapse rate following withdrawal is not as high as th at seen with cyclosporinc (45). lt is in teresting to note chat, in rhe present study as well as in earlier reports, corticosteroids were aggressively mpere~ o r discontinued following the cyclosporine response.…”

Section: In This Issue Of the Canadian ]Omnal Of Gascroentcrolog:vsupporting

confidence: 46%

Cyclosporine: Is There a Role in Inflammatory Bowel Disease?

Fedorak¹

1988

Canadian Journal of Gastroenterology

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T HE IDIOPA Tl IIC IN FLAM MA TOR y BOWEL DISEASES (mn) are a spectrum of disorders characterized by chronic inflammation of the gastrointestinal tract. Genetic ( 1-5), enmonmental (6), dietary (7) and infectious agents (7 ,8-15) have been implicated in the cause of 180; however, much more evidence is required before any is considered proven.Because the exact etiology of IBO has thus far been difficult to establish many investigators consider that the basis of the disease lies in an endogenous immunolog1cal defect. Thtrty years ago Broberger and Pearlmann (16) first demonstrated chat IBO was associated with anti-epithelial cell antibodies in both blood and draining lymph nodes in patients with ulcerative colitis. Since then a large body of evidence has grown co support the immunologic hypothesis of IBO pathogenesis.Prior co examining the concept chat 180 is a consequence of an immunologic process it is important to review the function of the mucosa I immune system in normal i ndividuals. The gastrointestinal luminal environment contains numerous substances capable of activating rhe immune system. However, the face chat chis does not occur can be attributed co the mucosa! immune systems 'programmed' unCorrespondence: Dr Richard N Feclorak, Orn1ron of Gwcroentcrolo,n,

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Section: In This Issue Of the Canadian ]Omnal Of Gascroentcrolog:vsupporting

confidence: 46%

Cyclosporine: Is There a Role in Inflammatory Bowel Disease?

Fedorak¹

1988

Canadian Journal of Gastroenterology

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“…Even the use of clinical severity indices has not provided completely satisfactory methods for diagnostic and management studies in these patients (3)(4)(5)(6)(7). The development of a sensitive and reliable marker of intestinal mucosal disease would be important and useful.…”

Section: Introductionmentioning

confidence: 99%

Plasma postheparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat.

Luk

Bayless²,

Baylin³

1983

J. Clin. Invest.

115

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A B S T R A C T Diamine oxidase (DAO; EC 1.4.3.6) is an enzyme found in high activity in the mature cells of the upper villus of rat small intestinal mucosa and in very much lower activity in all other tissues in the nonpregnant rat. This study was designed to determine whether a provocative test for increasing the level of plasma DAO activity by heparin administration could be used to monitor the extent and severity of acute, severe, small intestinal mucosal injury. In adult rats, small intestinal loops of varying lengths were perfused with 2,100 mosM sodium sulfate solution for 60 min to produce selective damage to villus epithelium. Plasma postheparin DAO (PHD) activity (180 min after 400 U/kg i.p. heparin) was measured 7 h after initiation of perfusion. With increasing length of intestinal mucosal injury, there was a progressive decrease in both basal and plasma PHD activity. The decrease in plasma PHD activity closely reflected the length of intestinal mucosa injured (n = 128, r = 0.86, P < 0.001), and it was much more sensitive (threshold limit of detection = 13% of total length, range = 67 U/ml for 100% length of injury) than unstimulated basal levels of plasma DAO (threshold = 40%, range = 2.1 U/ml). Our previous data have suggested that DAO is unique among intestinal mucosal enzymes in that circulating levels can serve as a marker of mucosal injury; this study illustrates that the addition of a lowdose heparin administration enhances the use of DAO even further as a sensitive, quantitative, circulating marker for monitoring the extent of small intestinal mucosal injury in the rat.Dr.

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“…Azathioprine is commonly used as an immunosuppressive agent for organ transplant patients and people suffering from chronic inflammatory diseases including ulcerative colitis and Crohn syndrome (4,5). After oral administration and absorption, ϳ90% of the prodrug azathioprine is converted to 6-mercaptopurine from attack by sulfhydryl-containing compounds such as glutathione and cysteine (6,7).…”

mentioning

confidence: 99%

Mutagenic and Cytotoxic Properties of 6-Thioguanine, S-Methylthioguanine, and Guanine-S6-sulfonic Acid

Yuan

Wang

2008

Journal of Biological Chemistry

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Thiopurine drugs, including 6-thioguanine ( S G), 6-mercaptopurine, and azathioprine, are widely employed anticancer agents and immunosuppressants. The formation of S G nucleotides from the thiopurine prodrugs and their subsequent incorporation into nucleic acids are important for the drugs to exert their cytotoxic effects.S G in DNA can be methylated by S-adenosyl-L-methionine to give S 6 -methylthioguanine (S 6 mG) and oxidized by UVA light to render guanine-S 6 -sulfonic acid ( SO3H G). Here, we constructed single-stranded M13 shuttle vectors carrying a S G, S 6 mG, or SO3H G at a unique site and allowed the vectors to propagate in wild-type and bypass polymerasedeficient Escherichia coli cells. Analysis of the replication products by using the competitive replication and adduct bypass and a slightly modified restriction enzyme digestion and post-labeling assays revealed that, although none of the three thionucleosides considerably blocked DNA replication in all transfected E. coli cells, both S 6 mG and SO3H G were highly mutagenic, which resulted in G3 A mutation at frequencies of 94 and 77%, respectively, in wild-type E. coli cells. Deficiency in bypass polymerases does not result in alteration of mutation frequencies of these two lesions. In contrast to what was found from previous steady-state kinetic analysis, our data demonstrated that 6-thioguanine is mutagenic, with G3 A transition occurring at a frequency of ϳ10%. The mutagenic properties of 6-thioguanine and its derivatives revealed in the present study offered important knowledge about the biological implications of these thionucleosides.

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Treatment of Crohn's Disease with 6-Mercaptopurine

Cited by 959 publications

References 20 publications

Cyclosporine: Is There a Role in Inflammatory Bowel Disease?

Cyclosporine: Is There a Role in Inflammatory Bowel Disease?

Plasma postheparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat.

Mutagenic and Cytotoxic Properties of 6-Thioguanine, S-Methylthioguanine, and Guanine-S6-sulfonic Acid

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