Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine.

OBJECTIVE: Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP. METHODS: A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment. RESULTS: A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day. CONCLUSION: In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.

Nitrite-induced mutations in a forward mutation assay: influence of nitrite concentration and pH.

The mutagenicity of sodium nitrite at three pHs (7.4, 6.4 and 5.4) has been investigated by treating a shuttle vector plasmid in vitro and assaying for mutations within the supF target gene following replication of the damaged plasmid in human Ad293 cells. Mutation frequency increased with increasing nitrite concentration and decreasing pH. Among treatments from which a significant number of mutants could be collected, the most commonly induced mutations were GC-->AT transitions (44-56% of total mutations), followed by GC-->TA transversions (24-30%). The types of mutations induced at different nitrite concentrations and different pH's were similar, though some differences in their distribution throughout the supF gene were noted. These results provide information on the types of mutations that may be produced following the processing of nitrite-induced DNA damage in human cells.