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Effects of -Difluoromethylornithine on the Growth of Experimental Wilms' Tumor and Renal Adenocarcinoma¹

Surgical Services, Shriners' Burns Institute and Massachusetts General Hospital, and Department of Surgery, Harvard Medicial School, Boston, Massachusetts 02114 [A. N. K., R. A. M.]; Merrell Dow Research Center, Cincinnati, Ohio 45215 [P. P. M., K. A. D.]; and Department of Pathology, Berkshire Medical Center, Pittsfield, Massachusetts 01201 [J. S. R.]

Because polyamines are essential for cellular growth and differentiation, and because human renal carcinomas have spermidine levels that are higher than those in normal renal tissue, effects of 2-difluoromethylornithine (DFMO) on the growth of experimental renal tumors were investigated. DFMO is a specific enzyme-activated irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme controlling polyamine biosynthesis. DFMO (2%) in drinking water was administered to BALB/c mice with intrarenal transplants of a renal adenocarcinoma cell suspension and to Wistar/Furth rats with s.c. transplants of a Wilms' tumor. At 28 days, renal carcinomas in DFMO-fed mice weighed 72% less than those in control animals (p < 0.001). Wilms' tumor weight was not affected by DFMO feeding. DFMO caused 72 to 75% inactivation of ornithine decarboxylase activity and reduced putrescine levels in renal carcinoma and Wilms' tumor, reduced spermidine levels in Wilms' tumor, and apparently raised spermine levels in the latter as a consequence. DNA content was not affected by DFMO feeding. The mean number of lung metastases in DFMO-fed, renal carcinoma-bearing mice was 0.1 and in controls was 1.4 (p < 0.001). DFMO feeding increased survival of mice bearing renal carcinomas by 3.0 ± 0.8 (S.E.) days (p < 0.05), i.e., from 30.5 ± 0.8 days to 33.5 ± 1.2 days. DFMO did not affect the growth of Wilms' tumor; however, in renal adenocarcinoma, it reduced growth, prevented lung metastases, and increased survival.

¹ Supported by the Stanley Thomas Johnson Foundation.

² To whom requests for reprints should be addressed.

Received 8/16/82. Accepted 5/27/83.