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Effect of Intravenous -Difluoromethylornithine on the Polyamine Levels of Normal Tissue and a Transplantable Fibrosarcoma¹

Departments of General Surgery [V. B. G., D. M. O., K. N.], Medical Oncology [J. A. A.], and Biochemistry and Molecular Biology [K. N.], The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77030

The effect of a continuous i.v. infusion of -difluoromethylornithine (DFMO) on the polyamine metabolism of tumor and normal host tissue was determined. Non-tumor-bearing Fischer 344 rats or rats bearing a transplantable fibrosarcoma received continuous infusions of DFMO through a central venous catheter at three dose levels. Treatment with DFMO resulted in a time- and dose-dependent, cytostatic effect on the growth of the tumor. In fibrosarcoma-bearing rats the tumor putrescine levels were reduced after 6 and 12 days of DFMO treatment. Tumor spermidine levels were consistently reduced after 6 and 12 days of treatment with the reduction being dose dependent. The decrease in tumor ornithine decarboxylase activity was dose dependent. Erythrocyte putrescine levels were decreased in tumor- and non-tumor-bearing rats, suggesting that DFMO reduces the tumor contribution to the erythrocyte pool. Erythrocyte spermidine levels of fibrosarcoma- and non-tumor-bearing rats were elevated at the lower DFMO doses administered for 12 days but returned to normal as the dose was increased. Erythrocyte spermine levels were elevated in both groups of rats at all DFMO doses. Although normal host tissue weights were not affected by treatment with DFMO, the putrescine and spermidine levels of liver, spleen, and kidney and ornithine decarboxylase activity of the liver and kidney were decreased. These data demonstrate that i.v. DFMO has a cytostatic effect toward a rapidly growing fibrosarcoma associated with the depletion of both tumor putrescine and spermidine levels.

¹ This investigation was supported by USPHS Grant CA 34465 awarded by the National Cancer Institute, Department of Health and Human Services, and by a grant from Baxter-Travenol Laboratories, Inc.

² To whom requests for reprints should be addressed, at the Department of General Surgery, Box 106, The University of Texas M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Avenue, Houston, TX 77030.

Received 2/10/86. Revised 7/31/86. Revised 12/17/86. Accepted 1/ 7/87.