Effects of alpha-difluoromethylornithine on the growth of experimental Wilms' tumor and renal adenocarcinoma.

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 less than 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 less than 0.001). DFMO feeding increased survival of mice bearing renal carcinomas by 3.0 +/- 0.8 (S.E.) days (p less than 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]  P. Sunkara,et al.  An essential role for polyamines in tumor metastases , 1982, FEBS letters.

[2]  J. Koch-weser,et al.  Effects of alpha-difluoromethylornithine alone and combined with adriamycin or vindesine on L1210 leukemia in mice, EMT6 solid tumors in mice, and solid tumors induced by injection of hepatoma tissue culture cells in rats. , 1981, Cancer research.

[3]  M. Siimes,et al.  Synergistic action of two polyamine antimetabolites leads to a rapid therapeutic response in childhood leukemia , 1981, International journal of cancer.

[4]  P. McCann,et al.  Potentiation of the antitumor therapeutic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. , 1981, Cancer research.

[5]  E. Hölttä,et al.  Several inhibitors of ornithine and adenosylmethionine decarboxylases may also have antiproliferative effects unrelated to polyamine depletion. , 1981, Biochimica et biophysica acta.

[6]  O Heby,et al.  Role of polyamines in the control of cell proliferation and differentiation. , 1981, Differentiation; research in biological diversity.

[7]  A. Sjoerdsma.  Suicide enzyme inhibitors as potential drugs , 1981, Clinical pharmacology and therapeutics.

[8]  L. Marton,et al.  Sensitization of 9L rat brain gliosarcoma cells to 1,3-bis(2-chloroethyl)-1-nitrosourea by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. , 1981, Cancer research.

[9]  R. Cohen,et al.  A rapid and efficient microassay of ornithine decarboxylase. , 1980, Analytical biochemistry.

[10]  A. Sjoerdsma,et al.  Inhibition of EMT6 tumor growth by interference with polyamine biosynthesis; effects of alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase. , 1980, Life sciences.

[11]  B. Feuerstein,et al.  The generality of methylglyoxal bis(guanylhydrazone)-induced mitochondrial damage and the dependence of this effect on cell proliferation. , 1979, Cancer research.

[12]  P. Schechter,et al.  Effect of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on L1210 leukemia in mice. , 1978, Cancer research.

[13]  U. Dunzendorfer,et al.  Altered polyamine profiles in prostatic hyperplasia and in kidney tumors. , 1978, Cancer research.

[14]  J. Jänne,et al.  Polyamines in rapid growth and cancer. , 1978, Biochimica et biophysica acta.

[15]  L. Marton,et al.  More sensitive automated detection of polyamines in physiological fluids and tissue extracts with omicron-phthalaldehyde. , 1975, Clinical chemistry.

[16]  Williams Pd,et al.  Testing of chemotherapeutic agents in murine renal cell adenocarcinoma. , 1974 .

[17]  A. Schenone,et al.  Specific inhibition of the enzymic decarboxylation of S-adenosylmethionine by methylglyoxal bis(guanylhydrazone) and related substances. , 1974, The Biochemical journal.

[18]  P. Hannonen,et al.  Effect of methylglyoxal bis(guanylhydrazone) on polyamine metabolism in normal and regenerating rat liver and rat thymus. , 1973, The Biochemical journal.

[19]  G. Murphy,et al.  Investigation of a new renal tumor model. , 1973, The Journal of surgical research.

[20]  G. Murphy,et al.  A murine renal cell carcinoma. , 1973, Journal of the National Cancer Institute.

[21]  P. Tomashefsky,et al.  The Furth-Columbia rat Wilms tumor. , 1972, The Journal of urology.

[22]  J. Burchenal,et al.  Potentiation of methylglyoxal-bis-guanylhydrazone by alpha-difluoro- methyl ornithine, stilbamidine and pentamidine in mouse leukemia. Abstr. , 1981 .

[23]  J. Richie,et al.  Phase I--II trial of methyl-GAG in the treatment of patients with metastatic renal adenocarcinoma. , 1981, Cancer treatment reports.

[24]  K. Burton.  [105] Determination of DNA concentration with diphenylamine , 1968 .

[25]  J. DiPaolo,et al.  The antimitochondrial action of 2-choloro-4', 4"-bis(2-imidazolin-2-yl)terephthalanilide and methylglyoxal bis(guanylhydrazone). , 1966, Cancer research.