PT  - JOURNAL ARTICLE
AU  - Yamanaka, Hisashi
AU  - Kubota, Masaru
AU  - Carson, Dennis A.
TI  - Synergistic Inhibition of Polyamine Synthesis and Growth by Difluoromethylornithine plus Methylthioadenosine in Methylthioadenosine Phosphorylase-deficient Murine Lymphoma Cells
DP  - 1987 Apr 01
TA  - Cancer Research
PG  - 1771--1774
VI  - 47
IP  - 7
4099  - http://cancerres.aacrjournals.org/content/47/7/1771.short
4100  - http://cancerres.aacrjournals.org/content/47/7/1771.full
SO  - Cancer Res1987 Apr 01; 47
AB  - The antiproliferative effects of the ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO) are limited by the inability of the compound to deplete completely cellular polyamine pools. 5′-Deoxy-5′-methylthioadenosine (MeSAdo), the purine end product of the polyamine biosynthetic pathway, is an inhibitor of spermine and spermidine synthesis. Furthermore, a substantial number of human tumors are deficient in MeSAdo phosphorylase, and cannot degrade MeSAdo. It therefore seemed possible that DFMO and MeSAdo could interact synergistically to inhibit polyamine synthesis in MeSAdo phosphorylase-deficient malignant cells. To test this hypothesis, we have analyzed the effects of DFMO, in combination with MeSAdo, on polyamine synthesis and growth in a MeSAdo phosphorylase-deficient murine lymphoma cell line (R1.1-H), and a MeSAdo resistant mutant (R1.1-H3). Cultivation of the R1.1-H3 cells in medium containing 250 µm DFMO and 500 µm MeSAdo caused profound depletion of putrescine, spermidine, and spermine, and the accumulation of both decarboxylated S-adenosylmethionine and its acetylated derivative to levels that exceeded by nearly 3-fold the total cellular content of S-adenosylmethionine. Similarly, DFMO sensitized the lymphoma cells to the growth inhibitory effects of MeSAdo. Supplementation of the medium with putrescine, spermidine, or spermine partially protected R1.1-H3 cells from the DFMO-MeSAdo drug combination. It is conceivable that MeSAdo, or related nucleosides, may potentiate the cytostatic effects of DFMO toward MeSAdo phosphorylase-deficient tumors. ©1987 American Association for Cancer Research.