NK-mediated reduction of malignancy in human melanoma cells treated with theophylline.
Theophylline-treated cells of the human melanoma line showed an increase in NK-sensitivity in vitro and a concomitant decrease in tumorigenicity and spontaneous metastasis in Balb/c nude mice. The MeWo cells were heterogeneous and contained related subpopulations which were cloned to produce two cell lines, one hypodiploid (Cd-16) and one hypotetraploid (Ct-1). Prolonged (3 months) or short-term (4 days) treatment of these cell lines with 1 mM theophylline markedly reduced the incidence and size of tumors in Balb/c nude mice early after s.c. injection and their ability to metastasize spontaneously to the lung was also reduced. The effect was much more pronounced with Cd-16 cells, which contain amplified DNA compared to Ct-1 cells which lack DNA amplification. Part of the tumor inhibition caused by theophylline was due to natural killer (NK) cells. Thus, in vivo treatment of nude mice with anti-asialo GM1, a procedure known to remove NK cells, partially reversed the inhibitory effects of theophylline on tumor formation and generation of metastasis by Cd-16 cells. Consistent with this observation theophylline treatment enhanced the in vitro NK sensitivity of Cd-16 cells four-fold whereas Ct-1 was enhanced only slightly. The data suggest that theophylline can act preferentially on certain tumor cell subpopulations to enhance their NK-sensitive phenotype and thereby inhibit their capacity to form tumors and to metastasize in nude mice.
Gitelman
I
I
Department of Immunology, University of Toronto, Canada.
Abramow-Newerly
W
W
Roder
J C
JC
D000818:Animals; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D005677:G(M1) Ganglioside; D006028:Glycosphingolipids / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D013806:Theophylline / Q000494:pharmacology*
D006028:Glycosphingolipids; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D013806:Theophylline