ABSTRACT
Guanosine is shown to potentiate markedly the antiproliferative effect of cytosine-beta-D-arabinoside (ara-C) on B16 F10 mouse and SKMEL-28 human melanoma cell lines. Several metabolic consequences of the synergistic interaction between ara-C and guanosine on cell growth were determined in B16 F10 mouse melanoma cells. Treatment of the cells with guanosine for 24 hr resulted in an increase in the percentage of cells in the S phase of the cell cycle, a threefold increase in intracellular GTP concentration, and an increase in the incorporation of ara-C into acid-insoluble material and phosphorylated metabolites. These findings suggest that guanosine potentiates the growth-inhibitory effect of ara-C in B16 F10 melanoma cells by increasing the intracellular concentration of its active metabolites.
Subject(s)
Cytarabine/pharmacology , Guanosine/pharmacology , Melanoma/pathology , Animals , Cell Cycle/drug effects , Cell Division/drug effects , Cytarabine/metabolism , Drug Synergism , Humans , Melanoma/metabolism , Melanoma, Experimental/pathology , Mice , Tumor Cells, CulturedABSTRACT
The effect of the nucleoside anti-metabolite tiazofurin (TR) was examined on the growth and phenotypic alterations of MCF-7 breast cancer and HBL-100 normal breast cell lines. TR was shown to inhibit MCF-7 cell growth. This inhibition could be reversed by exogenous addition of guanosine. The anti-proliferative effect of TR is accompanied by phenotypic alterations that include lipid accumulation and an increase in alkaline phosphatase activity. In contrast to MCF-7 cells, the HBL-100 breast milk derived cell line is relatively resistant to inhibition by TR. Alkaline phosphatase is not affected by TR and untreated cells accumulate lipid droplets, similar to TR-treated MCF-7 cells. Determination of GTP and ATP pools in both cell lines revealed that TR markedly reduces GTP content in MCF-7 cells. In HBL-100 cells, TR induces only a small decrease in GTP and does not affect ATP levels. The prototypic IMP dehydrogenase inhibitor, mycophenolic acid (MA), markedly inhibits HBL-100 cell growth, similarly to its effect on MCF-7 breast cancer cells. These findings may suggest differential metabolism of TR in MCF-7 and HBL-100 cells.
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Breast Neoplasms/pathology , Milk, Human/cytology , Ribavirin/therapeutic use , Ribonucleosides/therapeutic use , Adenosine Triphosphate/analysis , Breast Neoplasms/analysis , Breast Neoplasms/drug therapy , Cell Division/drug effects , Cell Line , Female , Guanosine Triphosphate/analysis , Humans , Mycophenolic Acid/pharmacology , Ribavirin/analogs & derivatives , Tumor Cells, Cultured/analysis , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/pathologySubject(s)
Breast Neoplasms/pathology , IMP Dehydrogenase/antagonists & inhibitors , Ketone Oxidoreductases/antagonists & inhibitors , Mycophenolic Acid/pharmacology , Adenosine Triphosphate/metabolism , Breast Neoplasms/enzymology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Female , Guanosine/pharmacology , Guanosine Triphosphate/metabolism , Humans , Mitosis/drug effects , Mycophenolic Acid/antagonists & inhibitors , Phenotype , Tumor Cells, Cultured/drug effectsABSTRACT
The effect of LiCl on melanoma cell growth and differentiation was studied in mouse and human melanoma cell lines. LiCl markedly inhibited B16 and HT-144 melanoma cell growth in vitro. Clonogenicity in soft agar of the melanoma cells was also markedly inhibited by LiCl. Pretreatment of B16 mouse melanoma cells with LiCl delayed the appearance of melanoma tumours in syngeneic mice. Growth inhibition of cells was accompanied by morphological and biochemical alterations. LiCl induced cell enlargement and formation of dendrite-like structures. The activity of NADPH cytochrome c reductase, an enzymatic marker of endoplasmic reticulum was significantly (2-3 fold) increased. Addition of myo-inositol to cell cultures partially reversed the anti-proliferative and morphological effects of LiCl on melanoma cells. This finding may suggest that the anti-proliferative effect of LiCl is related to its effect on phosphatidylinositol metabolism.
