Effect of ribonucleotide reductase inhibitors on the growth of human colon carcinoma HT-29 cells in culture

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Abstract
The effects of ribonucleotide reductase inhibitors on the growth of the human colon carcinoma cell line HT-29 were examined. Inhibitors were chosen for these studies that were specifically directed at each of the subunits of ribonucleotide reductase. The concentrations of drugs required to inhibit the growth of HT-29 cells by 50% (IC50) for hydroxyurea, 2,3-dihydro-IH-pyrazole-[2,3a]imidazole (IMPY), and 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone (MAIQ) were 206, 996, and 3.2 µM, respectively. Although the IC50 for deoxyadenosine alone was >2,000 µM, in the presence of 5 µM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), which protects deoxyadenosine from deamination by adenosine deaminase, it was reduced to 112 µM. The IC50 for deoxyguanosine was 1,060 µM. The addition of 8-aminoguanosine to protect deoxyguanosine from phosphorylysis by purine nucleoside phosphorylase did not increase the toxicity of deoxyguanosine in HT-29 cells. The combination of MAIQ or IMPY and deoxyadenosine/EHNA gave strong synergistic inhibition of HT-29 cell growth. The results of these studies indicate that ribonucleotide reductase inhibitors effectively block the growth of human colon carcinoma HT-29 cells and that combinations of inhibitors directed at the individual subunits of reductase result in synergistic inhibition of HT-29 cell growth in culture.