Different cell lines, 2 from human colon carcinoma (LoVo and HT29) and 1 from Chinese hamster ovary (CHO K-I), were examined to assess the effect of deoxycoformycin (dCF), an inhibitor of adenosine deaminase (ADA), and 2'-deoxyadenosine (dAdo) on their growth. When used alone, neither dCF or dAdo were cytotoxic for the 3 cell lines, while their combination caused inhibition of cell growth, with the following sensitivity: CHO K-I > LoVo > HT29. We studied the pattern of enzymatic activities involved in the metabolism of dAdo in the 3 cell lines. The phosphorylation of dAdo by adenosine kinase appears to play a central role in the toxicity of the deoxynucleoside in combination with dCF. In fact, CHO K-I cells, which are the most sensitive, possess the highest level of this enzyme. Moreover, the cytotoxic effect was almost completely reversed in the 3 cell lines when inhibitors of adenosine kinase, such as 5'-amino-5'-deoxyadenosine and iodotubercidine, were added to the culture medium together with dCF and dAdo. In addition, baby hamster kidney (BHK) adenosine-kinase-deficient (AK-) cells were highly resistant to this treatment. Uptake inhibition of dAdo using dipyridamole also caused reversal of the toxicity. The AMP and deoxyAMP dephosphorylating activities, much lower in the CHO K-I cells, also appear to play a central role in the toxicity of dAdo when adenosine deaminase is inhibited. However, our data suggest that other factors may modulate the toxic effect, such as S-adenosyl-homocysteine-hydrolase inhibition by dAdo at high concentrations.

Purine enzyme profile in human colon‐carcinoma cell lines and differential sensitivity to deoxycoformycin and 2′‐deoxyadenosine in combination

Deoxycoformycin (DCF), a powerful inhibitor of adenosine deaminase1, by virtue of its immunosuppresive action2, has found clinical application for the treatment of several types of lymphatic leukemia3, 4. In fact, the prevention of the catabolism of deoxyAdo to deoxylno, results both in the accumulation of intracellular deoxyATP5, an inhibitor of ribonucleotide reductase, and in the depletion of ATP6. Indeed, it has been reported that human T lymphocyte cells are very sensitive to the cytotoxic action of deoxyAdo, and that their sensitivity to DCF is higher than B lymphocyte cells probably as a result of a reduced cytosolic 5’deoxynucletidase activity, with a concomitant preservation of the deoxyATP pool7. While many studies have been performed on the cytotoxicity of DCF on human lymphocytes and several reports describe its possible mechanism of action in this type of cells8, 9, the effect of this drug on different mammalian cells has not been thoroughly examined so far, also on account of the reported inefrkacy of DCF on the growth of cultured cells 10. Human colon carcinoma cultured cells are a model for the study of the responsiveness of this solid tumor to possible Chemotherapic agents. In view of the involvement of the purine salvage enzymes in the activation of purine analogs, the knowledge of their program in tumor cells might be of great help not only for the understanding of the analog mechanism of action, but also for the design of specific pro-drugs. In this line is the present study on the cytotoxicity of DCF in combination with deoxyAdo on both two human colon carcinoma (LOVO and HT29) and a Chinese hamster ovary (CHO K-l) cell Unes. The different sensitivity of the three cell lines to DCF is well related to their distinct purine salvage enzyme pattern, thus supporting, in a general point of view, the enzymatic approach to the choice of a suitable Chemotherapic agent.

Cytotoxicity of deoxycoformycin on human colon carcinoma cell lines.

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Cytotoxicity of deoxycoformycin on human colon carcinoma cell lines.