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Nitric Oxide/Nucleophile Complexes Inhibit the in Vitro Proliferation of A375 Melanoma Cells via Nitric Oxide Release¹

Chemistry Section, Laboratory of Comparative Carcinogenesis, Division of Cancer Etiology [C. M. M., L. K. K.]; Laboratory of Molecular Immunoregulation, Division of Cancer Treatment [J. M. W., J. J. O.]; and PRI/DynCorp [J. A. H.]; National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Cell-mediated antitumor effects have, in part, been attributed to the production of NO. Compounds which generate NO might, therefore, be useful in attenuating the growth of tumor cells. Six nitric oxide/nucleophile adducts that release NO spontaneously in solution were tested for their effectiveness in inhibiting DNA synthesis in A375 human melanoma cells. The complexes of NO with spermine, 3-(n-propylamino)propylamine (PAPA/NO), and diethylamine reduced thymidine incorporation by 50% at concentrations of 24, 44, and 128 µM, respectively. The degree of inhibition was, in general, related to the rate and extent of NO release in solution. A melanoma cell clone sensitive to interleukin 1-mediated cytostasis (A375-C6) was no more sensitive to PAPA/NO than a clone resistant to interleukin 1 (A375-C5), suggesting that the differing inhibitory effects of interleukin 1 in the two A375 cell clones are not due to a differential sensitivity to nitric oxide. Oxymyoglobin (125 µM), a known scavenger of NO, restored the ability of A375-C6 cells to incorporate thymidine in the presence of up to 200 µM PAPA/NO. When PAPA/NO was added to a solution of oxymyoglobin, nitrosylmyoglobin was formed, indicating that the protective effect of mygolobin was due to scavenging of NO. The results are consistent with a nitric oxide-mediated mechanism for NO/nucleophile cytostasis and suggest that such compounds may be useful as tools for investigating the role of reactive nitrogen intermediates in cytostasis and cytotoxicity.

¹ Supported in part by contract NO1-CO-74102 from the National Cancer Institute to PRI/DynCorp.

² To whom requests for reprints should be addressed, at National Cancer Institute, Frederick Cancer Research and Development Center, Building 538, Frederick, MD 21702.

Received 7/17/92. Accepted 11/10/92.

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