Human melanoma cells sensitive to deoxyadenosine and deoxyinosine.
In an in vitro study conducted without the use of adenosine/deoxyadenosine deaminase inhibitors, two human melanoma cell lines, MM96L and MM127, were found to be highly sensitive to killing by continuous treatment with deoxyadenosine (dAdo) (D37 47 microM and 68 microM respectively) compared with fibroblasts (D37 440 microM), Hela cells (D37 1.1 mM) and other melanoma cell lines (D37 0.8 to 2.5 mM). Cross-sensitivity was found to deoxyinosine (dIno) and in part to adenosine but not to related metabolites such as inosine or hypoxanthine. Hypersensitivity to dAdo was associated with deficiency in cell membrane 5'-deoxynucleotidase but not in deaminase activity. dAdo toxicity could be prevented in MM96L by addition of the other three deoxynucleosides together but not by removing dAdo after a brief (2 hr) treatment. Resistant melanoma cells, however, required more than 24 hr dAdo treatment to produce toxicity. DNA synthesis in MM96L cells was reversibly inhibited, and cells tended to accumulate in G1/S. No DNA strand breaks were detected. These results showed that in contrast to the resistant cell line, asynchronous MM96L cells are highly sensitivity to brief treatment, toxicity resulting from an effect associated with inhibition of DNA synthesis. dAdo and dIno, either combined with a deaminase inhibitor or as deaminase-resistant derivatives, may have a favourable therapeutic index for some melanomas in vivo.
D015720:5'-Nucleotidase; D000243:Adenosine Deaminase / Q000378:metabolism; D000970:Antineoplastic Agents; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003839:Deoxyadenosines / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism*; D009708:Nucleotidases / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013997:Time Factors
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003839:Deoxyadenosines; D012334:RNA, Neoplasm; D007288:Inosine; D009708:Nucleotidases; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; C012271:deoxyinosine