Relationships among cell survival, O6-alkylguanine-DNA alkyltransferase activity, and reactivation of methylated adenovirus 5 and herpes simplex virus type 1 in human melanoma cell lines.
O6-Alkylguanine-DNA alkyltransferase (ATase) activity and host cell reactivation (HCR) of 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC)-methylated viruses were compared in human melanoma cell lines that were sensitive or resistant to killing by the antitumor DNA-methylating agent MTIC. Enhanced HCR of adenovirus 5 (defined as the Mer+ phenotype) generally showed a semiquantitative correlation with the natural or induced resistance of the host cells to the toxic effects of MTIC and to the level of ATase activity. However, one MTIC-resistant cell line was found (MM170) which had a low level of ATase and intermediate HCR of adenovirus. The HCR of herpes simplex virus type 1 (HSV-1) was enhanced in the Mer+ cells that had natural resistance to MTIC compared with Mer- cells. On the other hand, HCR of HSV-1 in Mer+ cells with induced resistance to MTIC was similar to that in Mer- cells. Neither adenovirus 5 nor HSV-1 infection induced ATase activity in Mer- cells. This indicates that resistance to the toxic effects of methylating agents is not invariably associated with high levels of ATase activity in human melanoma cells. Furthermore, while induction of the Mer+ phenotype from Mer- cells was usually accompanied by the recovery of ATase activity, induced Mer+ cells had less proficient repair than natural Mer+ cells, as judged quantitatively by slightly lower cellular resistance and qualitatively by deficient HCR response for HSV-1. These results suggest that the Mer- and induced Mer+ cells lack an ATase-independent DNA repair mechanism. No differences in MTIC-induced DNA repair synthesis or strand breaks were found between the Mer-, natural Mer+, and induced Mer+ phenotypes. However, UV-induced DNA repair synthesis was higher in the natural Mer+ than in the Mer- or induced Mer+ cells, both of which had increased cellular sensitivity to the antimetabolites methotrexate and hydroxyurea. These differences may be related to the effects observed with MTIC. A wide range of ATase activities was found in human melanoma biopsy material.
Maynard
K
K
Queensland Institute of Medical Research, Herston, Australia.
Parsons
P G
PG
Cerny
T
T
Margison
G P
GP
D000260:Adenoviruses, Human / Q000187:drug effects*; D000477:Alkylating Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D018139:Simplexvirus / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide