Alkylating agents and compounds converted metabolically to alkylating agents form an important class of carcinogens and mutagens that includes a number of environmentally important /V-nitrosocompounds. A number of alkylating agents are also useful antitumor drugs. There are many factors determining the sensitivity to the toxic, mutagenic, and carcinogenic poten tial of these compounds (1-4).2 One of these is the capacity to

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Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents.

Anticancer drug resistance in primary human brain tumors.

DNA repair and cancer stem-like cells – Potential partners in glioma drug resistance?

✓ The level of O6-alkylguanine-deoxyribonucleic acid (DNA) alkyltransferase (AT) was determined in 15 human brain-tumor xenografts in athymic mice. This enzyme is a primary intracellular repair mechanism for lesions produced at the O6 position of guanine by a wide range of alkylating agents, including nitrosoureas and procarbazine. Its activity ranged from undetectable in five tumor lines to 2338 fmol/mg protein in N-1941, a human glioblastoma xenograft. The sensitivity of 10 of these xenografts to procarbazine was determined and it was found that four of the five tumor lines with AT levels of more than 100 fmol/mg protein had growth delays after procarbazine treatment of less than 20 days, whereas all five lines with undetectable AT levels had growth delays of over 30 days. The primary cytotoxic DNA adduct produced by procarbazine (namely, O6-methylguanine) was found to be significantly higher in two sensitive lines with low AT levels than in a highly resistant line with a high AT level. These data sugge...

O6-Alkylguanine-DNA alkyltransferase and sensitivity to procarbazine in human brain-tumor xenografts

Importance of the DNA repair enzyme O6-alkyl guanine alkyltransferase (AT) in cancer chemotherapy

We investigated the cytotoxic and cytogenetic effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment on two cell lines derived from human glioma biopsy specimens. SF-188 cells are 3-fold more resistant to the cytotoxic effects of BCNU and 14-fold more resistant to sister chromatid exchange (SCE) induction caused by BCNU treatment than are SF-126 cells. After treatment with BCNU, 60% fewer DNA interstrand crosslinks were found in SF-188 than in SF-126 cells. The O6-methylguanine alkylation product was removed rapidly from DNA in SF-188 cells treated with [3H]methylnitrosourea, but very little repair of alkylation product occurred in SF-126 cells. These results suggest that one of the mechanisms responsible for cellular resistance to BCNU treatment is increased repair of O6-alkylguanine products in DNA, which reduces the number of crosslinks formed and thereby increases survival and reduces the number of SCEs induced in resistant cells.

Increased repair of O6-alkylguanine DNA adducts in glioma-derived human cells resistant to the cytotoxic and cytogenetic effects of 1, 3-bis(2-chloroethyl)-1-nitrosourea

Toshimitsui Aida

Papers

Increased repair of O6-alkylguanine DNA adducts in glioma-derived human cells resistant to the cytotoxic and cytogenetic effects of 1, 3-bis(2-chloroethyl)-1-nitrosourea