Modulation of human lymphocyte O6-alkylguanine-DNA alkyltransferase by streptozotocin in vivo.
The ability to modulate DNA repair has been proposed as an effective method to overcome cytotoxic drug resistance in human tumors. However, no studies have shown that it is possible to achieve modulation of DNA repair in humans in vivo. This study analyzes modulation of O6-alkylguanine-DNA alkyltransferase, a DNA repair protein that protects cells from cytotoxic DNA adducts formed by nitrosoureas. Streptozotocin has been shown to inactivate the alkyltransferase in vitro and sensitize tumor cells to other nitrosoureas. Thus, we determined whether biochemical modulation of alkyltransferase activity could be documented in patients receiving therapeutic doses of streptozotocin and whether the modulation was specific to streptozotocin or occurred in patients undergoing treatment with other DNA-damaging agents as well. Normal peripheral blood lymphocytes were used to analyze modulation of the alkyltransferase. We found that lymphocyte alkyltransferase activity was significantly decreased 20 h after treatment with streptozotocin (500 mg/m2) or high dose 1,3-bis-(2-chloroethyl)-1-nitrosourea (350 mg/m2) but not after treatment with the other DNA-damaging agents or lower doses of 1,3-bis-(2-chloroethyl)-1-nitrosourea. A cumulative decline in lymphocyte alkyltransferase activity occurred with daily streptozotocin treatment, reaching 26 +/- 9% of control after the third day of treatment (P less than 0.0005). Thus, the alkyltransferase DNA repair protein can be modulated in vivo in humans given systemic drug treatment. While further studies are needed to document that biochemical modulation can be achieved in the target tumor in humans, this study supports the development of clinical trials using streptozotocin as a biochemical modulator of nitrosourea resistance in human malignancies.
Gerson
S L
SL
Department of Medicine, University Hospital of Cleveland, Ohio.
D002330:Carmustine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D008130:Lomustine / Q000494:pharmacology; D008214:Lymphocytes / Q000201:enzymology*; D008780:Methyltransferases / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013311:Streptozocin / Q000494:pharmacology*
D004273:DNA, Neoplasm; D013311:Streptozocin; D008130:Lomustine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D002330:Carmustine