Severe and delayed myelosuppression is a major side effect encountered with the clinical use of nitrosourea-type chemotherapeutic drugs. The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) has been shown to repair nitrosourea-induced DNA damage. We therefore investigated the effect of expressing MGMT in hematopoietic cells (via retrovirus-mediated gene transfer) on nitrosourea-...

position of l-methyl-l-nitrosourea, a bone marrow toxin in animals, results in the formation of a nonmyelosuppressive but diabetogenic antitumor agent streptozotocin (10). An additional observation was the identification of a class of NO nitrosoureas and nitrosamine compounds with a R@!!4@ (C H 2)12H end group that depresses pyridine nucleotide concentrations in liver, the proposed mechanism of...

The diabetogenic activity of streptozotocin has been correlated with a reduction in pyridine nucleotide synthesis in the mouse pancreatic islet. To determine the specificity of this reduction for diabetogenicity, a comparative study of streptozotocin, its cytotoxic moiety, 1-methyl-1-nitrosourea, and alloxan was performed. Streptozotocin administered intraperitoneally (i.p.) producd a dose-rela...

In an attempt to evaluate whether the radiation sensitizer misonidazole (MISO) could enhance the responsiveness of chemoresistant tumors, MISO was combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) for the treatment of BALB/c X DBA/2 F1 (hereafter called CD2F1) and C3H/HeJ mice bearing nitrosourea-resistant L1210/BCNU or KHT/CCR ...

Incubation of crude enzyme preparations from leukemia L1210 ascites cells with l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) caused decreases in the DNA nucleotidyltransferase activity. l-(2-Chloroethyl)-3-cyclohexyl-l-nitrosourea was as active as BCNU, but l-(2-chloroethyl)-l-nitrosourea and 1methyl-1-nitrosourea were much less active. 2-Chloroethyl isocyanate was about equal to BCNU in activity...

The possibility was examined that the carbamoylating activity of some chloroethylnitrosoureas could interfere with the activity of normal human cells to survive treatment with these drugs; 1-(2-chloroethyl)-3-(trans-4-hydroxycyclohexyl)-1-nitrosourea, which has strong carbamoylating activity, inhibited the rejoining of drug or X-ray-induced DNA strand breaks in IMR-90 cells, whereas the noncarb...

The nitrosoureas are widely used in the chemotherapy of brain tumors, two of the most common being 1,3-bis(2-chloroethyl)nitrosourea and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. However, we do not understand how these compounds work, nor do we know which part of the molecule has antitumor activity. In six patients with brain tumor, we measured the kinetic behavior of positron-labeled 1,3-b...

The chloroethylnitrosoureas, such as 1,3-bis(2-chloroethyl)-1-nitrosourea, are alkylating agents which are thought to exert antitumor activity by initiating lethal DNA interstrand cross-links. Although nitrosoureas are among the most active agents against childhood and adult gliomas, the utility of this class of agents has been limited by severe and cumulative myelosuppression, which can be fat...

The monofunctional alkylating agent jV-ethyl-TV-nitrosourea has become known as a highly potent transplacental pulse carcinogen, specifically directed against cells associated with the nervous system. In the present study, the formation of the alkylation product 7-ethylguanine in the nucleic acids of brain and liver of both fetal and adult BD-IX rats (18th day of gestation) was demonstrated by ...

The monofunctional alkylating agent jV-ethyl-TV-nitrosourea has become known as a highly potent transplacental pulse carcinogen, specifically directed against cells associated with the nervous system. In the present study, the formation of the alkylation product 7-ethylguanine in the nucleic acids of brain and liver of both fetal and adult BD-IX rats (18th day of gestation) was demonstrated by ...