Endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) of Escherichia coli has been shown to break phosphodiester bonds in alkylated DNA and depurinated DNA. The hypothesis that depurination is a step in the mechanism of the reaction with alkylated DNA is supported by in vitro experiments with DNA reacted with N-methyl-N-nitrosourea. Endonuclease II releases O(6)-methylguanin...

The ability of various nitrosoureas to induce sister chromatid exchanges (SCEs) in 9L rat brain tumor cells was investigated. Treatment of cells for 1 hr with the alkylating and cross-linking agents 1,3-bis(2-chloroethyl)-1-nitrosourea or chlorozotocin produced concentration-dependent increases in SCEs; elevations above controls were detected at concentrations of 1 microM or more. Above 0.25 mM...

Thirty-six patients with advanced gastrointestinal carcinoma were treated sequentially with full therapeutic doses of l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea followed by 5-fluorouracil. 5-Fluorouracil could be safely administered at 6 weeks although patients still demonstrated peripheral hematological depression secondary to the earlier l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea therapy....

The physiological disposition of l-(2-chloroethyl)-3cyclohexyl-1-nitrosourea, a highly active agent against intraperitoneal and intracranial mouse leukemia L1210, was studied in mice, rats, dogs, and monkeys with the 14C label in each of 3 positions of the molecule, the ethylene, carbonyl, and cyclohexyl moieties. l-(2-Chloroethyl)-3-cyclohexyl-l-nitrosourea is lipid soluble and, after parenter...

O6-Alkylguanine-DNA alkyltransferase partially purified from cultured human lymphoblasts (CEM-CCRF line) was inactivated with DNA substrates that had been treated separately with five methylating agents or with five chloroethylnitrosoureas. The extent of depletion of the transferase by alkylated DNA was compared with its inactivation by direct reaction with these ten agents. As expected, DNA su...

The effects of 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexl-1-nitrosourea, and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea on two nonmitochondrial DNA polymerases (I and II) purified from rat liver and hepatoma were examined. The activity of DNA polymerase I was not altered by treatment with any of the nitrosoureas or the corresponding isocyanates, 2-chlo...

A water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU, NSC-245382), was tested for its antitumor activity against some kinds of transplantable mouse tumors. The compound was markedly active against myeloid leukemia C1498, plasmacytoma X5563, Ehrlich ascites carcinoma, and mammary tumor FM3A43, and moderately active against ma...

clinically useful nitrosounea derivative (32); it is readily soluble in alcohol, and its results in coborectal cancer approximated those obtained with MeCCNU, the best nitrosourea agent for this particular type of tumor (28). We did not use MeCCNU because this drug cannot be dissolved easily in a variety of solvents (15). cis-Acid is a new water-soluble nitrosourea (30) that was shown by Corbet...

To assess the rationale of ¡ntraarterial (i.a.) l-(4-amino-2-methyl-5pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea chemotherapy, dis tribution of 14C-labeled l-(4-amino-2-methyl-5-pyrirnidinyl)methyl-3(2-chloroethyl)-3-nitrosourea in rat glioma was studied after i.a. or i.v. infusion. Immediately after infusion, the tumor located in the hemisphere of intracarotid infusion received 4.6-fol...

A formulation of 1-[2-chloroethyl-U-14C]-3-cyclohexyl-1-nitrosourea in ethanol:propylene glycol (1:4, v/v) was administered to rats previously infiltrated with RT6 glioma tumors (astrocytic series); the organ and tumor tissue distribution was followed at 1, 4, 12, and 24 hr postinjection. From 0 to 1 hr, rapid blood disappearance of the 1-[2-chloroethyl-U-14C]-3-cyclohexyl-1-nitrosourea was obs...