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PubMed1994

DNA damage and mutagenesis induced by nitrogen mustards.

The nitrogen mustards are bifunctional alkylating agents which, although used extensively in cancer chemotherapy, are themselves highly carcinogenic. All nitrogen mustards induce monofunctional guanine-N7 adducts, as well as interstrand N7-N7 crosslinks involving the two guanines in GNC.GNC (5'-->3'/5'-->3') sequences. In addition, the aromatic mustards melphalan and chlorambucil also induce substantial alkylation at adenine N3, while cyclophosphamide forms phosphotriesters with relatively high frequency. Nitrogen mustards are genotoxic in virtually every assay, and produce a wide array of mutations, including base substitutions at both G.C and A.T base pairs, intragenic as well as multilocus deletions, and chromosomal rearrangements. Mutational spectra generated by these agents in various model systems vary widely, and no single lesion has been implicated as being primarily responsible for mustard-induced mutagenesis. On the contrary, adducts of both adenine and guanine, and monofunctional as well as bifunctional adducts, appear to be involved. Further, it is still not known which types of mutation are responsible for mustard-induced cancers, since no genes have yet been identified which are consistently altered in these malignancies.

Animals↗
PubMed1996

Gas chromatographic-mass spectrometric assay for N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in rat plasma.

A sensitive and specific method for the quantitative analysis of N-2-chloroethylaziridine (CEA), a volatile cytotoxic metabolite of cyclophosphamide, has been developed using gas chromatography-mass spectrometry and stable isotope dilution techniques. The high volatility problem of CEA during isolation procedure was overcome by the combined use of a deuterium-labeled analog as the internal standard and a Snyder column-concentrator assembly. The assay was found to be linear from 16.7 to 2667 ng/ml in rat plasma with a routine detection limit of 5 ng/ml. The within-run precision at 33, 333 and 1333 ng/ml (n = 6) was found to be 4.8, 4.9, and 6.1%, respectively. The between-run precision was 6.4% (n = 6). The dichloromethane extraction recoveries at 33, 333, and 1333 ng/ml were found to be 101, 98, and 91%, respectively (all at n = 6). However, the overall recovery through extraction and evaporation was only 18.3, 15.2, and 27.7% at 33, 333, and 1333 ng/ml levels, respectively. The analytical method was used to evaluate the generation of CEA from its precursors in sodium phosphate buffer, in cell culture media, and the degradation of CEA in these media. In pH 7.4, 0.067 M sodium phosphate buffer at 37 degrees C, both phosphoramide mustard (PM) and nornitrogen mustard (NNM) were degraded in an apparent first-order fashion with half-lives of 24.8 and 14.5 min, respectively. The generated CEA was rather stable in this buffer and degraded with a half-life of 20 h. It was found that 32% PM and 91% NNM were converted to CEA in pH 7.4, 0.067 M sodium phosphate buffer at 37 degrees C, respectively, and 41% PM was transformed into CEA in RPMI 1640 tissue culture media containing 10% FBS at 37 degrees C. The generated CEA was very stable in the culture media with a degradation half-life of 265 h.

Animals↗
PubMed1992

Use of [8-3H]guanine-labeled deoxyribonucleic acid to study alkylating agent reaction kinetics and stability.

Alkylation at the N7 position of guanine in DNA renders the C8-hydrogen acidic. This serves as the basis for an assay of guanine N7 alkylation using [8-3H]-guanine-labeled DNA. I modified the assay by preparing a high specific activity substrate in vitro and by replacing the distillation step with charcoal adsorption of substrate. Using the appearance of noncharcoal-adsorbable label as a measure of guanine-N7 alkylation I examined the reaction of DNA with dimethyl sulfate and mechlorethamine. The rate of reaction of dimethyl sulfate with the N7 position of guanine in DNA was constant over time, i.e., loss of label from DNA proceeded linearly with time. On the other hand, the rate of reaction of mechlorethamine with DNA increased with time, consistent with the initial formation of the reactive aziridinium ion. The assay can also be used to compare the reaction rates of various alkylating agents with DNA. Thus, the acridine mustards ICR-170 and quinacrine mustard were far more potent alkylating agents than mechlorethamine. Furthermore the assay may be used to determine the alkylating potency and stability of various alkylating agent preparations: while frozen solutions of acridine mustards in organic solvents retained alkylating activity for several months, different commercial preparations of quinacrine mustard had little or no alkylating activity.

Alkylating Agents↗
PubMed1985

Enhanced nitrosourea cytotoxicity in cell culture by sodium butyrate.

In HeLa S3 cells, sodium butyrate was found to potentiate the cytotoxicity of chloroethylnitrosoureas and alkylating agents in vitro. Using a soft-agar colony-forming assay, 2.5 and 5.0 mM sodium butyrate pretreatment for 22 h increased the cell killing efficacy of both methyl- and chloroethylnitrosoureas by between 30 and 70%. The potentiation of cytotoxicity of bifunctional nitrogen mustards by butyrate was less than that of nitrosoureas, with a 15-30% increased cell kill at 5 mM butyrate. Sodium butyrate per se reduced plating efficiency and caused growth delay if residual levels (calculated at 100 microM for starting concentrations of 5 mM) were not removed by washing prior to plating.

Butyrates↗