Monofunctional alkylating agents

Vogel, E. and Natarajan, A.T. The relation between reaction kinetics and mutagenic action of monofunctional alkylating agents in higher eukaryotic systems Interspecies comparisons. IN deSerres, F.J. and Hollaender, A., eds. Chemical Mutagens Principles and Methods for Their Detection, Volume 7. New York Plenum Press. 1982. p. 295-336. 

Jensen, D, and Ramel, C. (1980). Relationship between chemical damage of DNA and mutations in mammalian cells. 1. Dose-response curves for the induction of 6-thioguanine resistant mutants by low doses of monofunctional alkylating agents, x rays and UV radiation in V79 Chinese hamster cells, Mutat. Res. 73,339. 

Natarajan, A.T., Simons, J.W.I.M., Vogel, E.W. van Zeeland, A.A. (1984) Relationship between cell killing, chromosomal aberrations, sister-chromatid exchanges and point mutations induced by monofunctional alkylating agents in Chinese hamster cells. A correlation with different ethylation products in DNA. Mutat. Res., 128, 31-40... 

Roldan-Arjona, T., Luque-Romero, F.L., Ruiz-Rubio, M. Pueyo, C. (1990) Quantitative relationship between mutagenic potency in the Ara test of Salmonella typhimurium and carcinogenic potency in rodents. A study of 11 direct-acting monofunctional alkylating agents. Carcinogenesis, 11, 975-980... 

Endonuclease II of E. coli was first recognized by Friedberg and Goldthwait as an activity in extracts of E. coli mutants lacking endonuclease I, that specifically attacked double-stranded DNA alkylated with the monofunctional alkylating agent methyl methane sulfonate (56). It was subsequently found that the partially purified enzyme could in fact... 

D.T. Beranek, Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents. Mutat. Res. 231, 11-30 (1990)... 

Gichner, T., Ptacek, O., Stavreva, D.A. and Plewa, M.J. (1999) Comparison of DNA damage in plants as measured by single cell gel electrophoresis and somatic leaf mutations induced by monofunctional alkylating agents. Environmental and Molecular Mutagenesis, 33, 279-286. 

Schematic representation of the disruption of DNA replication by monofunctional alkylating agents. Cross-linked DNA arising from the actions of bifunctional agents would not be available for replication.

Ethyl carbamate (urethan), another monofunctional alkylating agent, when administered intraperitoneally (100 mg/kg) will not have any noticeable effect on meiotic chromosomes. If the same dose is given to F2 male Armenian hamsters derived from grandsires treated with ethyl methane-sulfonate, totally different results are obtained—1 to 7 days after treatment there are no chromosome anomalies on day 8 the number of bivalents is reduced from 11 to ten and nine. In 80% of the spermatocytes ten bivalents can be encountered, and in about 10% of the spermatocytes nine bivalents are encountered. The reduction in the number of bivalents was due to associations of two and/or three bivalents. 

Schwartz JL, Morgan WF, Weichselbaum RR (in press) Different efficiencies of interaction between 3-aminobenzamide and various monofunctional alkylating agents in the induction of sister chromatid exchanges. Carcinogenesis... 

Monofunctional alkylating agents (dacarbazine and temozolomide) (SEDA-32, 827)... 

In contrast to the results with SAB, when cells were exposed to the monofunctional alkylating agent, N-methyl-N -nitro-N-nitrosoguanidine (MNNG), SCE frequency remained low in those cells exposed in mid to late S phase and was highest in cells exposed in Gi or early S phase. Thus, as has been shown by others with ultraviolet light or 8-methoxypsoralen-induced DNA lesions (12, IS), MNNG exposure resulted in lesions that lead to SCE formation only when the lesions were produced prior to the replication of the chromosome, i.e., ahead of the repUcation foik. 

It seems certain that the effect of SAB on the cytotoxicity and DNA repair of cells treated with monofunctional alkylating agents is mediated via an inhibition of ADP-ribosyl transferase activity (7, 8). Nevertheless, the pleiotropic effects of SAB could result in the modulation of the cytotoxicity of other dmgs independent of ADP-ribosyl transferase inhibition. In this paper, we describe the cytotoxic effects of SAB on a range of purine base and nucleoside analogues. The data lead us to hypothesize that SAB modulates purine analogue cytotoxicity by mechanism(s) independent of DNA repair inhibition, but involving effects on de novo purine biosynthesis and nucleoside transport. 

Fig. 1. Base analogue cytotoxicity is potentiated by the benzamides. Survival of CHO-K1 cells treated with base analogues in the presence (O) or absence ( ) of 3mM 3-aminobenzamide (3AB). Potentiation of cytotoxicity of a monofunctional alkylating agent, dimethyl sulphate, by 3AB is shown for comparison.

In conclusion, SAB enhances the cytotoxicity of a range of purine analogues by a mechanism which is probably independent of ADP-ribosyl transferase inhibition. The DBF values obtained are comparable or greater than those obtained with a monofunctional alkylating agent, DMS. Furthermore, the purine analogues are of major clinical value and these data indicate a role for the benzamides in chemotherapy. 

Methyl-methan-sulphonate (MMS) is a monofunctional alkylating agent producing alkylation of the bases (mainly guanine and adenine) and therefore apurinic sites that are easily transformed to single strand breakage (1). Our data obtained with "in vivo" treatments indicate 1) a modest reduction of the hyperchromicity due to... 

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