Alkylation of the O6 of guanine is only one of many chemical events that may initiate carcinogenesis.

The original hypothesis that chemical alteration of DNA can ultimately lead to carcinogenesis had been extended to a concept that the presence and persistence (lack of removal) of O6-alkyl G in an organ or cell population is the important requirement for tumorigenesis by alkylating agents. There are, however, many examples given in the text in which the organ specificity does not correlate with the amount of O6-alkyl G, and indeed, in some instances, no tumors result even though it can be shown that the DNA of many organs contains O6-alkyl G and that cell proliferation occurs. In some cases, there are clearly genetic factors. For example, the brain tumor incidence in two mouse strains differ but O6-alkyl G persistence is the same. Differing amounts or repair capability of O6-alkyl G in species, organs, or cells is not sufficient to explain variations in tumor incidence. Consideration must be given to other alkyl derivatives formed by alkylating carcinogens since at least six derivatives can lead to mispairing. Additionally, depurination has profound biological effects and evidence is emerging that bulky carcinogens such as aflatoxin and N-hydroxy-acetylaminofluorene cause rapid depurination (42). The role of phosphotriesters is as yet unknown. In attempting to come to a conclusion concerning the mode of tumor initiation by alkylating agents, we must not ignore the differences between alkyl groups. Dr. Pegg's paper focuses mainly on methylation, while my arguments stress ethylation. When the number of O6-methylguanines greatly exceeds that of O-methyl-pyrimidines, the former is more likely to be the initiating event. However, ethylation is generally more carcinogenic than methylation, if one considers that much less total alkylation is necessary for tumor development. The O-ethylpyrimidines produced by N-nitroso ethylating agents are more numerous than the O6-ethylguanines and they appear to be more persistent; that is, poorly repaired. Table 3 in Dr. Pegg's paper gives strong support to the potential initiation efficiency of the O4-ethylthymine and perhaps even to the idea that some yet-unidentified event is responsible for the carcinogenicity of diethylnitrosamine.(ABSTRACT TRUNCATED AT 400 WORDS)