Comparative carcinogenicity of alkylating agents: comparisons of a series of alkyl and aralkyl bromides of differing chemical reactivities as inducers of sarcoma at the site of a single injection in the rat.

A series of alkylating and aralkylating bromides was used in a comparative study of chemical reactivity (using 4-(p-nitrobenzyl) pyridine as standard nucleophile), and carcinogenic activity (using single injections by the subcutaneous route in 6-week old female CB-hooded rats). Benzyl, ethyl, isopropyl, and trityl bromides were inactive as carcinogens at doses up to 0.83, 12.5, 8.3 and 0.25 mmol/kg, respectively. 7-Bromomethylbenz[a]anthracene and 7-bromomethyl-12-methylbenz[a]anthracene gave high yields of sarcomas at the injection site (in the right flank); at the highest doses used, 35% yield of tumors was obtained using 0.25 mmol/kg 7-bromomethylbenz[a]anthracene, and 75% yield with 0.056 mmol/kg of the 12-methyl homologue. The order of chemical reactivity was trityl greater than 7-bromomethyl-12-methylbenz[a]anthracenyl greater than 7-bromomethyl-benz[a]anthracenyl greater than benzyl greater than ethyl greater than isopropyl. The relationship suggested between carcinogenicity and reactivity is that the highest reactivity permitted little in vivo penetration to essential cellular receptor sites because of immediate solvolysis, whereas the lower reactivities did not ensure sufficient alkylation of such receptors. The bromomethylbenz[a]anthracenes (of intermediate chemical reactivity) are known to react with DNA in vivo, but so far no differences in reactivity between them can account for their quantitatively different carcinogenic potencies.