1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]
hydrazine (
KS119) is a
prodrug of the 1,2-bis(sulfonyl)hydrazine class of
antineoplastic agents designed to exploit the
oxygen-deficient regions of cancerous tissue. Thus, under reductive conditions in hypoxic cells this agent decomposes to produce the reactive intermediate
1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), which in turn generates products that alkylate the O(6)-position of
guanine in
DNA. Comparison of the cytotoxicity of
KS119 in cultured cells lacking
O(6)-alkylguanine-DNA alkyltransferase (AGT) to an agent such as
Onrigin, which through base catalyzed activation produces the same critical
DNA G-C cross-link lesions by the generation of 90CE, indicates that
KS119 is substantially more potent than
Onrigin under conditions of
oxygen deficiency, despite being incompletely activated. In cell lines expressing relatively large amounts of AGT, the design of the
prodrug KS119, which requires intracellular activation by
reductase enzymes to produce a cytotoxic effect, results in an ability to overcome resistance derived from the expression of AGT. This appears to derive from the ability of a small portion of the chloroethylating species produced by the activation of
KS119 to slip through the cellular protection afforded by AGT to generate the few
DNA G-C cross-links that are required for
tumor cell lethality. The findings also demonstrate that activation of
KS119 under
oxygen-deficient conditions is ubiquitous, occurring in all of the cell lines tested thus far, suggesting that the
enzymes required for reductive activation of this agent are widely distributed in many different
tumor types.