pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs

5 years ago

pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs

Philip G. Penketh, Elena S. Ratner, Raymond P. Baumann, Krishnamurthy Shyam, Rachel Sauro, Richard A. Finch

Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl-based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells. Laromustine is a prodrug of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE), a component with confirmed anticancer activity, and methyl isocyanate, a component of speculated benefit. Laromustine exhibits superior in vivo activity to analogs generating only 90CE. However, treatment with combinations of prodrugs that separately generate 90CE or methyl isocyanate resulted in antagonism. An alternative non-isocyanate-dependent explanation for the superior tumor selectivity of laromustine is presented based upon the pH sensitivity of its activation, and the typically more alkaline intracellular pH of tumor cells.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13057