Effects of carbamoylating agents on tumor metabolism

Abstract

Carbamoylation of macromolecules occurs by the displacement of hydrogen on several groups, but the most stable addition at neutral pH is on amino groups. This reaction occurs predominantly with proteins and results from the administration in vivo of inorganic cyanate or organic isocyanates. The latter act more rapidly, but also are more rapidly hydrolyzed in aqueous solution. This instability has been a factor limiting study of the pharmacological properties of organic isocyanates. However, organic isocyanates are released from some nitrosoureas of value in cancer therapy such as 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). The carbamoylating activities of BCNU and CCNU are generally considered less significant than their alkylating activity in the action of these drugs on tumors, but carbamoylation may serve to inhibit DNA repair. There is evidence that carbamoylating agents can exert selective inhibitory effects on metabolite uptake and macromolecular synthesis in neoplastic tissues. Such selectivity is much more notable in vivo than in vitro. In the case of cyanate, the selectivity in vivo has been variously attributed to a requirement for metabolic activation, to selective effects on circulation in solid tumors, and to diminished pH in tumors. It is the distinction between such factors and the identification of critical cellular targets which provide major challenges in present studies on the effects of carbamoylating agents on tumor metabolism.