The kinetic properties of switch antimetabolites.
BACKGROUND
Maintaining homeostasis is the biological function of negative feedback, a process that plays a well-understood role in the biochemistry of antimetabolite drugs. An equally important property of living systems--the ability to respond to external stimuli by switching rapidly from one state to another--is mediated by positive feedback. Kinetic analysis of multi-enzyme biochemical pathways has shown that pathways containing positive feedback coupled with negative feedback may act as biochemical switching systems in which multiple steady states are possible.


OBJECTIVE
A computer model was used to study the kinetic effects of antimetabolites that inhibit biochemical pathways at positive feedback sites and to determine whether the kinetics of such systems differed from those of classical antimetabolites.


METHODS
Kinetics were simulated by microcomputer to model the effects of inhibitors on a simplified metabolic pathway.


RESULTS
Antimetabolite drugs that act at positive feedback sites are predicted to display highly nonclassical properties. Three nonclassical properties are kinetically possible. First, the drugs may switch off the pathway at substoichiometric concentrations; classical antimetabolites require stoichiometric levels and sometimes much more. Second, instead of demonstrating classical continuous inhibition, antimetabolite drugs that act at positive feedback sites may give "all-or-none" dose-response curves with discontinuity at a specific value. Inhibitor concentrations below this value would have no overall effect on the system, while inhibitor concentrations at or above this value would give an abrupt transition to an inhibited steady state. Third, the inhibited system may show hysteresis and remain switched off after the inhibitor is removed.


CONCLUSIONS
These findings suggest that antimetabolites acting at switch points could have kinetic properties very different from those of classical antimetabolites and could provide a noncytotoxic method of switching off pathways in neoplastic cells, perhaps leading to cell stasis.


CONCLUSIONS
Experimental validation of these conclusions will require identification of the positive feedback sites of metabolic and signaling pathways and exploration of the effects of inhibitors of these sites. The properties of "switch antimetabolites" should prompt a search for new kinds of targets for drug design.
Jackson
R C
RC
Agouron Pharmaceuticals, Inc., San Diego, CA 92121.
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005246:Feedback / Q000502:physiology; D007700:Kinetics; D008838:Microcomputers; D008956:Models, Chemical; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic