A theoretical explanation of "concomitant resistance".

Concomitant resistance is a tumor growth dynamic which results when the growth of a second tumor implant is inhibited by the presence of the first. Recently, we modeled tumor growth in the presence of a regenerating liver after partial hepatectomy (Michelson and Leith, Bull. Math. Biol. 57, 345-366, 1995), with an interlocking pair of growth control triads to account for the accelerated growth observed in both tissues. We also modeled tumor dormancy and recurrence as a dynamic equilibrium achieved between proliferating and quiescent subpopulations. In this paper those studies are extended to initially model the concomitant resistance case. Two interlocking model systems are proposed. In one an interactive competition between the tumor implants is described, while in the other purely proportional growth inhibition is described. The equilibria and dynamics of each system when the coefficients are held constant are presented for three subcases of model parameters. We show that the dynamic called concomitant resistance can be real or apparent, and that if the model coefficients are held constant, the only way to truly achieve concomitant resistance is by forcing one of the tumors into total quiescence. If this is the true state of the inhibited implant, then a non-constant recruitment signal is required to insure regrowth when the inhibitor mass is excised. We compare these theoretical results to a potential explanation of the phenomenon provided by Prehn (Cancer Res. 53, 3266-3269, 1993).