Molecular Basis of the Reversibility of the Stage of Tumor Promotion

27 May

The theoretical  and practical aspects of ligand-receptor  interactions  have been previously  re- viewed (cf. Pitot, 1995). Herein such relationships are considered as they concern the action of tumor promoters. The basic assumption of the ligand-receptor interaction is that the effect of the agent is directly proportional to the number of receptors occupied by that chemical ligand and that a maximum response of the target is obtained only when all receptors are occupied. As seen in Figure 7.13, a simple bimolecular interaction between the ligand and receptor can be utilized to determine a dissociation constant, KL, of the receptor-ligand complex. Although a variety of

mathematical relationships may be derived from this simple equation (cf. Ruffolo, 1992), only the dose-response relationship is considered here. The dose-response of the receptor-ligand  in- teraction takes the shape of a sigmoidal curve identical to that seen with the inhibition of TPA binding depicted in Figure 7.5. The figure denotes a threshold response at very low doses and a maximal  effect above a specific  dose. Theoretically,  the linear conversion  of the sigmoidal curves, such as seen in Figure 7.5, may indicate effects at even lower doses than those usually studied, but this depends on the association constant of the ligand-receptor complex and the sub- sequent fate of the complex (Aldridge, 1986). Withdrawal of the ligand reverts the system to its original  state. Thus, the regulation  of genetic expression  that occurs by the ligand-receptor mechanism  predicts  a threshold  and reversible  effect unlike that of genotoxic  carcinogenic agents, in which an irreversible  nonthreshold  response is assumed on theoretical grounds and can be demonstrated in a variety of instances (Druckrey, 1967; Zeise et al., 1987). Furthermore,

at very low doses of some carcinogenic agents, an apparent reversal or “protective” effect of the agent can actually be demonstrated. This phenomenon has been termed hormesis (Teeguarden et al., 1998). Regardless of whether this latter effect can be more generalized, it is apparent that both the measured dose response and the receptor mechanisms of tumor promotion imply a no- effect or threshold level for the action of these agents during carcinogenesis. Thus, the stage of tumor promotion, unlike that of initiation and progression, does not involve mutational or struc- tural events in the genome but rather is concerned with the reversible alteration of the expression of genetic information.

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