Alternative hypotheses for the role of promotion in chemical carcinogenesis.

A new protocol for carcinogenesis in rat liver is described in order that confirmatory experiments might be undertaken concurrently. The basic protocol, designated IPI (initiator + promoter + initiator), is presented in several alternative forms, including the possible use of X-irradiation as the initiator. The rationale is discussed in terms of the two-hit somatic mutation theory of Armitage and Doll, with an initial hit produced by the first dose of initiator and expansion of single cells to sizable clones by promotion thereby increasing the probability of a second hit by the second dose of initiator. The question of relevant mutations was taken up and it was proposed that genes for chalones (C) and for chalone receptors (R) are logical targets for consideration in a two-mutation sequence. Alternative hypotheses pertaining to promoter action were described in terms of possible mechanisms by which nonelectrophilic promoters might simulate a second mutation by increasing or decreasing the levels of a nonchromosomal replicating particle in target cells.