Page 210 - 20dynamics of cancer

CARCINOGENS 195

Test.—Apply a mutagen continuously. If all steps are affected equal-
ly, then untreated and treated animals should have approximately the
same slope of the incidence curve (log-log acceleration, LLA), because
they have the same number of rate-limiting steps. The treated animals
should, however, have a higher intercept for their age-incidence curve,
because their transitions happen at a faster rate. If some transitions are
more sensitive than others, then the LLA of the incidence curve should
decrease with increasing dose because, as dose rises, an increasing num-
ber of steps should change from rate limiting to not rate limiting. The
fewer the number of rate-limiting steps, the lower the LLA.

Hypothesis for mechanism of initial carcinogen treatment.—The primary
effect is mutation of the first rate-limiting step in multistage progres-
sion.

Test.—Compare age-onset curves in mice with wild-type H-ras and H-
ras mutated in one of the carcinogenic codons, each mouse genotype
either treated or not treated with a single dose of an initial carcino-
gen. To get enough tumors for comparison, the mice could have a
cancer-predisposing genotypic background with changes distinct from
the functional consequences of H-ras mutation. If the initial carcinogen
treatment only has a tumorigenic effect through mutation of H-ras as the
first rate-limiting step, then the untreated, wild-type mice would have to
pass one more step than either of the other three treatments: mutated
H-ras with or without initial carcinogen treatment and wild-type H-ras
treated with an initial carcinogen. An additional rate-limiting step to
pass should cause the slope of the incidence curve (LLA) to be one unit
higher than in treatments that rapidly pass that step.

Hypothesis for order of stages affected.—Certain carcinogens affect only
a particular transition in an ordered series of stages of progression.

Test.—Suppose carcinogen A is thought to affect primarily an early stage,
such as H-ras mutation in skin tumors, and carcinogen B is thought to
affect primarily a late stage, such as p53 mutation in skin tumors. The
following comparisons support the hypothesis. If A acts early and B
acts late, then the difference in incidence between A early and A late is
greater than the difference between B early and B late. If A acts early
and B acts late, then the combination of A applied early and B applied
late has a stronger effect than B applied early and A applied late.