[New approach in the pharmacologic treatment of cancer]

Carcinogenesis comprises a progressive disorganization of architectural structure as well as a derangement of regulation of normal cell replication and differentiation. This transpires over a variable length of time at each biologic stage. Starting at the molecular level, inherited or acquired errors are associated with alterations in phenotype at successively higher levels of subcellular, cellular and architectural structure and function. Thus the well-known "Vogelgram" invokes as a unifying theme the presence of multiple, sequential, functional and structural genetic perturbations that in the aggregate, cause a temporal progression in tumor formation. While these have commonly been thought of as "steps" or "stages" of initiation, promotion and progression, pathologically regarded as the dysplasia or adenocarcinoma sequence, a given series of tumors examined for these changes shows considerable variation in the nature of the manifested genetic changes. Thus progression toward invasive neoplasia is not inexorable, and is opposed by restorative factors that normally operate in healthy and even damaged tissues. Limited damage is recognized and repaired, while cells damaged beyond repair are culled and replaced. As might be expected, such restorative functions perform most effectively early in the mutagenic/carcinogenic process where relatively normal structure and function persist. The evolutionary conflict between these multiple opposing forces likely results in the multi-step and multipath natures described in current models of carcinogenesis.