Kinetics of induction and growth of enzyme-deficient islands involved in hepatocarcinogenesis.

A single application of various hepatocarcinogens to rats results in the formation of islands of enzyme-deficient liver cells, which are mainly irreversible and very probably represent the first cellular stage involved in the process of liver cancer formation. Comparison of the island-size distributions obtained for different carcinogens indicated that proliferation is a common property of islands that is independent of the inducing carcinogen and does not need any further presence of carcinogen or other stimulating factors. Toxic doses resulted in all cases in an enhanced island size. The number of islands induced by a single dose of carcinogen was enhanced by a prior partial hepatectomy only in the case of the dialkylnitrosamines, dimethylnitrosamine, and diethylnitrosamine. Dose-response relationships measured with diethylnitrosamine, the carcinogen with the lowest toxicity as compared with the carcinogenic action, indicated that island formation is due to a one-hit process, i.e., that one specific alteration in the target cell is responsible for the precancerous transformation. These kinetics and the low probability of transformation might indicate that the crucial hit is scored at the genetic level. The irreversible action of carcinogen (memory effect) and the influence of time on cancer formation (time effect) are discussed in terms of induction and proliferation of irreversible cell populations serving as precursor of the cancer cell. The number of specific alterations (hits) involved in the development of the malignant cancer cell is also briefly discussed.