TRANSFORMING GROWTH-FACTOR BETA(1)-INDUCED CELL-DEATH IN PRENEOPLASTIC FOCI OF RAT-LIVER AND SENSITIZATION BY THE ANTIESTROGEN TAMOXIFEN

Previous studies have shown 5- to 10-fold higher rates of apoptosis in prestages of liver cancer (putative preneoplastic cell foci [PPF]) th an in unaltered liver; fasting or withdrawal of tumor promoters enhanc ed apoptosis even further. We studied whether transforming growth fact or beta(1) (TGF-beta(1)), an inducer of apoptosis in normal liver, mig ht be involved in induction of apoptosis in PPF. PPF were produced in 7-week-old female Sprague-Dawley rats with a single oral dose of the g enotoxic carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). At 24 weeks of age, TGF-beta(1) was injected into animals (40 mu g/kg intravenous ly) either once and they were killed 4 hours later (single-dose experi ment) or eight times at 24-hour intervals and they were killed 24 hour s after the last administration (multiple-dose experiment). Further su bgroups received daily subcutaneous injections of tamoxifen (TAM) (8 m g/kg) for 4 consecutive weeks before TGF-beta(1) treatment. In normal liver, the apoptosis incidence was low in solvent- and TAM only-treate d animals, in the single- as well as the multiple-dose experiment, TGF -beta(1) increased the apoptosis incidence severalfold, and the combin ed administration of TGF-beta(1) with TAM caused a further strong incr ease. The already-elevated basal apoptotic incidence in PPF was furthe r increased by TGF-beta(1) and particularly by TGF-beta(1) plus TAM tr eatments, which resulted in a reduction of foci number and size. In su mmary, these results show that TGF-beta(1) can induce apoptosis in PPF , This apoptosis-inducing activity is strongly enhanced by the additio nal treatment with the antiestrogen TAM, which by itself does not have any cell death-inducing effect in the liver or PPF. The elevated apop totic activity of PPF in response to TGF-beta(1) can lead to a selecti ve reduction of the liver load with preneoplastic cells.