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The neoplastic cellular phenotype expresses many embryonic features. These features are believed to occur by derepression of embryonic genes during the carcinogenic process. A specific case is the ability of ethionine, a hepatocarcinogen, to induce an embryonic protein known as alpha-fetoprotein. A mechanism is proposed for this derepression process along with supporting evidence. It is hypothesized that the repressor protein for the alpha-fetoprotein gene must be modified (methylated) before it is functional and if for any reason this does not occur, alpha-fetoprotein will be produced. This simple theory can explain a variety of states of the liver cell in which alpha-fetoprotein is expressed namely i) fetal, ii) ethionine-treated, iii) neoplastic, and iv) tyrosinemic liver cells.

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Dimethylaminoazobenzene, carbon tetrachloride, and ethionine, which can induce cancer cells in rat liver, were found to increase rat liver tRNA methylase activity. Other chemicals (aminoazobenzene, acetylaminofluorene, alpha-naphthylisothiocyanate, beta-naphthylisothiocyanate, dimethyl and diethylnitrosamine, and methylcholanthrene), which may be hepatotoxic or carcinogenic, produced either no increase or only slight increases in liver tRNA methylase activity of rat liver tissue. Although no increase was observed with the powerful hepatocarcinogen aflatoxin, others have recently reported an increase in tRNA methylase activity using larger doses than those reported here. Ethionine was able to increase liver tRNA methylase activity in guinea pigs as well as rats, as previously described, but not in chicks.

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Immunoelectrophoresis showed that rabbit anti-human alpha-fetoprotein (AFP) cross-reacts with monkey AFP which was not detectable in the serum from an adult non-pregnant monkey. A heterologous radioimmunoassay of monkey AFP was developed using this antiserum which circumvented the need for purified monkey AFP. The radioimmunoassay is of sufficient sensitivity to measure AFP in maternal and fetal serum and amniotic fluid in the rhesus monkey.

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Serial maternal serum alpha-fetoprotein (AFP) levels were determined by radioimmunoassay in patients with abnormal pregnancies and after saline-induced abortion. Results from patients presenting with mild or severe preeclampsia, fetal growth retardation and severe diabetes did not differ from the normal range. However, in patients with premature labor, the majority of AFP levels were significantly below the normal range, and peak AFP levels were achieved approximately one month earlier than normal. In patients whose pregnancies were terminated by abortion, the AFP levels exhibited a significant rise within a few hours after induction because of resorption of fetal elements into the maternal circulation.

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Retardation of growth and death of fetal rats were produced after uteroplacental ischaemia was induced by surgical ligation of the uterine arteries. Changes in maternal plasma levels of alpha-fetoprotein (AFP) were measured by radioimmunoassay. In rats in which the uterine blood supply was totally occluded, the resultant increase in maternal plasma AFP was due to resorption of fetal elements, because AFP levels in maternal rat plasma did not increase following hysterectomy in a control group. Maternal plasma AFP levels in rats with a partly occluded blood supply (and therefore some dead and some live fetuses) paralleled those of sham-operated rats, suggesting that increased placental transfer of AFP to maternal plasma may have offset the anticipated decline of AFP due to a decreased number of live fetuses.

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A method is described for the isolation of mg quantities of two forms of rat alpha-fetoprotein (AFP) from amniotic fluid by preparative disc-gel column electrophoresis using a continuous elution system. AFP isolated by this method is suitable for use as an antigen, can be labelled for use in a radioimmunoassay and serves as a reference standard. The characteristics of a new antiserum to AFP are also described. The protocol for a radioimmunoassay is outlined which permits the measurement of AFP in several fetal-maternal physiological compartments throughout gestation. Levels of AFP in fetal liver and fetal plasma suggest that secretion of AFP from liver occurs soon after synthesis with minimal hepatic storage. The pattern for AFP in maternal serum parallels that observed in amniotic fluid and fluctuations in maternal serum levels of AFP appear to be buffered by AFP accumulation in amniotic fluid. Fetal clearance of AFP under normal conditions may be relatively constant from Days 11-20 of gestation since an amniotic fluid: maternal serum AFP ratio of 30:1 is maintained during this period.

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Serial measurements of alpha-fetoprotein (AFP) were made in 63 normal pregnancies throughout gestation using a radioimmunoassay. Significant levels of AFP, which were detected as early as at 10 weeks gestation, showed a gradual rise until 32 weeks, after which the levels declined until term. The limits of the normal gestational pattern have been defined and the intrapatient variability of the assay was examined. A comparison of the clinical characteristics of the pregnancies with levels of AFP was made. Higher birth weights were correlated with later attainment of peak levels of AFP and peak levels were achieved earlier in gestation in female fetuses. Higher levels of AFP and lower oestriol/AFP ratios were correlated with an earlier onset of labour.

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An experiment was conducted to determine if any changes resulted in the proportion of hepatic messenger RNA following treatment with ethionine, a hepatocarcinogen. The relative specific activity of the total RNA isolated from nontumor-like tissues was increased in Sprague-Dawley rats fed ethionine. However, the percentage of total RNA that was message was found to be decreased in the ethionine-treated rats.

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Human alpha-fetoprotein (AFP) was isolated from cord serum on an immunoadsorbent column obtained by covalently linking rabbit anti AFP to cyanogen bromide activated Sepharose. Bound AFP was eluted with 8 M urea with better than 50% recovery. The purified AFP was iodinated prior to its use in a double antibody radioimmunoassay. The purification and radioimmunoassay employ commercially available materials. A standard inhibition curve was obtained which allowed determination of AFP levels between 50 and 100 ng/ml in human serum. The assay was verified by measureing AFP levels in normal female serum, pregnancy serum, cord serum, hepatoma ascitic fluid and a standardized AFP solution.

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