The estrogenic and antiestrogenic activities of tamoxifen ICI 47,699, enclomiphene, zuclomiphene, and the geometric isomers of monohydroxytamoxifen and CI628 were determined in the 3-day immature rat uterine weight test. Tamoxifen, enclomiphene, and the releated geometric isomers of monohydroxytamoxifen and CI628 were partially estrogenic with antiestrogenic properties. ICI 47,699 and zuclomiphene were predominantly estrogenic; however, an antiestrogen effect for zuclomiphene (100 micrograms daily) was demonstrable and large doses of ICI 47,699 (1 or 10 mg daily) inhibited full estrogen action. In contrast, the geometric isomers of monohydroxytamoxifen and CI628 related to ICI 47,699 and zuclomiphene were partially estrogenic with antiestrogenic properties. The estrogenic properties of ICI 47,699 were classified in three ways: elevation of uterine wet weight, increase in whole uterine DNA, and increase in the mitotic activity of luminal epithelial cells. In general, ICI 47,699 was able to initiate estrogenic responses of DNA synthesis or mitosis by translocation of fewer cytoplasmic estrogen receptors to the nuclear compartment than tamoxifen. A model is proposed to explain antiestrogen action in terms of the geometric requirements for receptor binding. It is suggested that the position in space of the alkylaminoethoxyside chain is of fundamental importance. Overall, these data lend support to the view that a structurally specific ligand-estrogen receptor complex can influence the future events within a target tissue to produce either an agonist or an antagonist response.

One of the major practical applications of carcinoembryonic antigen (CEA) assay is the monitoring of colorectal carcinoma patients after complete tumor resection. During the last 5 years, we have followed by repeated CEA assays 66 patients with histologically confirmed colon or rectum adenocarcinoma. Among 19 patients who developed a tumor recurrence, 17 had increased CEA levels preceding the clinical diagnosis by 2 to 26 months. Among the 47 patients who did not show any clinical evidence of tumor recurrence, 35 had CEA values remaining below the limit of 5 ng/ml, whereas 12 had moderate elevations of CEA level fluctuating around this limit. The majority of patients in this last group were heavy smokers or had liver enlargement, but in a few of them we did not find a satisfactory explanation for their moderately increased CEA levels. While our results confirm that repeated CEA assays can predict tumor recurrence with a lead time of several months over clinical diagnosis, they also give a word of warning concerning the interpretation of moderate elevations of CEA level. A moderate increase of CEA level can be the result of early distant metastases, local recurrence or exacerbation of an inflammatory disease. We feel that the decision of second look operations based on CEA results should be made only if increasing CEA values have been observed on three different blood samples taken within a period of 3 months and if no nonmalignant diseases known to increase CEA level are present. Ultimately only randomized clinical studies will determine if second look operations motivated by elevated CEA levels can improve the quality and length of survival of patients with colorectal carcinoma.

No abstract