Summary.-In a retrospective study the postoperative time courses of CEA in colorectal cancer patients with recurrent disease were analysed. In 87/114 cases with increasing concentrations of circulating CEA under close follow-up a linear relationship between log CEA and time could be established during disease recurrence. The individual doubling times of the serum CEA concentration in the log CEA period were calculated and found to cover distinct ranges dependent on the diagnosis of disease recurrence. The CEA doubling times concomitant with local recurrence or second primary carcinomas ranged from 142 to 868 days, visceral metastasis other than liver metastasis from 47 to 231 days and liver metastasis from 10 to 102 days. Patients with bone metastases exhibited CEA doubling times of 54-60 days and a patient with brain metastasis had a CEA doubling time of 598 days.

Summary.-In a clinical investigation of observed postoperative survival, 563 patients have been registered for primary surgical treatment of colorectal cancer since 1974. The potential prognostic factors examined within the first days of hospitalization for primary resection included age of the patients, operability, location of the tumour, tumour extension and the preoperative serum CEA level. Statistical treatment of the data revealed that each of the clinical parameters except tumour location covers ranges associated with highly significant differences in survival of the patients. The preoperative serum CEA level gave prognostic information in addition to operability or tumour extension. The prognostic significance of the preoperative CEA level was still evident when selected subgroups of patients with distinct resectability and tumour extension were examined. The results indicate that the preoperative serum CEA level is an independent prognostic parameter.

Immunohistochemical methods were used to determine abundance and subnuclear distribution of DNA topoisomerase I and the Bax protein in normal and excision-repair-deficient xeroderma pigmentosum (XP) fibroblasts after irradiation of cells with gamma rays or UV light, or exposure to the topoisomerase I inhibitor topotecan. DNA topoisomerase I and Bax were monitored using antisera raised against the human proteins. In addition, topoisomerases IIalpha and IIbeta were made visible with specific antibodies. In untreated cells, DNA topoisomerase I was found to occur in the cytoplasm and in nucleoli. Irradiation with gamma rays (2-12 Gy) or UV light (0.3-1.2 mW/cm2) changed the staining pattern in nuclei such that a multitude of small topoisomerase-I-rich centers occurred, which were evenly distributed over the karyoplasm. Simultaneously nucleoli disintegrated. Treatment of fibroblasts with topotecan (6-100 microM concentrations) resulted in similar alterations although the changes were much more pronounced. Combinations of topotecan and gamma irradiation caused additive effects. We conclude that the increase in the number of topoisomerase-I-positive spots and the high fluorescence intensity of the latter may reflect three biological processes: (i) enhanced transcriptional activity (e.g. of DNA damage response genes), (ii) tagging of damaged DNA sites for repair, or (iii) initiation of apoptosis. In separate assays using normal and XP cells, a dose-dependent increase in protein reacting with Bax antibody was observed in nuclei, following treatment with gamma rays or topotecan. In addition, topotecan induced a netlike arrangement of this Bax protein in nuclei. The meshes of the net structure resembled vesicles. DNA staining with 4',6-diamidino-2-phenylindole dihydrochloride revealed that the vesicle-type structures contained DNA. Upon further incubation with topotecan, cells showing the netlike Bax arrangement eventually died. We conclude that topotecan-induced changes made visible by nuclear Bax protein are associated with apoptosis. XP cells, when treated with topotecan, responded more readily than normal cells with both an increase in nuclear Bax protein and rearrangement of Bax, indicating that UV repair functions may be required to process DNA damage inflicted by topotecan. Monitoring of DNA topoisomerases IIalpha and IIbeta in gamma-irradiated cells with antibodies revealed a dramatic increase in the IIalpha form and a redistribution of the IIbeta form representing fragmentation of nucleoli.

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