Natural and recombinant interferons (IFNs) have already demonstrated therapeutic efficacy, including cytogenetic remissions, in patients with chronic myelocytic leukemia (CML). We investigated at the level of ligand-receptor interaction the question whether heterogeneity of receptor number or affinity might contribute to primary or secondary treatment failures in CML. We therefore analyzed IFN-gamma and IFN-alpha receptor expression and regulation during treatment with recombinant IFN-gamma and IFN-alpha in 15 patients with advanced CML. We found no difference in number or affinity of constitutively expressed IFN-gamma receptors (mean 1,100) and, on average, a 30% reduction of IFN-alpha receptors (mean 750) on peripheral blood mononuclear cells (PBMNC) of patients with chronic or accelerated CML as compared to mature granulocytes and/or bone marrow cells of healthy controls, which express on average 1,050 and 1,100 IFN-gamma and IFN-alpha receptors, respectively. While IFN-gamma receptor expression on PBMNC is not influenced upon treatment with rIFN-gamma, there is a substantial downregulation of IFN-alpha receptors in the course of rIFN-alpha therapy. Our data also show a differential pattern of receptor downregulation between patients achieving complete hematologic remission (CHR) (4 out of 12) compared with patients with partial hematologic remission (PHR) and non-responders. We conclude that differences in IFN receptor number cannot explain primary or secondary treatment failures. However, the differential ligand induced downregulation of IFN-alpha receptors in patients achieving CHR compared to those with PHR or non-responders suggest a prospective value of IFN-alpha receptor determination.
Serum circulating immune complexes (CIC) were repeatedly measured by means of the CIq binding assay (Cba) and the Raji cell assay (Rca) in 158 patients with metastatic breast cancer (mbc). Frequency of occurrence and levels of CIC were only slightly increased in mbc when compared to age-matched healthy women. They were identical to those of patients with localized breast cancer prior to mastectomy and to those of post mastectomy patients without evidence of recurrent disease. In mbc the results of the Cba and the Rca showed a poor correlation, whereas in a control group of patients with rheumatoid arthritis both tests showed significantly elevated levels of CIC. Patients with mbc were followed up clinically and biochemically by serially measuring CIC for an average of 10 months. Patients with positive CIC did not prove to be an unfavorable group regarding progression of disease and response to chemotherapy. When CEA and CIC levels were compared, CIC, unlike CEA, was a poor tumor marker. In conclusion, CIC as measured by CIq binding assay and Raji cell assay are not clinically significant tumor markers or prognostic indicators in patients with metastatic breast cancer.
Im Rahmen von zwei Phase-I-Prüfungen wurde rekombinanter Tumor-Nekrose-Faktor-alpha (rTNF-alpha) zur Behandlung von 44 Patienten mit fortgeschrittenen Tumoren unterschiedlichster Histologien eingesetzt. Bei 30 Patienten wurde rTNF-alpha 3 ×/Woche intramuskulär in Dosen zwischen 25–300 meg verabreicht, 14 Patienten erhielten rTNF-alpha intra/peritumoral 1–3 ×/Woche ebenfalls in diesem Dosisbereich. Die maximal tolerierte Dosis (MTD) lag für beide Applikationsformen bei 150 meg/m2 rTNF-alpha. Die Behandlungs-dauer bei systemischer Gabe betrug 1–26 Wochen, bei lokaler Applikation 2–20 Wochen. 25 Patienten, die rTNF-alpha i.m. erhielten, konnten bzgl. ihres Tumorresponse ausgewertet werden. Bei 2 Patienten wurde ein Minor Response (MR), bei 9/25 Patienten ein Wachstumsstillstand beobachtet. 5/14 Patienten, die rTNF-alpha intra/peritumoral erhielten, zeigten eine vorübergehende Tumorrückbildung (3 PR, 2 MR). An wesentlichen subjektiven Nebenwirkungen traten dosisabhängig Fieber, Schüttelfrost, Appetitlosigkeit und Übelkeit auf. In den Dosisgruppen > 50 meg/m2 wurden Blutdruckerniedrigungen bis WHO-Grad III gemessen. An hämatologischen Veränderungen wurden vorübergehende Erniedrigungen von Leuko- und Thrombozyten gemessen, ohne daß sich Hinweise für eine kumulative hämatologische Toxizität ergaben. Andere Organtoxizitäten wurden nicht nachgewiesen. Die Ergebnisse aus beiden Studien belegen eine potentielle antitumorale Aktivität von rTNF-alpha, wobei eine lokoregionale Applikation auf eine höhere Effektivität hindeutet. Die bisher dokumentierten subjektiven Toxizitäten scheinen zunächst eine umfangreichere An-wendung in klinischen Studien zu limitieren.
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