Fucosylated forms of alpha-1-antitrypsin that predict unresponsiveness to chemotherapy in ovarian cancer

Abstract

We have discovered modified fucosylation of alpha 1-antitrypsin (F-AT) in the sera of ovarian cancer patients. This was detected by SDS/electrophoresis and silver-staining after extracting the sera with the fucose-binding lectin, Lotus tetragonolobus, and was identified as alpha 1-antitrypsin by Western blotting. Initially, high F-AT levels appeared to be related to the recurrence of cancer, but later measurements showed that elevated levels were also present in patients who did not respond to therapy. Using an arbitrary grading system, the level of F-AT was assessed in pairs of sera from 29 ovarian cancer patients undergoing therapy; one specimen collected just after the start of therapy and the other on a later occasion. In 75% of the 15 non-responders, F-AT was higher when measured on a second occasion; whereas in 86% of the 14 responders the second measurement was either unchanged or lower, being frequently undetectable. F-AT levels were also low or undetectable in sera from healthy women. Eight responders were monitored for F-AT throughout cyclophosphamide chemotherapy. Despite a high tumour burden at the start of therapy, all patients had relatively low levels of F-AT and this was maintained throughout remission; the levels only becoming elevated with the recurrence of tumour growth. Increased F-AT expression did not appear to be particularly associated with the presence of liver metastases and frequently predated any clinical signs of a recurrence. The interesting characteristics of these molecules could make them useful in the management of ovarian cancer.