KININ-GENERATING CASCADE IN ADVANCED CANCER-PATIENTS AND INVIVO STUDY

The role of the bradykinin-generating system in the pathogenesis of cancer was explored by simultaneously measuring plasma prekallikrein (PK), the precursor of kallikrein, which is the major enzyme responsible for kinin generation, and plasma kininogens (KNG), which are precursors of kinin, in patients with various cancers. The mean value of plasma PK in healthy volunteers was 2.5 +/- 0.5 (mean +/- SD) units/mg plasma protein and that in cancer patients (all stage IV) was 1.7 +/- 0.7 units/mg plasma protein. The mean value of plasma KNG in healthy volunteers was 12.5 +/- 2.0 ng kinin equivalents/mg plasma protein and that in cancer patients was 10.9 +/- 2.8 ng. These data showed that plasma PK and plasma KNG values were significantly lower in cancer patients compared with healthy volunteers (P less-than-or-equal-to 0.0005 for PK; 0.0005 < P less-than-or-equal-to 0.005 for KNG; n = 28 for healthy subjects; n = 29 for cancer patients). These data appear to indicate that conversion of PK to kallikrein would probably occur with concomitant consumption of KNG by newly generated kallikrein for kinin generation in cancer patients. Early stage cancer patients showed little difference from healthy volunteers. For the in vitro study, activation of purified Hageman factor (HF) and PK was examined by using cancer cell lines and virus-transformed cells that produced plasminogen activator (PA) at a high rate. Both HF and PK were activated in the presence of plasminogen. Diploid cell lines and primary fibroblasts, which did not produce PA, activated neither HF nor PK. Taking all these data together, we conclude that kinin generation does occur in the plasma of patients with advanced cancer, and that one of the initiation mechanisms of the kini-generating cascade appears to be mediated by plasmin and to depend on cancer cell-derived PA activity.