PREPROVIP-DERIVED PEPTIDES IN TISSUE AND PLASMA FROM PATIENTS WITH VIP-PRODUCING TUMORS

To elucidate the biosynthetic processing of the precursor for vasoactive intestinal peptide (prepro-VIP) in tumours producing VIP we have used newly developed radiommunoassays directed against the five functional domains of the VIP precursor molecule: prepro VIP 22-79, peptide histidine methionine (PHM), preproVIP 111-122, VIP and preproVIP 156-170 in combination with HPLC to identify and quantify the peptides in tumour specimen and plasma from patients with the watery diarrhoea syndrome. Elevated quantities of all the five peptides were found in the 13 tumours (nine neurogenic tumours, one pheochromocytoma, three pancreatic carcinomas) examined. The preproVIP derived peptides were expressed in non-equimolar amounts and the relative proportion of the various peptides differed markedly from tumour to tumour. The pheochromocytoma was the only tumour type which contained large amounts of preproVIP 156-170 in comparison with the other peptides. A proportion of the VIP precursor which varied from 7% to 73% followed a pathway in which the dibasic conversion site after PHM was uncleaved as evidenced by the presence of PHV, a C-terminally extended form of PHM. It was also found that unlike normal tissue a fraction of the C-terminal VIP precursor peptide, preproVIP 156-170, was having its C-terminal lysine residue removed during processing. The findings indicate that various post-translational processing pathways of preproVIP exist. All the peptides sequences produced in the tumour tissue were secreted as evidenced by their presence in plasma in elevated concentrations. The plasma levels of preproVIP 22-79, preproVIP 111-122 and PHV exceeded those of the remaining preproVIP-derived peptides suggesting that determination of these peptides in patients with VIP-secreting tumours may be better markers than VIP.