NUCLEOTIDE-METABOLISM AND CHROMOSOME ALTERATIONS IN HUMAN-MALIGNANT MELANOMA XENOGRAFTS

The karyotypes of human melanomas exhibit multiple chromosome alterati ons. Recurrent deletions of 9p, 10q and 14q arms, which carry genes en coding for enzymes of purine metabolism, were also found in human glio mas, another neuroectodermal tumor previously studied for both cytogen etics and nucleotides metabolism. Postulating that this metabolism mig ht also be modified in melanomas, the activities of eleven enzymes inv olved in catabolic and synthetic pathways of purine metabolism were me asured, in addition to two enzymes of the pyrimidine synthesis. Assays were performed on six melanoma mestastases, five nodal and one cutane ous, after transplantation into nude mice. The purine metabolism was c haracterized by a more active catabolic than synthetic pathway, a poss ible imbalance between de novo and salvage pathways for adenylates syn thesis, rather in favor of the de novo pathway, and a more active aden ylate than guanylate synthesis. The skin metastasis exhibited quite di fferent cytogenetic and metabolic patterns, when compared to the nodal metastases. Considering the relationships between cytogenetic and met abolic data, low activities of methylthioadenosine phosphorylase, aden osine kinase, adenosine monophosphate deaminase, nucleoside phosphoryl ase and 5'-nucleotidase were observed in melanomas, as well as frequen t losses of 9p, 10q, Ip, 14q and 6q arms respectively carrying genes e ncoding for these enzymes, most of these rearrangements were confirmed by chromosome painting. The two enzymes exhibiting the highest activi ties were adenosine deaminase and adenylosuccinate lyase, encoded by g enes mapped on chromosomes 20 and 22 respectively, frequently in exces s in melanomas. Thus, for these tumors, the metabolic pattern roughly parallels the cytogenetic profile, even if the absence of case to case correlation suggests that gene dosage effect, if it occurs, is not th e only parameter involved. The main enzymatic and cytogenetic differen ce between melanomas and gliomas, concerns both adenylosuccinate lyase activity and the balance of chromosome 22, high in melanomas and low in gliomas.