5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE AND P16(INK4) DEFICIENCY IN MULTIPLE TUMOR-CELL LINES

5'-Deoxy-5'-methylthioadenosine phosphorylase (MTA-Pase) gene is local ized at the 9p21 region linked to the recently identified putative tum or suppressor gene, p16(INK4), which appears implicated in the control of cell division cycle, The phosphorylase is a housekeeping enzyme in volved in the purine and amino acid metabolism whose activity is evide ntiable in all the normal tissues, Chromosomal deletions encompassing both MTAPase and p16(INK4) genes cause the total absence of the enzyma tic activity only in malignant cells, thus resulting in defined metabo lic differences between malignant and normal cells, MTAPase deficiency was investigated by direct radiochemical assay method and by immunoch emical techniques in 35 different human malignant cell lines establish ed from several tumor types, The enzyme-deficient cells derived from b reast, lung, ovary and liver cancer, malignant melanomas, malignant gl iomas and liposarcomas, Two of the MTAPase-deficient cell preparations (from a liver carcinoma and from a melanoma) are primary cultures thu s directly representing the original cancer genotypes, Several of the MTAPase-negative cells were studied for p16(INK4) gene deletions and f or p16(INK4) protein deficiency, In all the examined samples a full co rrelation exists between the lack of MTAPase and that of p16(INK4). A similar result was obtained analysing extracts of Vero cell line, whic h is a fibroblast MTAPase-negative cell line established from the kidn ey of a normal adult monkey, Conversely, Cos cells, which also are fib roblasts derived from monkey kidney, show both MTAPase and p16(INK4) p rotein, These results: (i) demonstrate that the phosphorylase deficien cy is distributed among almost all the most important human cancers; ( ii) confirm and extend the tumor types were p16(INK4) gene inactivatio n is observable and (iii) suggest that deletions at 9p21 (in humans) o r at syntenic chromosomes (in other species) might represent a general mechanism of p16(INK4) gene loss of function and possibly, in turn, o f cancer development and/or progression.