Methylthioadenosine phosphorylase deficiency in human non-small cell lung cancers.
Methylthioadenosine (MeSAdo) phosphorylase, a purine metabolic enzyme, is present in all normal mammalian tissues. A deficiency of this enzyme has been reported in some human leukemias and lymphomas and in a few solid tumors. In the present study, a specific immunoassay was used to assess the enzyme levels in human non-small cell lung cancer cell lines and primary tumors. We also tested the effects of MeSAdo phosphorylase-selective chemotherapy on the in vitro growth of enzyme-positive and enzyme-negative lung cancer cell lines. Of 29 non-small cell lung cancers, 9 (6 cell lines and 3 primary tumors, 31%) lacked detectable immunoreactive enzyme protein. Both 5,10-dideazatetrahydrofolate, an inhibitor of de novo purine synthesis, and methionine depletion, combined with MeSAdo, prevented the growth of the enzyme-negative non-small cell lung cancer cells under conditions in which enzyme-positive cells utilized MeSAdo to endogenously synthesize purine nucleotides and methionine. Our data suggest that MeSAdo phosphorylase deficiency is frequently found in non-small cell lung cancers and can be exploited in designing enzyme-selective chemotherapy.
Department of Medicine, University of California, San Diego, La Jolla 92093-0663.
T
T
Nobori
I
I
Szinai
D
D
Amox
B
B
Parker
O I
OI
Olopade
D L
DL
Buchhagen
D A
DA
Carson
D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology*; D003839:Deoxyadenosines / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency*; D013763:Tetrahydrofolates / Q000494:pharmacology / Q000627:therapeutic use; D013872:Thionucleosides / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D003839:Deoxyadenosines; D013763:Tetrahydrofolates; D013872:Thionucleosides; C008500:5'-methylthioadenosine; C045894:lometrexol; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase