Biochemical programs of slowly and rapidly growing human colon carcinoma xenografts
Weber, G.; Hager, J.C.; Lui, M.S.; Prajda, N.; Tzeng, D.Y.; Jackson, R.C.; Takeda, E.; Eble, J.N.
Cancer Research 41(3): 854-859
1981
ISSN/ISBN: 0008-5472 PMID: 7459871 Document Number: 172564
The enzymic programs of pyrimidine, carbohydrate and purine metabolism and the pattern of pyrimidine and purine ribonucleotides were studied in 2 lines of human colon carcinoma xenografts of different growth rates. The slower-growing colon tumor line was well differentiated; the more rapidly growing line was a poorly differentiated one. The carcinoma xenografts were carried in nude mice. The increased malignancy and growth rate of the rapidly growing colon tumor were characterized by a markedly amplified imbalance in the enzymic programs and nucleotide patterns. In the rapidly growing carcinoma line, the activities of synthetase, orotidine 5'-monophosphate decarboxylase, orotate phosphoribosyltransferase and those of thymidine kinase, uracil phosphoribosyltransferase and uridine kinase were markedly higher than those in the slower-growing tumor line. The activities of hexokinase, phosphofructokinase, pyruvate kinase and of those of glucose-6-phosphate and 6-phosphogluconate dehydrogenases and transaldolase were also elevated in the rapidly growing neoplasm. The activity of phosphoribosylpyrophosphate synthetase was also augmented. In the purine metabolism of the rapidly growing carcinoma, there was an increase in the activity of glutamine phosphoribosylpyrophosphate amidotransferase; the activities of xanthine oxidase and inosine phosphorylase were decreased. The activities adenosine 5'-phosphate deaminase and of inosine 5'-phosphate dehydrogenase also were elevated in the rapidly growing colon tumor lines. The enzymes that were identified as progression linked in the rat hepatoma system were also progression linked in the 2 human colon carcinomas of different growth rates (CTP synthetase, thymidine, kinase, hexokinase, phosphofructokinase, pyruvate kinase, inosine 5'-phosphate dehydrogenase and adenosine 5'-phosphate deaminase). There was a marked enlargement of the pools of adenylates, guanylates, uridylates and cytidylates in the rapidly growing neoplasm. The high activities of de novo and salvage pathways of pyrimidine biosynthesis and the elevated enzymic capacities in carbohydrate catabolism and in purine biosynthesis, along with the large pools of pyrimidine and purine ribonucleotides, may account for, in part at least, the clinical difficulties encountered in the chemotherapy of human colon neoplasia. The molecular correlation concept should be helpful in the rational design of enzyme pattern-targeted chemotherapy of colon tumors.