Biochemical programs of slowly and rapidly growing human colon carcinoma xenografts.

The purpose of this investigation was to elucidate the enzymic programs of pyrimidine, carbohydrate, and purine me tabolism and the pattern of pyrimidine and purine ribonucleotides in two 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 car ried in nude (athymic) mice. The increased malignancy and growth rate of the rapidly growing colon tumor were characterized by a markedly ampli fied imbalance in the enzymic programs and nucleotide pat terns. In the rapidly growing carcinoma line, the activities of enzymes of the pyrimidine de novo biosynthesis (cytidine 5'triphosphate synthetase, orotidine 5'-monophosphate decarboxylase, orotate phosphoribosyltransferase) and those of the salvage pathways (thymidine kinase, uracil phosphoribosyl transferase, uridine kinase) were markedly higher than those in the slower-growing tumor line. The activities of the glycolytic enzymes (hexokinase, phosphofructokinase, pyruvate kinase) and of those of pentose phosphate production (glucose-6phosphate and 6-phosphogluconate dehydrogenases, transaldolase) were also elevated in the rapidly growing neoplasm. The activity of the enzyme that converts ribose 5-phosphate into phosphoribosylpyrophosphate (phosphoribosylpyrophosphate synthetase) was also augmented. In the purine metabo lism of the rapidly growing carcinoma, there was increase in the activity of the first enzyme committed to de novo biosyn thesis (glutamme phosphoribosylpyrophosphate amidotransferase); by contrast, the activities of the opposing purine catabolic enzymes (xanthine oxidase, inosine phosphorylase) were decreased. The activities of the enzyme that produces inosine 5'-phosphate from adenylates (adenosine 5'-phosphate deaminase) and of the rate-limiting enzyme of guanylate biosynthesis (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 two human colon carcinomas of different growth rates (cytidine 5'-triphosphate synthetase, thymidine kinase, hexokinase, phosphofructokinase, pyruvate kinase, inosine 5'-phosphate dehydrogenase, and adenosine 5'-phosphate deaminase). ' Recipient of USPHS Grants CA-13526 and CA-05034. To whom requests for reprints should be addressed. 2 Present address: Department of Immunology, Michigan Cancer Foundation, Detroit, Mich. 48201. 3 Permanent address: National Cancer Institute, Budapest, Hungary. ' Recipient of USPHS Grant CA-18129. 5 Permanent address: Department of Pediatrics, Tokushima University School of Medicine. Tokushima City, Japan. Received July 7, 1980; accepted November 11, 1980. There was a marked enlargement of the pools of adenylates, guanylates, uridylates, and cytidylates in the rapidly growing neoplasm, in line with the increased enzymic capacities. Par ticularly marked rises were observed in the concentrations of xanthosine 5'-phosphate, uridine 5'-diphosphate, cytidine 5'phosphate, and cytidine 5'-diphosphate (11to 18-fold). The high activities of both 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 results indicate the applicability of the molecular corre lation concept to human colon neoplasia and should be helpful in the rational design of enzyme pattern-targeted chemo therapy of colon tumors.