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Biochemical Programs of Slowly and Rapidly Growing Human Colon Carcinoma Xenografts

Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46223 [G. W., M. S. L., N. P., D. Y. T., R. C. J., E. T., J. N. E.], and Department of Medicine, Roger Williams General Hospital, Brown University School of Medicine, Providence, Rhode Island 02903 [J. C. H.]

The purpose of this investigation was to elucidate the enzymic programs of pyrimidine, carbohydrate, and purine metabolism 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 carried in nude (athymic) 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 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 phosphoribosyltransferase, 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-6-phosphate 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 metabolism of the rapidly growing carcinoma, there was increase in the activity of the first enzyme committed to de novo biosynthesis (glutamine 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).

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. Particularly marked rises were observed in the concentrations of xanthosine 5'-phosphate, uridine 5'-diphosphate, cytidine 5'-phosphate, and cytidine 5'-diphosphate (11- to 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 correlation concept to human colon neoplasia and should be helpful in the rational design of enzyme pattern-targeted chemotherapy of colon tumors.

¹ 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.

⁴ Recipient of USPHS Grant CA-18129.

⁵ Permanent address: Department of Pediatrics, Tokushima University School of Medicine, Tokushima City, Japan.

Received 7/ 7/80. Accepted 11/11/80.

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