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Tryptophan Pyrrolase Activity in Transplanted "Minimal-Deviation" Hepatomas

( Laboratory of Biochemistry, National Cancer Institute, Bethesda, Maryland)

Administration of L-tryptophan directly into the renal artery of kidneys bearing "tissue-isolated" transplants of Hepatoma 5123 failed to increase the tryptophan pyrrolase (TP) activity in the tumors. This failure in substrate induction was also observed following the intraperitoneal route of administration of L-tryptophan. The livers of the host rats showed equally elevated activities after either route of administration. Thereafter, TP activities of a series of fifteen transplanted hepatoma lines or sublines, including 5123, and of the livers of the host rats were measured before and after attempted induction by the intraperitoneal administration of L-tryptophan. A kinetic method for measuring TP activity was also used in these studies in which homogenates of subcutaneously and/or intramuscularly transplanted tumors were analyzed at 15-minute intervals for 75–105 minutes. The livers of the rats carrying the different tumor lines behaved in similar fashion, showing greater activity after administration of L-tryptophan, with variations among individual rats in the absolute amounts of activity, both before and after substrate induction. The tumors, however, fell into three groups with respect to their TP be havior: (a) hepatomas that contained questionable TP activity, since it was erratic in behavior, fluctuating in samples analyzed at 15-minute intervals and showing no progressive increase during incubation of the homogenates with the substrate. These tumors also behaved erratically and showed no elevation in activity after attempted induction with L-tryptophan; (b) hepatomas that contained small amounts of TP activity which increased with time during incubation, and which showed significantly greater absolute amounts following administration of L-tryptophan to the host rats; and (c) hepatomas that contained more enzyme than those of Group 2, and in which the activity increased regularly during incubation and responded to substrate induction with elevated activity similar in behavior to the TP activity of liver. Thus, the failure of the TP of the hepatoma lines of Group 1 to respond to L-tryptophan induction in vivo appears to be associated with an atypical behavior of the enzyme which throws some doubt on its actual presence in the tumor cells. In the hepatoma lines of Groups 2 and 3, where the enzyme acted qualitatively like the TP of liver during incubation, substrate induction of activity was as effective as that of the TP of liver, although the absolute amounts of activity were considerably less in the tumors, especially of Group 2, than in the livers.

The results of these studies confirm the accumulated evidence from other laboratories that transplanted minimal-deviation hepatoma lines show wide variation in their enzyme activities, even when the original tumors are induced by the same chemical under similar experimental conditions.

Preliminary studies with intact rats also demonstrated that tumors of Group 3 behaved like the livers of host rats in the response of their TP activity to induction by cortisone acetate and in the interference of puromycin with the elevation in TP activity caused by injection of L-tryptophan.

Received 7/19/63.