Summary of Informal Discussion on Basic Concepts in Neoplasia.

DR. DOUGHERTY raised an important point re garding the possibility that some of the enzyme activity alterations may not reflect variation in enzyme amount but may simply reflect rate limiting changes in the availability of a cofactor. DR. PITOT said that this was not true in his cx periments because the enzymes were always assayed in the presence of an excess of their respec tive cofactors. DR. DOUGHERTY suggested that it would be a valuable approach to explore whether the enzymes discussed may respond through variations in the cofactor content at the cellular level. DR. PIT0T answered that to his knowledge that experiment has not yet been done. DR. KENSLER inquired whether there is a gen eral rule of reciprocal relationship between a num ber of enzymes in liver neoplasms. DR. PITOT cx plained, “I didn't mean to imply that with all the enzymes that were discussed there is a reciprocal relationship in the liver. This relationship of Zwischenferment and threonine dehydrase was dis covered by Dr. Bottomley in our laboratory working with Dr. Potter and myself. We were interested in seeing whether the reciprocity of these two enzymes was present in hepatocellular carcinomas. You will have noticed, however, there was one exception. We do have one tumor, the Morris 7800, in which the threonine dehydrase is inducible but not the Zwischenferment.― “Whenthe tumor-bearing hosts were adrenalec tomized, then almost without exception the threo nine dehydrase of all the neoplasms dropped virtually to the Y axis, that is, almost to zero.― DR. NIcH0L drew attention to problems arising from the term “induction― as applied to mam malian cells. He emphasized the lack of complete evidence whether in mammalian cells we deal with an actual induction or whether the process really involves a repression. He stressed that in using the term “substrate― we are really referring to small molecules or drugs; indeed this is a drug effect because the inducing doses of tyrosine and tryptophan are quite toxic to the animal. In view of this, he felt that “substrate induction― is not a completely correct term and pointed out the ad visability of clarifying our concepts in this respect and finding other suitable terms. DR. ROSEN stressed the importance of the find ing that tyrosine transaminase was increased in Morris hepatoma 51@3. In connection with this, he mentioned that adrenalectomy does not affect the activity of hepatic tyrosine transaminase. How ever, the liver becomes greatly sensitive to corti costeroid induction of this enzyme. He was able to decrease this sensitivity to normal by treating adrenalectomized rats with deoxycorticosterone. He suggested that it would be of interest to inject hepatoma-bearing animals with deoxycorticoster one to see whether or not the high levels of tyro sine transaminase would decrease in the hepatoma. Dr. Rosen also referred to experiments with Dr. Nichol in which they were able to block the induc tion of tryptophan pyrrolase when growth hormone was administered simultaneously with cortisol. He interpreted this phenomenon as the channeling away of amino acids in the liver into structural protein, interfering with the pool available for the synthesis of the inducible enzyme. DR. PARDEE referred to his talk in which he out lined that there were two kinds of mechanisms for the increased amount of enzyme in a cell : (a) The conversion of an enzyme already present to an active form ; for instance, the combination of tryptophan pyrrolase with its hematin cofactor. (b) New enzyme formation; e.g., more tryptophan pyrrolase molecules are produced. These two mechanisms can operate simultaneously, produc ing an increased amount of enzyme, and they do not have to be exclusive processes (1—3). DR. NICHOL pointed out that in relation to the substrate specificity of induction it must be kept in mind that tryptophan and related compounds are very effective in inducing tyrosine transaminase. He mentioned that Dr. Rosen recently showed that a number of indoles are capable of inducing tyrosine transaminase in adrenaleetomized ani