It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.

http://science.sciencemag.org/content/sci/194/4260/23.full.pdf

The clonal evolution of tumor cell populations

The biology of cancer: metabolic reprogramming fuels cell growth and proliferation

The concentrations of bases, nucleosides, and nucleosides mono-, di- and tri-phosphate are compared for about 600 published values. The data are predominantly from mammalian cells and fluids. For the most important ribonucleotides average concentrations ±SD (μM) are: ATP, 3,152±1,698; GTP, 468±224; UTP, 567±460 and CTP, 278±242. For deoxynucleosidestriphosphate (dNTP), the concentrations in dividing cells are: dATP, 24±22; dGTP, 5.2±4.5; dCTP, 29±19 and dTTP 37±30. By comparison, dUTP is usually about 0.2 μM. For, the 4 dNTPs, tumor cells have concentrations of 6–11 fold over normal cells, and for the 4 NTPs, tumor cells also have concentrations 1.2–5 fold over the normal cells. By comparison, the concentrations of NTPs are significantly lower in various types of blood cells. The average concentration of bases and nucleosides in plasma and other extracellular fluids is generally in the range of 0.4–6 μM; these values are usually lower than corresponding intracellular concentrations. For phosphate compounds, average cellular concentrations are: Pi, 4400; ribose-1-P, 55; ribose-5-P, 70 and P-ribose-PP, 9.0. The metal ion magnesium, important for coordinating phosphates in nucleotides, has values (mM) of: free Mg2+, 1.1; complexed-Mg, 8.0. Consideration of experiments on the intracellular compartmentation of nucleotides shows support for this process between the cytoplasm and mitochondria, but not between the cytoplasm and the nucleus.

Physiological concentrations of purines and pyrimidines.

Chemistry of biologically important synthetic organoselenium compounds.

Polyamines in rapid growth and cancer

Summary Sodium cyanate at a dose level of 125 or 250 mg/kg i.p. caused an inhibition of incorporation of 3 H-labeled amino acids into cytoplasmic and nuclear proteins of the rapidly growing hepatoma 7777 and the slowly growing hepatoma 9618A. There was no inhibitory effect on 3 H-labeled amino acid incorporation into protein in the livers of rats bearing these tumors. Studies on the effects of sodium cyanate on incorporation of 3 H-labeled amino acids into total acidinsoluble material indicated that a greater than 85% inhibition could be achieved in hepatoma 5123C, hepatoma 9618A 2 , and the MK3 kidney tumor with either little or no effect in host liver, kidneys, brain, skeletal muscle, intestinal mucosa, and regenerating liver after partial hepatectomy.

https://cancerres.aacrjournals.org/content/canres/35/9/2321.full.pdf

Tumor-selective Inhibition of the Incorporation of 3H-Labeled Amino Acids into Protein by Cyanate

Summary Cyclic 3′,5′-nucleotide monophosphate phosphodiesterase activity was determined for seven hepatomas of different growth rates and host livers. Activity was measured in the soluble fraction of the cell (78,000 × g ) in the presence and absence of 40 mm imidazole. Phosphodiesterase activity in all hepatomas studied was decreased to levels of 60% or less of control livers of non-tumor-bearing rats. Corresponding decreases in the imidazole-stimulated phosphodiesterase activity were observed for hepatomas. Conversely, phosphodiesterase activity of 24-hr regenerating liver was elevated slightly above those for sham-operated controls. Reduced phosphodiesterase activity was observed only in host livers of animals bearing hepatomas 7800 and 7777. In the presence of imidazole, phosphodiesterase activity in all tissues was stimulated 110 to 135% of basal levels. Differences in the pH-activity profiles were observed between phosphodiesterase from normal and neoplastic liver. Phosphodiesterase of normal liver had a well-defined pH optimum at 7.4, whereas the activity from hepatoma had a broader optimum ranging from 6.2 to 7.4. Kinetic plots of the hydrolysis of cyclic adenosine 3′,5′-monophosphate exhibited anomolous behavior suggesting that both normal and neoplastic tissue contain at least two different phosphodiesterase activities. Apparent Michaelis constants for the high- and low-affinity enzymes ranged from 2.5 to 7.6 µm and from 39 to 54 µm, respectively.

https://cancerres.aacrjournals.org/content/canres/32/12/2651.full.pdf

Cyclic 3',5'-nucleotide monophosphate phosphodiesterase activity in hepatomas of different growth rates.

Summary Incorporation of [3H]TTP into membrane-denuded nuclei and fractions of these nuclei from host liver and Morris hepatomas has been compared. Treatment of sucrose nuclei with Triton X-100 removed 95% of the phospholipids and 15 to 20% of the protein. These membrane-denuded nuclei remained physically stable. The Triton X-100-extracted nuclei incorporated label into their DNA in a nuclear-incorporating system similar to sucrose nuclei with their membranes intact. Triton X-100-treated nuclei from hepatoma 7777 incorporated six times more label and those from hepatoma 7800 incorporated three times more label than Triton X-100-treated host liver nuclei. Nuclei from the three sources incorporated more label when exogenous DNA was added to the incubation system, but the difference in incorporation between the hepatoma nuclei and the host liver nuclei disappeared. When Triton X-100-treated nuclei, prepared from a tumor-bearing animal given injections of [3H]thymidine for 10 min were fractionated on sucrose gradients after disruption by high Mg2+ concentration, the fractions from hepatoma 7777 nuclei contained six times as much label as the host liver nuclear fractions. Nuclear fractions prepared from unlabeled hepatomas or host livers had DNA polymerase activity. The activity, however, is the same in fractions prepared from hepatoma 7777 or host liver nuclei. It is suggested that the nuclear membrane does not play an important role in nuclear DNA synthesis. It is further suggested that the increased incorporation found with hepatoma nuclei is dependent on a physical or chemical arrangement of components within the nucleus and not solely on different enzyme levels.

https://cancerres.aacrjournals.org/content/canres/35/10/2752.full.pdf

DNA synthesis in membrane-denuded nuclei and nuclear fractions from host liver and Morris hepatomas.

Summary The glutamic oxalacetic transaminase (GOT) activities of five transplanted malignant liver tumors were compared, as well as that of mammary adenocarcinoma 6338, the Walker carcinosarcoma 256, and the livers and sera of the host rats. Bile and urine were analyzed in some additional experiments with Hepatoma 5123. The GOT activity of Hepatoma 5123, unlike that of the Dunning, the Novikoff, the Morris 3683, and the Sidransky ethionine-induced hepatomas, was greater than that of liver. The livers of the host animals had approximately the same transaminase activities as livers of tumor-free animals of the same ages. No strain or sex differences were observed. An elevation in serum GOT was observed in rats bearing the transplanted tumors. The amount of elevation was sometimes insignificant with the Novikoff tumor and was moderate with the other tumors studied, except with Hepatoma 5123, which was associated with an elevation of 300-4000 per cent of normal. The degree of elevation was dependent upon the specific tumor type, but within the range of increase for the type, serum GOT activity increased proportionally with the weight of the transplant with 5123, and also with the Novikoff and the Sidransky liver tumors. Tumorectomy of 5123 was followed by a decrease to a normal level of serum GOT in 48 hours. Urine and bile contained very little GOT activity compared with that of serum. GOT activity was increased in these two excretory fluids with increased serum GOT, but the amount of increased activity found accounted for little of the activity that disappeared from the blood following tumorectomy of 5123, or following the intraperitoneal injection of a GOT-rich tumor extract. The high GOT activity in the slowly growing Hepatoma 5123, and the very low activity in the Novikoff, the fastest growing of the tumors examined, is in accord with an earlier observation of Cohen et al. that there is an inverse relation of GOT activity to rate of growth of tissues, including liver.

https://cancerres.aacrjournals.org/content/canres/21/11/1522.full.pdf

Transaminase Activities of Liver Tumors and Serum

Summary Several rat and mouse hepatomas and the liver and kidneys of the host animals were assayed for catalase activity. Little or no activity could be demonstrated in the subcutaneously transplanted Novikoff hepatoma, Hepatoma LC18, and Hepatoma 3683 of rats, and in a number of transplanted hepatomas of mice and hamsters. A relatively high activity was found, however, in the transplanted Hepatoma 5123 and the ethionine-induced hepatomas of rats, and in the spontaneous hepatomas of C3H mice, even though a definite depression was observed in the catalase activity of the liver and kidneys of these tumor-bearing animals. In animals bearing transplanted Hepatoma HC the catalase activity of the tumor was exceedingly high, often exceeding the levels observed in the liver and kidneys. The catalase level of Hepatoma 5123 was not altered under the stress of a protein-free diet which produced a characteristic lowering in the liver catalase of both normal and tumor-bearing animals. Similarly, both sex and age significantly altered the level of the tissue catalase activity of the host but had no apparent effect on the level of the hepatoma catalase. The site of the tumor implantation also did not change the levels of catalase activity of the tumor tissue. The significance of these data is discussed with reference to the concept of “toxohormone” being released by tumors to produce a lowering of the catalase activity in the host tissues.

http://cancerres.aacrjournals.org/content/canres/22/7_Part_1/874.full.pdf

Harold P. Morris

Papers

Tumor-selective Inhibition of the Incorporation of 3H-Labeled Amino Acids into Protein by Cyanate

Cyclic 3',5'-nucleotide monophosphate phosphodiesterase activity in hepatomas of different growth rates.

DNA synthesis in membrane-denuded nuclei and nuclear fractions from host liver and Morris hepatomas.

Transaminase Activities of Liver Tumors and Serum

Studies on the cachexia of tumor-bearing animals. II. Catalase activity in the tissues of hepatoma-bearing animals.