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

Tightly coupled mitochondria from the well-differentiated hepatoma 7800 failed to exhibit a significant 2,4-dinitrophenol-activated ATPase activity at concentrations of uncoupler sufficient to completely inhibit oxidative phosphorylation. ATPase activity could not be maximally activated by uncoupling agents more potent than 2,4-dinitrophenol, such as carbonylcyanide p-trifluoromethoxyphenylhydrazone and 5-chloro, 3-tert-butyl, 2′-chloro, 4′-nitrosalicylanilide, nor by Mg++ after the following treatments: sonication, freezing, detergent lysis, and digestion with trypsin. Gel electrophoresis patterns of the membrane proteins of the hepatome mitochondria revealed neither an absence of any one of the three different types of ATPase subunits characteristic of the homogeneous enzyme purified from normal liver mitochondria, nor a deficiency of the oligomeric molecule. Taken together, these data strongly suggest that the supramolecular structure of the membrane ATPase complex of mitochondria from hepatoma 7800 is altered in such a way that its capacity for ATP hydrolysis is severely diminished.

Deficiency of Uncoupler-Stimulated Adenosine Triphosphatase Activity in Tightly Coupled Hepatoma Mitochondria

Summary N -2-Fluorenylacetamide, a potent carcinogen in rats and some other species, appears to be noncarcinogenic in guinea pigs. The possibility of a difference in metabolism of the compound in rats and guinea pigs was investigated by means of C 14 -and N 15 -labeled N -2-fluorenylacetamide, to apprehend the possible causes for this species-connected divergence. After a single oral dose of the labeled chemical, the isotope was excreted rapidly by guinea pigs, and tissue levels were low. After 4–5 days about 80–90 per cent of a dose appeared in the urine and 10–20 per cent in the feces. The major portion was eliminated during the 1st day. Ether extractions and enzymic hydrolysis experiments of the urinary metabolites indicated that 1–2 per cent were unconjugated, ether-extractable compounds, 70–90 per cent were glucuronic acid, and 1–2 per cent sulfuric acid conjugates. Paper and column chromatographic technics showed that N -(7-hydroxy-2-fluorenyl)acetamide was the principal urinary metabolite, amounting to about 70 per cent of a dose of N -2-fluorenylacetamide. In addition, small amounts of the 8- and 5-hydroxylated derivatives, and only traces of the 1- and 3-hydroxylated compounds, were excreted in the urine. In contrast, rats produced considerably higher levels of these compounds, with a corresponding decrease in the 7-hydroxylated material. These species differences suggest the likelihood that there are several different enzymes hydroxylating aromatic rings. Carcinogenesis by N -2-fluorenylacetamide is discussed in terms of a possible involvement of the ortho -aminohydroxy derivatives produced by the metabolic transformation of the compound.

Differences in the Metabolism of N-2-Fluorenylacetamide in the Guinea Pig and the Rat

The induction of α-aminoisobutyrate (AIB) transport and tyrosine aminotransferase was studied in hepatomas and host livers of rats bearing Morris hepatomas 5123C, 7793, 7794A, 7794B, 7800, 9098, 9109, 9121, 9618A, 9618B, and 66, with the use of the following agents: N 6, O 2′-dibutyryl cyclic adenosine 3′,5′-monophosphate, epinephrine, glucagon, isoproterenol, and theophylline Tyrosine aminotransferase and AIB transport in hepatomas and host livers responded to the inducing agents in varying degrees from widely different basal levels Thus, a wide diversity in patterns of induction was observed, with no two hepatoma lines responding identically to all inducing agents

The basal levels of enzymic and transport activities were postively correlated in both tissues However, the correlation in the hepatomas was more pronounced than in the host livers The activities of both parameters in hepatomas were more sensitive than those in host liver to the endocrine state of the animal Bilateral adrenalectomy resulted in marked reductions in the basal activities of tyrosine aminotransferase and AIB transport in hepatomas 5123C, 7794B, and 9108, but not in the basal activities of host livers Differences in levels of AIB uptake were also noted for hepatomas carried in both sexes

Although the responses elicited by N 6, O 2′-dibutyryl cyclic adenosine 3′,5′-monophosphate mimicked those elicited by the hormones, the data obtained suggest that N 6, O 2′-dibutyryl cyclic adenosine 3′,5′-monophosphate is not an obligatory intermediate in the induction of either tyrosine aminotransferase or AIB transport

Naturally occurring and induced levels of amino acid transport and tyrosine aminotransferase in rats bearing Morris hepatomas.

In this investigation, we studied the effects of diet on the levels of activity of five enzymes that are involved in methionine metabolism in six rat hepatomas, in the livers of animals hosting the tumors, and in control livers. All tumors possess S -adenosylmethionine synthetase, cystathionine synthase, cystathionase, betaine-homocysteine methyltransferase, and methyltetrahydrofolate-homocysteine methyltransferase. The relative content of the enzymes varied from tumor to tumor and was not a predictable function of the growth rate. In contrast to the findings in control and host livers, the levels of four enzymes in the hepatomas rarely were affected by changes in the dietary protein content. Cystathionine synthase was the exception. An increase in this enzyme was observed in hepatomas 9633, 7794A, 7800, and 7787 when the host animals were fed a high-protein ration. However, protein feeding resulted in a decrease in cystathionine synthase in hepatoma 7777. Several examples of significant differences in enzyme activity between host and control liver were observed. These effects of the tumor were unpredictable.

https://cancerres.aacrjournals.org/content/canres/34/4/794.full.pdf

The Enzymology of Methionine Metabolism in Rat Hepatomas

Summary Four DNA-dependent DNA polymerases, which include a soluble nuclear polymerase, the mitochondrial polymerase, and two polymerases associated with the smooth membrane fraction, have been partially purified from normal rat liver and a fast-growing Morris hepatoma, 7777, by previously published procedures. The membrane-associated enzymes have been designated as the 0.10 and 0.25 smooth membrane polymerases on the basis of their elution from a diethylaminoethyl cellulose column with the respective concentration of KCl. The polymerases were shown to be separate enzymes by their ability to use synthetic polymers as templates and their response to several inhibitors. The mitochondrial DNA polymerase was readily distinguished from the smooth membrane polymerases by its ability efficiently to utilize poly(dA)d(pT) 10 as template and by its complete inhibition by concentrations of ethidium bromide which do not inhibit the other enzymes. Furthermore, the mitochondrial enzyme is the only one of the four polymerases which is insensitive to inhibition by p -hydroxymercuribenzoate. The various polymerases were also distinguished by the effects of monovalent salts and the alkaloid antibiotic, camptothecin, on their activities. NaCl (0.05 to 0.10 m) stimulates the mitochondrial and 0.10 smooth membrane polymerases but is inhibitory to the nuclear and 0.25 smooth membrane enzymes. Camptothecin inhibits the nuclear and 0.25 smooth membrane polymerases, stimulates the 0.10 smooth membrane enzyme, and has no effect on the mitochondrial polymerase.

https://cancerres.aacrjournals.org/content/canres/33/5/987.full.pdf

Harold P. Morris

Papers

Deficiency of Uncoupler-Stimulated Adenosine Triphosphatase Activity in Tightly Coupled Hepatoma Mitochondria

Differences in the Metabolism of N-2-Fluorenylacetamide in the Guinea Pig and the Rat

Naturally occurring and induced levels of amino acid transport and tyrosine aminotransferase in rats bearing Morris hepatomas.

The Enzymology of Methionine Metabolism in Rat Hepatomas

Partial Characterization of the DNA-dependent DNA Polymerases of Rat Liver and Hepatoma