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

Subcellular particles in tumors. IV. Lysosomes in hepatoma HC and Morris hepatomas 7794A, 7794B, 5123A, 7316A and 16.

Mitochondria were isolated from a slow-growing (9618A) and two intermediate-to-fast-growing (5123C, 5123tc) Morris hepatomas and host livers. The mitochondrial proteins were solubilized and fractionated on sodium dodecyl sulfate:polyacrylamide slab gels. One Coomassie bluestained band was absent or reduced in amount in all tumors relative to host livers. In addition, a major mitochondrial enzyme present in normal liver, carbamyl phosphate synthetase, was missing or greatly reduced in the slow-growing, highly differentiated hepatoma 9618A, a tumor that is considered to be similar to normal liver in many biochemical and morphological respects. Incubation of mitochondria with [35S]methionine and a suitable amino acid incorporation system resulted in labeling of specific mitochondrial proteins. Autoradiography of the slab gels disclosed four prominently labeled fractions and a number of minor fractions. Preparations from hepatoma 5123tc demonstrated two labeled bands that were absent or greatly reduced in host liver. Host liver preparations displayed a minor band that was absent or greatly reduced in hepatoma 5123C. However, no single change in labeling pattern was common to all three tumors, suggesting the absence of a causal relationship between carcinogenesis and mutations in mitochondrial DNA.

https://cancerres.aacrjournals.org/content/canres/38/6/1584.full.pdf

Differences in total mitochondrial proteins and proteins synthesized by mitochondria from rat liver and Morris hepatomas 9618A, 5123C, and 5123tc.

Microsomal electron transport components (NADPH oxidase, NADPH-ferricyanide reductase, cytochromes P-450 and b5) have been studied in Buffalostrain rat liver and in a series of Morris hepatomata (9618A-2, 7800, 7795 and 7787). Normal liver values differed significantly from those measured in livers of tumourbearing animals. In all hepatomata per se, very low levels were found.

Further Studies of Electron Transport Components in a Series of Morris Hepatoma-Bearing Rats

Glutamine phosphoribosylpyrophosphate amidotransferase (amidophosphoribosyltransferase, EC 2.4.2.14) from normal rat liver and rapidly growing Morris hepatoma 3924A has been purified 1622- and 1224-fold, respectively. Acrylamide gel electrophoresis demonstrated that the purified amidotransferase from liver and hepatoma had the same mobility. Kinetic studies established that the purified enzymes from liver and hepatoma 3924A were indistinguishable on the basis of their pH optima, affinity to substrates, sensitivity to AMP inhibition, and immunological characteristics. Both enzymes have a broad pH range of activity from 6.5 to 8.5. The liver and hepatoma enzymes exhibited very similar apparent Km9s for glutamine, 1.4 and 1.5 mm, and for phosphoribosylpyrophosphate, 0.57 and 0.64 mm, respectively. In the absence of nucleotides, both amidotransferases showed hyperbolic curves for phosphoribosylpyrophosphate. However, the addition of AMP or GMP yielded sigmoidal curves for phosphoribosylpyrophosphate. The concentration of AMP needed to inhibit 50% of the purified amidotransferase activity from normal liver and hepatoma was similar, 4.1 and 3.3 mm, respectively. The molecular weights of the amidotransferase from liver and hepatoma were estimated to be 190,000 to 215,000 and 188,000 to 205,000 by sucrose density gradient centrifugation and by Sephadex G-150 column gel filtration. Using the highly purified amidotransferase from liver and hepatoma 3924A, antibodies were produced in rabbits. Immunotitration studies showed that the increased enzyme activity observed in the hepatoma was due to an increase in the enzyme protein amount. These studies provide further evidence that in the neoplastic transformation a reprogramming of gene expression takes place, which is manifested in the emergence of increased concentrations of amidotransferase, which should provide an increased capacity for this initiating rate-limiting step in the de novo purine-biosynthetic pathway.

https://cancerres.aacrjournals.org/content/canres/39/2_Part_1/305.full.pdf

Purification, properties, and immunotitration of hepatoma glutamine phosphoribosylpyrophosphate amidotransferase (amidophosphoribosyltransferase, EC 2.4.2.14).

The ornithine aminotransferase [EC 2.6.1.13] content of Morris hepatoma 44 is about 15 times higher than that in normal liver. The turnover rates of ornithine amino-transferase in hepatoma 44 and host liver were determined using L-[14C]leucine. Studies on the incorporation of radioactive leucine into ornithine aminotransferase in rats bearing hepatoma 44 showed that the rate of synthesis of this enzyme in the hepatoma was about 5-fold higher than that in host liver. The half-life of ornithine aminotransferase in host liver was 0.98 day, which was the same as that in normal liver, whereas that in hepatoma 44 was 3.5 days. The rate constant of degradation of ornithine aminotransferase in hepatoma 44 was significantly less than that in host liver. These results show that the high ornithine aminotransferase content of hepatoma 44 is due to both increase in its rate of synthesis and decrease in its rate of degradation.

Harold P. Morris

Papers

Subcellular particles in tumors. IV. Lysosomes in hepatoma HC and Morris hepatomas 7794A, 7794B, 5123A, 7316A and 16.

Differences in total mitochondrial proteins and proteins synthesized by mitochondria from rat liver and Morris hepatomas 9618A, 5123C, and 5123tc.

Further Studies of Electron Transport Components in a Series of Morris Hepatoma-Bearing Rats

Purification, properties, and immunotitration of hepatoma glutamine phosphoribosylpyrophosphate amidotransferase (amidophosphoribosyltransferase, EC 2.4.2.14).

Studies on the turnover rates of ornithine aminotransferase in Morris hepatoma 44 and host liver.