Mary Faderan | National University, San Diego (original) (raw)

Papers by Mary Faderan

Biochemical and Biophysical Research Communications, Jul 18, 1984

Cancer Research, Jun 1, 1985

The purpose of this study was to elucidate the purine enzymic programs of human primary colorecta... more The purpose of this study was to elucidate the purine enzymic programs of human primary colorectal carcinomas. Marked al teration in the enzymology of the human colon neoplasm clearly distinguished it from that of the normal colon mucosa. In the human colon mucosa, the activities of ribonucleotide reductase, inosine phosphate dehydrogenase, formylglycinamidine ribonu cleotide synthetase, guanosine phosphate synthetase, and amidophosphoribosyltransferase were 0.042,5.2,5.6, 8.2 and 36.0 nmol/h/mg protein, respectively, and in the colon carcinomas the activities increased to 755, 575, 295, 280, and 294% of the normal values. The activities of the salvage enzymes, adenine and hypoxanthine-guanine phosphoribosyltransferases, were 310, 249, and 602 nmol/h/mg protein, respectively, whereas in the tumors, only the activity of adenine phosphoribosyltransferase was increased (2-fold). The markedly higher absolute en zymic capacity for salvage in the tumors accounts, in part at least, for the lack of chemotherapeutic success of inhibitors of enzymes of de novo synthesis that have been used in the clinical treatment of colorectal carcinomas. Combinations of inhibitors of de novo biosynthesis and blockers of the salvage enzymes or of salvage transport (e.g., dipyridamole) should improve the chemotherapy of colon neoplasms. Since in the colon carcinoma the activities of glutamine-utilizing enzymes (guanosine phos phate and formylglycinamidine ribonucleotide synthetase and amidophosphoribosyltransferase)

Cancer Research, Apr 1, 1992

Journal of Biological Chemistry

Tiazofurin, a C-nucleoside, was cytotoxic in hepatoma 3924A cells grown in culture with an LCao =... more Tiazofurin, a C-nucleoside, was cytotoxic in hepatoma 3924A cells grown in culture with an LCao = 7.5 WM. In the culture, a closely linked dose-related response of tumor cell-kill and depletion of GTP pools was observed after tiazofurin treatment. In rats carrying subcutaneously transplanted hepatoma 3924A solid tumors, a single intraperitoneal injection of tiazofurin (200 mg/kg) caused a rapid inhibition of IMP dehydrogenase (EC 1.2.1.14) activity and depleted GDP, GTP, and dGTP pools in the tumor; concurrently, the 5-phosphoribosyl 1-pyrophosphate (PRPP) and IMP pools expanded 8-and ls-fold, respectively. Tiazofurin decreased tumoral IMP dehydrogenase activity and dGTP pools in a dose-dependent manner over a range of 50-200 mg/kg; by contrast, the depletion of GTP and the accumulation of IMP and PRPP pools were near maximum at 50 mg/kg. The increase in PRPP pools may be attributed to an inhibition by IMP of the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8). The IMP dehydrogenase

Mechanisms of resistance to 5-fluorouracil (FUra) were compared between a cell line resistant to ... more Mechanisms of resistance to 5-fluorouracil (FUra) were compared between a cell line resistant to a short-term exposure (4 h) to this agent (HCT-8/FU4hR) and a cell line resistant to a prolonged exposure (7 days) to the fluoropyrimidine (HCT-8/FU7dR). The two cell lines were obtained by repeatedly exposing 2 x I(T cells to a constant concentration of FUra (1000 MMfor 4

Pädiatrie und Pädologie, 1988

Aim of this study was to elucidate insulin regulatory effects on purine and pyrimidine metabolism... more Aim of this study was to elucidate insulin regulatory effects on purine and pyrimidine metabolism. Livers of alloxan diabetic and insulin treated rats were freeze clamped and nucleotide pools measured using HPLC techniques. Activities of key enzymes of de novo and salvage pathways were analyzed with radioassays. In diabetic liver nucleotide triphosphate pools were reduced between 46 and 75% of controls, nucleotide monophosphate concentrations increased. Activities of de novo biosynthetic enzymes amidophosphoribosyltransferase, FGAM synthase, IMP dehydrogenase, GMP synthase, carbamoylphosphate synthase II were curtailed by 16-61%, those of salvage enzymes hypoxanthine-guanine-phosphoribosyltransferase, adenine-phosphoribosyltransferase, thymidine kinase also decreased to 31-58%. Insulin treatment for 2 and 7 days normalized nucleotide pools, activities of key enzymes of de novo and salvage pathways were increased between 2.4 and 4.1 fold compared to diabetic untreated. Activation of ...

Cancer research, 1985

Veterinary Microbiology, 2000

A broth microdilution technique was used to determine the antimicrobial susceptibility of 15 ®eld... more A broth microdilution technique was used to determine the antimicrobial susceptibility of 15 ®eld isolates of Mycoplasma hyorhinis to 10 antimicrobial agents, representative of different classes, and contrasting newer agents to existing ones. For the macrolides, the MIC 90 for tylosin and tilmicosin was 1 and 4 mg/ml, respectively, but was !16 mg/ml for erythromycin. Tetracycline, lincomycin and enro¯oxacin each had an MIC 90 of 2 mg/ml. The mycoplasma had similar levels of susceptibility to the aminoglycoside and aminocyclictol classes exhibiting an MIC 90 of 4 mg/ml for gentamicin and 2 mg/ml for spectinomycin. The isolates exhibited high MICs to trimethoprim/sulfamethoxazole with an MIC 90 !16/304 mg/ml. In summary, M. hyorhinis isolates from the US had low MICs against a variety of antimicrobials tested, with the exception of erythromycin and trimethoprim/ sulfamethoxazole. #

Journal of Cancer Research and Clinical Oncology, 1990

The effect of growth phase on enzymatic activities of the de novo and salvage pathways for purine... more The effect of growth phase on enzymatic activities of the de novo and salvage pathways for purine and pyrimidine nucleotide synthesis was studied in a hepatocyte-derived cell line from the rat. The cells were in lag phase after plating for 36 h; log phase started at 48 h and persisted up to 120 h of culture. Then the cells stopped growing and entered into plateau phase (144 h). In non-proliferating cells (144 h of culture) the basal activities of the enzymes of purine de novo biosynthesis were 1.7- to 6.8-fold higher than in normal rat liver, those of pyrimidine de novo synthesis showed 0.6- to 30-fold increase in activity. The purine salvage enzymes were unchanged, and the pyrimidine salvage enzymes were 3.1- to 7.4-fold higher compared to normal liver. During the growth cycle all enzymes except the purine salvage enzymes, which did not change, showed a peak in activity at 72 h of culture (log phase). The increase in activity in log phase compared to plateau phase was 1.3- to 2.4-fold for purine de novo synthetic enzymes, 1.1- to 2.4-fold for pyrimidine de novo enzymes, and 1.4- to 4.7-fold for pyrimidine salvage enzymes. The specific activities of the enzymes in exponentially growing cells were comparable either to that in 24-h regenerating liver, or to that in hepatomas of low or medium growth rate. It was concluded that the enzymatic pattern and metabolic state of the cells shared some features with regenerating liver, others with tumors, although they were not tumorigenic after transplantation into athymic nude mice.

Biochemical Pharmacology, 1986

Tiazofurin (2-@-D-ribofuranosylthiazole-4-carboxamide, NSC-286193) has shown potent cytotoxic and... more Tiazofurin (2-@-D-ribofuranosylthiazole-4-carboxamide, NSC-286193) has shown potent cytotoxic and antitumor activity against hepatoma 3924A carried in the rat [Lui et al. J. biol. Chem. 259,

Biochemical and Biophysical Research Communications, 1984

Advances in Enzyme Regulation, 1983

Experimental and clinical studies revealed that marked inhibition of de novo pathways of purine a... more Experimental and clinical studies revealed that marked inhibition of de novo pathways of purine and pyrimidine metabolism by antimetabolites failed to produce lasting remissions in neoplastic diseases. In elucidating the mechanism of action of the anti-glutamine agent, acivicin, we observed that after injection of this drug in hepatoma-bearing rats the activities of glutamine utilizing enzymes of de novo purine and pyrimidine biosynthesis were markedly decreased in the tumor (1, 2). However, the concentrations of only GTP and CTP declined, whereas those of ATP and UTP did not (1, 2). The protection of the adenylate and uridylate pools was tentatively attributed to the contribution of the salvage pathways (1). To test this hypothesis, we compared in liver and hepatomas the activities of the key enzymes of de novo pathways (ribonucleotide reductase, carbamoyl-phosphate synthetase II, CTP synthetase, amidophosphoribosyitransferase, IMP dehydrogenase with those of salvage enzymes (uridine-cytidine, deoxycytidine and thymidine kinases; adenine and hypoxanthine-guanine phosphoribosyltransferases). The results showed that in liver the activities of the enzymes of salvage pathways were orders of magnitude higher in both purine and pyrimidine metabolism than those of de novo synthesis. In hepatomas in pyrimidine metabolism the activities of the de novo and the salvage enzymes were elevated and the increase was transformation-and progression-linked. In contrast, in purine metabolism, the de novo enzyme activities were elevated, but the activities of the salvage enzymes did not show a transformation-or progression-linked alteration.

Advances in Enzyme Regulation, 1984

Advances in Enzyme Regulation, 1985

The purpose of this investigation was to elucidate the factors that regulate the pattern of gene ... more The purpose of this investigation was to elucidate the factors that regulate the pattern of gene expression in purine and pyrimidine metabolism in normal liver and hepatoma. For this purpose, the action of a hormone, insulin, and the development of resistance to a chemotherapeutic agent, tiazofurin, were studied. This investigation brought detailed evidence showing that in the rat insulin exerted a profound effect on liver purine and pyrimidine metabolism by regulating the concentrations of nucleotides through controlling the activities of strategic enzymes involved in their biosynthesis. When rats were made diabetic by alloxan treatment, in the average liver cell concentrations of ATP, GTP, UTP and CTP decreased to 66, 62, 54 and 63%, respectively, of those of normal liver. Administration of insulin for 2 days returned the hepatic nucleotide concentrations to normal range; further insulin treatment for an additional 5 days raised the concentrations of ATP, GTP, UTP and CTP to 197, 352, 412 and 792% of values observed in the liver of diabetic rats. In diabetic rats the hepatic activities of OMP decarboxylase, orotate phosphoribosyltransferase, uridine phosphorylase, uridine-cytidine kinase and uracil phosphoribosyltransferase decreased to 44, 48, 70, 36 and 41% of the activities of normal liver. Insulin treatment for 2 days returned activities to normal range. Continued insulin treatment for an additional 5 days increased the enzymic activities to 3.9- to 5.3-fold of those of the liver of the diabetic rats. The regulation by insulin treatment of the activities of enzymes of de novo and salvage synthesis of UMP should explain, in part at least, the decline and increase of the uridylate pool in diabetes and after insulin treatment. In the diabetic rat hepatic CTP synthetase, the rate-limiting enzyme of CTP biosynthesis, decreased to 53% and insulin administration for 2 days restored activity to normal range. Insulin treatment for an additional 5 days increased the synthetase activity to 4-fold of the values of the diabetic liver. Thus, the behavior of liver CTP synthetase activity is tightly linked with that of the CTP pool. In the diabetic rat liver, the activity of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, decreased to 24% of that of the normal liver. Insulin administration for 2 days returned the activity to normal range, yielding a 4.5-fold increase in the activity from the diabetic to the insulin-treated state.(ABSTRACT TRUNCATED AT 400 WORDS)

Advances in Enzyme Regulation, 1982

Chemotherapy should be directed against the biochemical commitment of cancer cells to replicanon.... more Chemotherapy should be directed against the biochemical commitment of cancer cells to replicanon. The biochemical commitment to replication appears to be hnked with a pattern of transformation-and progression-linked alteranons which have recently been identified in the enzymic and metabolic activlnes of hepatomas of different growth rates (I, 2). Recent studies also revealed that the specific activities of key enzymes involved in glutamine utilization in both purine and pyrimidlne biosynthesis were increased in hepatomas and in other types of animal and human solid tumors. Increases in activities were reported for amidophosphoribosyltransferase (EC 2.4.2.14) (3), GM P synthetase (EC 6.3.5.2) (4), carbamoyl-phosphate synthetase II (EC 6.3.5.5) (5) and CTP synthetase (EC 6 3 4.2) (6). From these observations it appears that an appropriate antl-glutamine agent should inhibit the activities of several key enzymes in nucleic acid biosynthetic pathways. Thus, by a single agent multi-enzyme-targeted chemotherapy of cancer cells might be achieved Then, if necessary, combination chemotherapy with other anti-tumor agents could be utilized.

Books by Mary Faderan

This is an original screenplay which has been submitted to National University as part of fulfill... more This is an original screenplay which has been submitted to National University as part of fulfilling the requirements of a MFA degree.

Drafts by Mary Faderan