Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isoelectric focusing on agarose gel was used to separate the isoenzymes of serum galactosyltransferase (uridine diphosphogalactose: N-acetylglucosaminyl galactosyltransferase, EC 2.4.1.22) from 8 healthy women, and 11 ovarian cancer patients of whom 4 were in clinical remission. In all cases, we found 7 major peaks with isoelectric points ranging from 4.0-5.4. The most acidic peaks were preferentially elevated in the tumor-bearing patients, particularly the peak with pI 4.44.
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PMID:Alteration in isoenzyme patterns of serum galactosyltransferase activity in ovarian cancer patients: preliminary results. 212 Dec 94

Brequinar sodium (DUP-785) is a potent inhibitor of the pyrimidine de novo enzyme, dihydroorotic acid dehydrogenase (DHO-DH). In order to determine whether in vitro data could be extrapolated to the in vivo situation we investigated antipyrimidine effects of DUP-785 in mice bearing colon cancer. Two tumor models were used, Colon 26 and Colon 38, resistant and moderately sensitive to DUP-785, respectively. DUP-785 at 50 mg/kg caused a depletion of plasma uridine in mice, and depleted tissue uridine levels in Colon 38 down to 10%, which was retained for several days; in Colon 26 the decrease was less and tissue uridine levels recovered rapidly. In livers of these mice no significant effect on uridine was observed. DUP-785 depleted UTP in bone marrow cells within 2 hr to 25% of control levels, after 4 days normal levels were found. In livers of both Balb-c mice (bearing Colon 26) and C57Bl/6 mice (bearing Colon 38) a small decrease of uridine nucleotide pools was found. In Colon 26 DUP-785 increased uridine nucleotide pools to 170% after 2 hr, at 1 day normal levels were observed, but after 2 days again an increase was found. In Colon 38 DUP-785 decreased the uridine nucleotide pool by 50% after 1 and 2 days. DUP-785 did not affect cytidine nucleotide pools of livers and of Colon 26 and Colon 38. The ratio between uridine nucleotides and cytidine nucleotides decreased from 2.2 to 0.90 in Colon 38, in the other tissues the decrease was less. DHO-DH was measured in bone marrow cells and Colon 26 and 38 before and after treatment. Basal levels of DHO-DH were 3 times higher in Colon 26 than in Colon 38. In treated tumors DHO-DH was initially inhibited by more than 90%, after 7 days enzyme activity in Colon 26 was 50% and in Colon 38 about 200% of basal levels. In bone marrow cells DHO-DH was also rapidly inhibited but recovered within 4 days. It is concluded that the retention of antipyrimidine effects of DUP-785 in Colon 38 were more pronounced than in Colon 26, which is in agreement with the better antitumor effect of DUP-785 in Colon 38.
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PMID:Retention of in vivo antipyrimidine effects of Brequinar sodium (DUP-785; NSC 368390) in murine liver, bone marrow and colon cancer. 215 75

The effects of cortisol, its steric analog 11-epicortisol, and lysine vasopressin (LVP) on DNA and RNA synthesis in isolated adrenocorticotropic hormone-secreting human pituitary tumor cells obtained by transsphenoidal surgery were studied using [3H]thymidine incorporation in DNA and [3H]uridine in RNA. Cortisol suppressed RNA and, to a greater extent, DNA synthesis in these cells. This could explain the slow growth of pituitary tumors in patients with Cushing's disease and the rapid growth of Nelson's pituitary tumors after bilateral adrenalectomy. 11-Epicortisol also suppressed RNA synthesis, but it had a stimulatory effect on DNA synthesis, which indicates a high specificity of glucocorticoid receptors. When applied together with cortisol, 11-epicortisol antagonized the suppressive effects of cortisol on DNA synthesis. Although LVP stimulated RNA synthesis, it suppressed DNA synthesis in most of the tumor cells.
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PMID:The effects of cortisol, 11-epicortisol, and lysine vasopressin on DNA and RNA synthesis in isolated human adrenocorticotropic hormone-secreting pituitary tumor cells. 215 95

The activities of orotate phosphoribosyltransferase (OPRT), cytidine triphosphate (CTP) synthetase, deoxycytidine monophosphate (dCMP) deaminase, thymidine monophosphate (dTMP) kinase, uridine (Urd) kinase, thymidine (dThd) kinase, Urd and dThd phosphorylases, and DNA polymerase were examined in the eight human lung squamous cell carcinomas and five lung adenocarcinomas, and five tumor-adjacent normal lung tissues. All of these enzymes are involved in pyrimidine nucleotide synthesis. The metabolism of 5-fluorouracil (5-FU) was determined. The levels of these enzymes, except for OPRT, were high in tumor tissues and almost the same between lung squamous cell carcinomas and adenocarcinomas, with no statistical difference. The activities for phosphorylation and degradation of 5-FU were similar in each tissue type of tumor. As 5-FU is incorporated into tumor cells and is metabolized actively to 5-FU nucleotides in squamous cell carcinoma tissues, at almost the same level seen in adenocarcinoma tissues, this drug should have a wide clinical application.
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PMID:Comparison of pyrimidine nucleotide synthetic enzymes involved in 5-fluorouracil metabolism between human adenocarcinomas and squamous cell carcinomas. 216 41

1. Periodate-oxidized 3-aminopyridine-adenine dinucleotide phosphate inhibited the proliferation of oral epithelium cancer and breast cancer cell lines. 2. The fast growing less differentiated embryonic kidney cell was more affected by the reagent then the embryonic lung fibroblast cell. 3. Incorporation of [3H]leucine of the treated cancer cells was inhibited. Incorporation of [3H]uridine was increased. Incorporation of [3H]thymidine was first increased and then decreased. 4. Tumor malic enzyme activity was inhibited by the reagent; but the treated cells did not show any difference in malic enzyme or glucose-6-phosphate dehydrogenase levels.
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PMID:Inhibition of human cancer cell growth by periodate-oxidized 3-aminopyridine adenine dinucleotide phosphate. 217 73

Ditercalinium (NSC 335153) was synthesized as a bifunctional DNA intercalator. It is made of two 7-H pyridocarbazole rings joined by a rigid bis-ethyl bispiperidine chain. It binds to DNA with high affinity and elicits anti-tumor activity on a variety of animal tumors. 1H n.m.r. studies of ditercalinium bis-intercalated into d(CpGpCpG)2 have shown that the intercalation process occurs from the large groove of the DNA helix while the two intercalated rings are separated by two base pairs. Because of the linking chain rigidity of ditercalinium, DNA conformation has to be altered to permit the intercalation of the two rings. DNA must be bent toward the minor groove. In E. coli, ditercalinium elicits a specific toxicity on polA strains which is suppressed by an additional uvrA mutation. In vitro, the purified UvrA and UvrB proteins bind to the DNA-ditercalinium complex in an ATP dependent manner. The UvrABC complex induces single-strand nicks, but only when ditercalinium is bound to negatively supercoiled DNA. The life-time of the UvrAB-DNA-ditercalinium complex is greater than 50 min when free ditercalinium concentration is maintained constant in the incubation medium. The cytotoxicity of ditercalinium in E. coli results from the induction of a futile and abortive DNA repair. The reversible ditercalinium-DNA complex mimics a bulky DNA lesion, yet the UvrABC endonuclease is unable to cope with a reversible lesion since it cannot eliminate the causative agent. The interaction of UvrA and UvrB proteins has also been studied with DNA and other DNA-binding drugs forming high-affinity complexes such as distamycin. The Uvr protein recognition process appears to be associated with specific DNA structural alterations. In eukaryotic cells, ditercalinium is concentrated in mitochondria. Mitochondrial DNA is rapidly and totally degraded. Mitochondrial DNA coded proteins being no longer synthesized, the respiratory chain is progressively inactivated. The stimulation of the glycolytic pathway allows the cells to continue growth for several generations. Dihydro-orotate dehydrogenase is located in the inner membrane of mitochondria and its activity is dependent on mitochondria energization. It becomes inactive after ditercalinium treatment. A drop of the pyrimidine pool is then observed. Complementation of treated cells with uridine decreases 10-fold the ditercalinium toxicity. The cellular delayed toxicity of ditercalinium results from the slow induction of a pyrimidineless state associated with the progressive inactivation of mitochondria. The results show that DNA structural alterations induced by reversible drug-DNA complexes can be recognized by DNA repair enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recognition by the DNA repair system of DNA structural alterations induced by reversible drug-DNA interactions. 218 Apr 23

Active specific immunotherapy was performed in a phase I study in 20 colorectal cancer patients after surgical resection of the tumor. An autologous tumor cell vaccine surface modified by Newcastle disease virus (NDV) was used, which showed the following characteristics. After mechanical and enzymatic dissociation of the tumor tissue an average of 5 x 10(7) cells/g tissue was obtained. According to trypan blue dye exclusion assay the average viability was 72%. Following irradiation (200 Gy) the inactivation of proliferative activity of the cells could be demonstrated by the absence of incorporation of 3H-labelled thymidine. The cells were, however, still metabolically active as shown by the incorporation of [3H]-uridine and a mixture of 3H-labelled amino acids. Epithelium-specific antigens (detected by mAb HEA125) were expressed on more than 75% cells of the cell suspension indicating a high amount of (epithelium-derived) tumor cells. In order to increase the immunogenicity of the tumor cells the suspended cells were infected by the nonlytic, apathogenic Ulster strain of NDV. The successful modification of tumor cells with NDV could be shown by electron microscopy. Three weeks postoperatively cells were thawed, virus-modified, and inoculated intradermally in the upper thigh. Several cell and virus concentrations were tested in each patient. As control, tumor cells without NDV, NDV alone and normal colon mucosa were used. The number of tumor cells ranged from 2 x 10(6) up to 2 x 10(7) cells and NDV concentrations from 4 to 64 hemagglutination units (HU) were tested. Sixteen patients responded with a delayed-type hypersensitivity (DTH) skin reaction to the vaccine. The best DTH reaction, measured 24 h following vaccination, was obtained using a vaccine consisting of 1 x 10(7) tumor cells and 32 HU NDV (median induration of 8 mm). Response to NDV alone was seen in 2 patients only (median induration of 3 mm); 12 patients responded to tumor cells (1 x 10(7) alone (median induration of 4 mm). Of 10 patients tested with normal colorectal mucosa, 4 responded with a median induration of 3.5 mm. DTH responses to the vaccine of 1 x 10(7) tumor cells and 32 HU NDV increased throughout the repeated vaccinations to a median induration of 9.5 mm at the end of the therapy. No severe side-effects in the course of the immunotherapy, except for mild fever in 4/20 patients, were observed. The results of our phase I study show that this type of autologous colorectal tumor cell vaccine is ready for a large clinical trial to prove its efficacy.
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PMID:Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. 228 11

Diarylsulfonylureas have been shown to have therapeutic activity against rodent and human tumor models, notably causing regressions in some lines of human colon adenocarcinomas in mice. At present the mechanism of cytotoxicity is unknown, although preliminary data implicate mitochondria as a potential site of action. In this study, the cytotoxicity of the diarylsulfonylurea N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea (ISCU) has been examined in GC3/c1 human colon adenocarcinoma cells. At cytotoxic concentrations of ISCU, in the presence of albumin as a drug binding species, there was only slight inhibition of [3H]thymidine and [3H]uridine incorporation at concentrations of ISCU up to 140 micrograms/ml and no inhibition of synthesis of protein as determined by incorporation of L-leucine. In the absence of albumin, incorporation of [3H]thymidine into DNA or [3H]uridine into RNA was inhibited at greater than 70 micrograms/ml and 140 micrograms/ml, respectively. As ISCU is highly bound to serum albumin (greater than 99%), it would appear that inhibition of nucleic acid synthesis occurs only at supralethal concentrations of ISCU. The cytotoxicity of ISCU in proliferating or quiescent cell populations was examined. GC3/c1 cells grown in medium containing 0.5% fetal calf serum (FCS) had a 60% reduction in rate of growth, but were more sensitive than cells exposed for 24 h in 10% FCS-medium (IC50 1.9 and 31 micrograms/ml, respectively). When the albumin concentration was adjusted (240 mg/100 ml) to allow equivalent drug binding, IC50 values were similar. In cultures of GC3/c1 cells growth rate was related to the concentration of FCS. In the absence of serum, growth rate was 2.5 to 3.2% that of exponentially growing control cultures in the presence of 10% FCS. Addition of FCS to quiescent cultures after 1 to 6 days in serum-free conditions resulted in immediate growth of cells. Clonogenic potential was also unchanged for at least 6 days under serum-free conditions. Under these conditions, where albumin concentration was adjusted to be equivalent to medium containing 10% FCS, sensitivity of proliferatively quiescent GC3/c1 cells was similar to that in exponentially growing control cultures in which the population doubling time was approximately 22 h. Further, there was no recovery of clonogenic potential when cells were exposed for 24 h to ISCU and maintained in a quiescent state for up to 4 days prior to serum stimulation. These data suggest that the cytotoxic effects of ISCU are independent of the proliferative state of the cell population.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)urea, a novel agent equally cytotoxic to nonproliferating human colon adenocarcinoma cells. 229 71

The present study was designed to determine whether orotic acid, a liver tumor promoter in the rat, also promotes liver carcinogenesis in the mouse. Eight-week-old male BALB/c mice were initiated with diethylnitrosamine (90 mg/kg i.p.). One week later they were divided into 2 groups and given either a basal diet or the basal diet containing 1% orotic acid (OA). They were killed at 6 or 10 months after the administration of the carcinogen. At 6 months, no nodular lesions were seen in mice whether or not they were exposed to OA. However by 10 months 100% of mice in both groups developed hepatic nodules. OA neither shortened the latent period for the appearance of the nodular lesions not did it increase the size of the nodules. Although BALB/c mice exhibited an increase in uridine nucleotides and a decrease in adenosine nucleotides in the liver upon exposure to OA, the magnitude of the change was less compared with that seen in the rat liver. The resistance of BALB/c mouse to the tumor-promoting effects of OA may reflect in part the resistance of the mouse to OA-induced nucleotide pool imbalance.
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PMID:Studies on the effect of dietary orotic acid on mouse liver carcinogenesis induced by diethylnitrosamine. 230 98

A short-term antimetabolic assay based on the interference with 3H-thymidine and 3H-uridine incorporation after 3 hours of in vitro treatment was used to compare the cytotoxicity of a new halogenated anthracycline, 4'-Iodo-4'-deoxydoxorubicin (IDX), with that of its parent compound Doxorubicin (DX) against 44 human colorectal carcinomas. IDX had a marked dose-dependent effect, with frequencies of activity consistently greater than those of DX at all concentrations. The minimal dose of IDX required to induce a significant antimetabolic effect obtained by extrapolation from the dose-effect plots for each drug was 1/10 that of DX (2.3 micrograms/ml vs 23 micrograms/ml). When the relative activities of the two drugs on the same tumor specimen were determined, there was 71% to 86% overall agreement, depending on the concentration used. Lack of agreement was always attributed to sensitivity to IDX and resistance to the parent compound.
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PMID:Absolute and relative activities of 4' -iodo-4'-deoxydoxorubicin against human colo-rectal tumors, as evaluated by a short-term in vitro assay. 233 14


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