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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of tumor resistance to cytotoxic agents has important implications in the treatment of cancer. If supported by experimental data, mathematical models of resistance can provide useful information on the underlying mechanisms and aid in the design of therapeutic regimens. We report on the development of a model of tumor-growth kinetics based on the assumption that the rates of cell growth in a tumor are normally distributed. We further assumed that the growth rate of each cell is proportional to its rate of total pyrimidine synthesis (de novo plus salvage). Using an ovarian carcinoma cell line (2008) and resistant variants selected for chronic exposure to a pyrimidine antimetabolite, N-phosphonacetyl-L-aspartate (PALA), we derived a simple and specific analytical form describing the growth curves generated in 72 h growth assays. The model assumes that the rate of de novo pyrimidine synthesis, denoted alpha, is shifted down by an amount proportional to the log10 PALA concentration and that cells whose rate of pyrimidine synthesis falls below a critical level, denoted alpha 0, can no longer grow. This is described by the equation: Probability (growth) = probability (alpha 0 less than alpha-constant x log10 [PALA]). This model predicts that when growth curves are plotted on probit paper, they will produce straight lines. This prediction is in agreement with the data we obtained for the 2008 cells. Another prediction of this model is that the same probit plots for the resistant variants should shift to the right in a parallel fashion. Probit plots of the dose-response data obtained for each resistant 2008 line following chronic exposure to PALA again confirmed this prediction. Correlation of the rightward shift of dose responses to uridine transport (r = 0.99) also suggests that salvage metabolism plays a key role in tumor-cell resistance to PALA. Furthermore, the slope of the regression lines enables the detection of synergy such as that observed between dipyridamole and PALA. Although the rate-normal model was used to study the rate of salvage metabolism in PALA resistance in the present study, it may be widely applicable to modeling of other resistance mechanisms such as gene amplification of target enzymes.
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PMID:Mechanism-based model for tumor drug resistance. 150 73

Loss of cell cycle control and acquisition of chromosomal rearrangements such as gene amplification often occur during tumor progression, suggesting that they may be correlated. We show here that the wild-type p53 allele is lost when fibroblasts from patients with the Li-Fraumeni syndrome (LFS) are passaged in vitro. Normal and LFS cells containing wild-type p53 arrested in G1 when challenged with the uridine biosynthesis inhibitor PALA and did not undergo PALA-selected gene amplification. The converse occurred in cells lacking wild-type p53 expression. Expression of wild-type p53 in transformants of immortal and tumor cells containing mutant p53 alleles restored G1 control and reduced the frequency of gene amplification to undetectable levels. These studies reveal that p53 contributes to a metabolically regulated G1 check-point, and they provide a model for understanding how abnormal cell cycle progression leads to the genetic rearrangements involved in tumor progression.
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PMID:Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. 152 30

Modulation of pyrimidine metabolism or the metabolic fate of 5-fluorouracil by a number of different agents has permitted a significant increase in the response rate to this agent, particularly for colorectal cancers. Brequinar, a noncompetitive inhibitor of mitochondrial dihydroorotate dehydrogenase has been shown to achieve a tumor-specific modulation of the therapeutic effect of 5-fluorouracil. A selective decrease of uridine nucleotide pools in Colon tumor 38 compared to normal tissues of C57/BL6 mice was observed after Brequinar administration. This effect was achieved with very low nontherapeutic doses of Brequinar (8 to 27% of the maximum tolerated dose in this model). Pretreatment with Brequinar 4 and 24 h prior to administration of [3H]fluorouracil significantly increased incorporation of the fluoropyrimidine into Colon 38 tumor RNA, while minimal effects were seen in normal tissues of C57/BL6 mice. Brequinar (15, 30, and 50 mg/kg) was administered 4 h prior to fluorouracil (85 mg/kg) on a weekly basis in Colon 38-bearing mice. All combinations potentiated 5-fluorouracil antitumor activity and the lowest dose of Brequinar (15 mg/kg) showed a reduced toxicity (weight loss) compared to the same dose of 5-fluorouracil as a single agent. When Brequinar preceded fluorouracil by 24 h, greater toxicity and less antitumor activity were observed. A comparison of the optimal Brequinar-fluorouracil regimen with a previously optimized N-(phosphonoacetyl)-L-aspartic acid-fluorouracil combination in Colon 38 tumor indicated that Brequinar-fluorouracil was more effective and less toxic.
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PMID:Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools. 155 Oct 97

The antineoplastic agent 5-fluorouracil (5-FU) is used in the treatment of various tumor types. However, its antitumor activity is limited. To be active, 5-FU has to be metabolized. Its mechanisms of action have been largely elucidated but are complex. Combining 5-FU with biochemical modulating agents that interfere with 5-FU metabolism may enhance its therapeutic index. Uridine is one of these biochemical modulating agents. The aim of combining 5-FU with uridine is that the latter will reduce the toxicity of 5-FU while its antitumor activity is retained. This will enable the use of higher 5-FU doses with a potential increased antitumor effect. The combination 5-FU/uridine has shown clear activity in preclinical models. However, application in the clinic is limited. From the preclinical experience, it seemed that high doses of uridine giving rise to prolonged exposure of uridine to the tissues would be required to achieve the biochemical effect. Thus, initial clinical studies investigated tolerance and toxicities of high-dose uridine in humans. Dose-limiting toxicity was fever. High-dose uridine given as intermittent intravenous infusions was feasible and reversed 5-FU-induced leukopenia. High-dose uridine led to millimolar plasma concentrations of uridine. However, its half life was short due to rapid catabolism. Oral administration of uridine has also been studied, but bioavailability was low. Further studies are required to define the role of uridine in the biochemical modulation of 5-FU activity.
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PMID:Modulation of fluorouracil toxicity with uridine. 155 41

Doxorubicin (Dox) was conjugated via a dextran linker to the F(ab')2 fragment of monoclonal antibody (MAb) 1H10 which recognizes an antigen expressed on the surface of human cervical carcinoma cells and tissues. Drug-antibody conjugates (1H10-Dox) with a molar ratio of Dox to MAb ranging from 40:1 to 60:1 retained antigen-binding and pharmacological activities. Anti-tumor activity of the conjugate in vitro was evaluated by measuring inhibition of [5-3H]-uridine incorporation into cellular RNA. 1H10-Dox was found to be 30 times more toxic to cervical tumor cells than a control MAb-Dox conjugate and 150 times more potent than Dox coupled to dextran. In addition, 1H10-Dox was less toxic to antigen-negative cells in vitro, suggesting that 1H10-Dox killing of cervical carcinoma cells was antibody-mediated. 125I-labeled 1H10-Dox preferentially localized in solid human cervical carcinoma xenografts in athymic mice with tumor-to-blood ratios of 1H10-Dox reaching 17.9 after 24 hr and 32.8 after 48 hr. Treatment of athymic mice bearing human cervical tumors with 1H10-Dox resulted in a dose-dependent inhibition of tumor growth. Multiple administrations of 1H10-Dox at a dose corresponding to 20 micrograms doxorubicin significantly suppressed the growth of human cervical tumors in nude mice without significant side effects (weight loss), and this suppression was antibody specific. Both i.p. and i.v. administration of 1H10-Dox were found to be equally effective. Our results suggest that 1H10-Dox may be useful for the treatment of human cervical carcinoma.
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PMID:Doxorubicin: monoclonal antibody conjugate for therapy of human cervical carcinoma. 156 95

The rationale of the present study was to investigate the simultaneous effect of hypoxia and drugs with an "anti-pyrimidine effect" on tumor cell proliferation to evaluate putative changes in the sensitivity of cells to these kinds of chemotherapeutic treatment on reduced O2 tension. Pyrimidine de novo biosynthesis, at the stage of respiratory chain-dependent dihydroorotate dehydrogenase, was found to be a biochemical target site for oxygen deficiency as well as for Brequinar Sodium (6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinoline carboxylic acid sodium salt) (Brequinar). Increasing drug concentrations (0.1-50 microM) reduced the proliferation rate of in vitro cultured Ehrlich ascites tumor cells (IC50 = 0.25 microM). Decreasing concentrations of O2 reduced the proliferation rate (50% at approximately 3.5% O2). Brequinar at 2.5 microM stimulated the incorporation of exogenous [14C]uridine into RNA to 140 and 190% of controls, respectively, as a result of active salvage pathways, whereas it decreased the incorporation of [14C]NaHCO3 by the de novo pathway (to 20 and 5% of controls, respectively). Cells routinely grown in glucose-free, uridine-supplemented medium were resistant to 12.5 microM of the drug. The complete growth pattern of the tumor cells (increase in cell number and protein, RNA and DNA content of cultures during a 24-hr culture period) was examined (i) on reducing the O2 tension of the atmosphere stepwise from 20 to 1% O2; (ii) on addition of 0.125 microM Brequinar; and (iii) under both conditions. The combination was found to give an additive inhibitory effect under moderate hypoxia (5-20% O2) and a greater than additive effect if the oxygen tension was further reduced (1-5%).
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PMID:The "anti-pyrimidine effect" of hypoxia and brequinar sodium (NSC 368390) is of consequence for tumor cell growth. 159 14

Inhibition of human ovarian cancer cell proliferation in vitro and in vivo by Ginsenoside Rh2(Rh2) isolated from Red Ginseng was examined by using a cell line (HRA) derived from ascites of a patient with serous cystadenocarcinoma of the ovary. The HRA cell proliferation in vitro was inhibited in a dose-dependent manner with between 10 and 100 microM of Rh2. The uptake of radiolabeled precursors (3H-thymidine, 3H-uridine, and 3H-varine) by HRA cells was also inhibited in a dose-dependent manner with between 30 and 100 microM of Rh2. The growth of HRA cells transplanted into nude mice was not significantly inhibited by Rh2 alone. On the other hand, when cisplatin was administered together with 10 microM, 30 microM, or 50 microM Rh2, the growth of HRA cells was inhibited 31 and 35 days after tumor inoculation. Survival was also prolonged when cisplatin was administered with 10 microM and 30 microM Rh2. These results suggest that there is a synergistic effect between cisplatin and Rh2.
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PMID:[In vitro and in vivo effects of ginsenoside Rh2 on the proliferation of serous cystadenocarcinoma of the human ovary]. 161 19

Sparse fur hemizygous male mice are over 90% deficient in ornithine transcarbamylase and exhibit increased synthesis of orotic acid. Because our earlier studies have demonstrated that orotic acid is a liver tumor promoter in the rat, it was of interest to determine whether this genetic disorder also increases the risk of tumor promotion. The results revealed that the livers of mutant mice showed a fourfold increase in uridine nucleotides and a 50% decrease in adenosine nucleotides compared to corresponding controls, a pattern of nucleotide pool imbalance similar to that seen in the livers of rats exposed to orotic acid under promoting conditions. Creation of such an imbalance appears to be important for orotic acid to exert its promotional effects. Sparse fur mutant mouse may, therefore, be an ideal animal model to study the tumor-promoting effects of orotate.
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PMID:Abnormal hepatic nucleotide pools in sparse fur (spf) mutant mice deficient in ornithine transcarbamylase. 162 60

Rapid repopulation of tumor cells during conventional radiation therapy has been recently recognized as a factor that might significantly impair tumor response in several different tumor sites. One clinical strategy to overcome rapid tumor proliferation is to use S-phase-specific radiosensitizers such as hydroxyurea and the halopyrimidines 5-iododeoxyuridine (IUDR), 5-bromo-2'-deoxyuridine (BUDR), 5-fluoro-2'-deoxy-beta-uridine (FUDR), and 5-fluorouracil (5-FU). Indeed, several recent clinical trials have shown the positive antiproliferative effects of these radiosensitizers in various human tumors. In spite of this resurgence of clinical interest, the basic mechanism(s) of radiosensitization is not clearly understood. Although the halopyrimidines have similar biochemical pathways involving two key regulatory enzymes, thymidine kinase and thymidylate synthase, it appears that DNA-incorporation is important for radiosensitization by BUDR and IUDR but not for FUDR or 5-FU. Recent laboratory data suggest that biochemical modulation of the key regulatory enzymes can result in selective tumor radiosensitization with halopyrimidines. Hydroxyurea, like 5-FU, sensitizes cells when present prior to and following irradiation; this interaction may be related to cell synchronization as well as altered DNA damage repair. Exploiting differences in cell proliferation and cellular metabolism of these S-phase-specific radiosensitizers in tumors and normal tissues will be a major focus of clinical research in human tumor radiosensitization over the next few years.
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PMID:Radiosensitization and cell kinetics: clinical implications for S-phase-specific radiosensitizers. 164 56

Cytotoxic effects of vitamin K3 were evaluated utilizing the P388/S, L1210, EAT, S-180 and a multidrug-resistant variant of the P388 leukemia cells (P388/ADR). Antitumorigenic potential of vitamin K3 was assessed by MTT and DNA and RNA biosynthesis inhibition assay. A dose-dependent inhibition of P388/S and P388/ADR cell survival and [3H]thymidine and [3H]uridine incorporation (as a function of DNA and RNA biosynthesis) was observed in tumor cell types exposed to vitamin K3 concentrations ranging from 1 to 100 microM. One hundred mg/kg vitamin K3 caused a 32 and 52% increase in life span of the sensitive and resistant P388 leukemia tumor-bearing mice. Induction of DNA strand breaks at 100 microM vitamin K3 was greater in P388/S than in P388/ADR cells. In vitro treatment with vitamin K3 (100 microM) reduced the intracellular levels of GSH by 40, 47, 6, 15 and 14% in P388/S, P388/ADR, EAT, S-180 and L1210 tumor cells, respectively. In vivo treatment with 100 mg/kg vitamin K3 reduced the GSH content by 18 and 38% and increased the activity of the enzyme GSH-S-transferase and gamma-glutamyl transpeptidase. Effects of free radical scavengers and of compounds that modulate the GSH metabolism on the cytotoxicity of vitamin K3 were also investigated. Results indicate that vitamin K3 interacts with the tumor cell thiol pools while eliciting its antitumor effects and suggest the utility of vitamin K3 in dealing with the growing problem of multidrug resistance.
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PMID:Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells. 168 89


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