Mutants of human colon adenocarcinoma, selected for thymidylate synthase deficiency.

Houghton, Peter J.; Germain, Glen S.; Hazelton, Bonnie J.; Pennington, Janet W.; Houghton, Janet A.

doi:10.1073/pnas.86.4.1377

Cited by 19 publications

(9 citation statements)

References 21 publications

(11 reference statements)

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“…To determine the effect of total pyrimidine or thymidine starvation on C. psittaci AA Mp, we monitored its growth in three cell lines with mutations in different enzymes of pyrimidine metabolism ( Table 2). As a consequence of their mutations, the CHO DHFR- (32) and human TS- (14) cells are auxotrophic for thymidine and the CHO Urd-A cells are auxotrophic for pyrimidines (23). When cultured in the absence of thymidine, the DHFR-and TS-cells lack a detectable dTTP pool and the UTP and CIP pools in uridine-starved Urd-A cells are decreased by >90% (18a).…”

Section: Resultsmentioning

confidence: 99%

Pyrimidine metabolism by intracellular Chlamydia psittaci

McClarty

Qin

1993

J Bacteriol

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Pyrimidine metabolism was studied in the obligate intracellular bacterium Chlamydia psittaci AA Mp in the wild type and a variety of mutant host cell lines with well-defined mutations affecting pyrimidine metabolism.C. psittaci AA Mp cannot synthesize pyrimidines de novo, as assessed by its inability to incorporate aspartic acid into nucleic acid pyrimidines. In addition, the parasite cannot take UTP, CTP, or dCTP from the host cell, nor can it salvage exogenously supplied uridine, cytidine, or deoxycytidine. The (7,20). The species C. trachomatis and C pneumoniae are primarily human pathogens (6, 26).In contrast, C. psittaci has been isolated from humans and a very large number of avian and mammalian species, in which it produces a variety of diseases (26,28). Despite the clinical and economic importance of chlamydiae, many aspects of their basic biology have not been studied and the metabolic relationships that exist between the parasites and their hosts remain largely unknown (20). This is, in part, due to the fact that axenic growth of chlamydiae has not been realized. In addition, host-free chlamydiae display limited metabolic activity (12,20).Our laboratory is particularly interested in nucleotide metabolism in chlamydiae. To study nucleotide metabolism in C. trachomatis, we have employed an in situ approach with well-defined mutant host cell lines and several different radiolabelled nucleic acid precursors (4,5,18,24,29,30). The results generated indicate that C. trachomatis (i) cannot de novo synthesize purines or pyrimidines, (ii) lacks the ability to salvage preformed purine or pyrimidine nucleobases and (deoxy)nucleosides, (iii) can obtain all four ribonucleotides directly from the host cell, (iv) encodes a ribonucleotide reductase and thymidylate synthase for synthesizing deoxyribonucleotides from host-derived ribonucle-* Corresponding author. t Present address:

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Section: Resultsmentioning

confidence: 99%

Pyrimidine metabolism by intracellular Chlamydia psittaci

McClarty

Qin

1993

J Bacteriol

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“…GC 3 /c1 human colon cancer cells were established as previously described (18 anti-p53, TRAIL-R2, caspase-8, XIAP, cIAP1, and cIAP2 (MBL International), anti-survivin and cdc2 (Santa Cruz Biotechnology), anti-actin (Sigma Chemical), and anti-p21 (Upstate). Mapatumumab and lexatumumab, human monoclonal TRAIL-R1 and TRAIL-R2 antibodies, respectively, were kindly provided by Human Genome Sciences.…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Nawrocki¹,

Carew

Leslie³

et al. 2007

Cancer Research

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumabinduced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21 +/+ cells but not in the HCT116 p21 À/À cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab. [Cancer Res 2007;67(14):6987-94]

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“…Inhibition of DHFR or TS reduces the cellular pool of 2'-deoxythymidine-5'-monophosphate, impairing DNA replication and resulting in cell death [79,80]. Since trypanosomatids are auxotrophic for folates, the inhibition of the enzymes is expected to kill the parasites.…”

Section: Pteridine Reductase Inhibitorsmentioning

confidence: 99%

Structure-Based Drug Discovery for Tropical Diseases

Güido

Oliva

2009

CTMC

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Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.

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Mutants of human colon adenocarcinoma, selected for thymidylate synthase deficiency.

Cited by 19 publications

References 21 publications

Pyrimidine metabolism by intracellular Chlamydia psittaci

Pyrimidine metabolism by intracellular Chlamydia psittaci

Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels

Structure-Based Drug Discovery for Tropical Diseases

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