New antimetabolites in cancer chemotherapy and their clinical impact

Sb, Kaye

doi:10.1038/bjc.1998.747

Cited by 137 publications

(88 citation statements)

References 45 publications

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“…To address this question, we devised a strategy to arrest cells in S phase, where Chk1 levels are high (51). HeLa cells were blocked in S phase by treating them with a low concentration of gemcitabine, a nucleoside analog that is incorporated by DNA polymerase into replicating DNA, blocking further chain elongation (55,56). Gemcitabine-treated HeLa cells accumulated in S phase ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Arlander¹,

Eapen²,

Vroman³

et al. 2003

Journal of Biological Chemistry

163

148

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DNA damage and replication stress activate the Chk1 signaling pathway, which blocks S phase progression, stabilizes stalled replication forks, and participates in G 2 arrest. In this study, we show that Chk1 interacts with Hsp90, a molecular chaperone that participates in the folding, assembly, maturation, and stabilization of specific proteins known as clients. Consistent with Chk1 being an Hsp90 client, we also found that Chk1 but not Chk2 is destabilized in cells treated with the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). 17-AAG-mediated Chk1 loss blocked the ability of Chk1 to target Cdc25A for proteolytic destruction, demonstrating that the Chk1 signaling pathway was disrupted in the 17-AAG-treated cells. Finally, 17-AAG-mediated disruption of Chk1 activation dramatically sensitized various tumor cells to gemcitabine, an S phase-active chemotherapeutic agent. Collectively, our studies identify Chk1 as a novel Hsp90 client and suggest that pharmacologic inhibition of Hsp90 may sensitize tumor cells to chemotherapeutic agents by disrupting Chk1 function during replication stress.

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Section: Resultsmentioning

confidence: 99%

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Arlander¹,

Eapen²,

Vroman³

et al. 2003

Journal of Biological Chemistry

163

148

View full text Add to dashboard Cite

show abstract

“…Important anticancer agents, such as cytosine arabinoside (Ara-C), gemcitabine, capecitabine, decitabine and 5-aza-cytidine, are cytidine analogues [23]. Historically, nucleoside analogues were developed as cytotoxic drugs.…”

Section: Introductionmentioning

confidence: 99%

Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice

Beumer

Eiseman

Parise

et al. 2007

Cancer Chemother Pharmacol

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Cytidine analogues such as cytosine arabinoside, gemcitabine, decitabine, 5-azacytidine, 5-fluoro-2′-deoxycytidine and 5-chloro-2′-deoxycytidine undergo rapid catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU) is a potent CD inhibitor that has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU pharmacokinetics has not been fully characterized, which has impaired the optimal preclinical evaluation and clinical use of THU. Therefore, we characterized the THU pharmacokinetics and bioavailability in mice. Mice were dosed with THU iv (100 mg/kg) or po (30, 100, or 300 mg/kg). Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma pharmacokinetic parameters were calculated compartmentally and non-compartmentally. THU, at 100 mg/kg iv had a 73 min terminal half-life and produced plasma THU concentrations >1 μg/ml, the concentration shown to effectively block deamination, for 4 h. Clearance was 9.1 ml/min/kg, and the distribution volume was 0.95 l/kg. Renal excretion accounted for 36-55% of the THU dose. A three-compartment model fit the iv THU data best. THU, at 100 mg/kg po, produced a concentration versus time profile with a plateau of approximately 10 μg/ml from 0.5-3 h, followed by a decline with an 85 min half-life. The oral bioavailability of THU was approximately 20%. The 20% oral bioavailability of THU is sufficient to produce and sustain, for several hours, plasma concentrations that inhibit CD. This suggests the NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript feasibility of using THU to decrease elimination and first-pass metabolism of cytidine analogues by CD. THU pharmacokinetics are now being evaluated in humans.

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“…Subsequent studies showed that gemcitabine has activity against metastatic bladder cancer (Stadler et al, 1997) and gemcitabine combined with cisplatin is now the standard treatment for metastatic bladder cancer (von der Maase et al, 2000). Gemcitabine is also active against nonsmall-lung cancer (Schiller et al, 2002) and breast, ovarian and head and neck cancers (Possinger, 1995;Kaye, 1998).…”

Section: Nucleoside Analogs Currently Used In Cancer Chemotherapymentioning

confidence: 99%

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

et al. 2003

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The clinical efficacy of anticancer nucleoside drugs depends on a complex interplay of transporters mediating entry of nucleoside drugs into cells, efflux mechanisms that remove drugs from intracellular compartments and cellular metabolism to active metabolites. Nucleoside transporters (NTs) are important determinants for salvage of preformed nucleosides and mediated uptake of antimetabolite nucleoside drugs into target cells. The focus of this review is the two families of human nucleoside transporters (hENTs, hCNTs) and their role in transport of cytotoxic chemotherapeutic nucleoside drugs. Resistance to anticancer nucleoside drugs is a major clinical problem in which NTs have been implicated. Single nucleotide polymorphisms (SNPs) in drug transporters may contribute to interindividual variation in response to nucleoside drugs. In this review, we give an overview of the functional and molecular characteristics of human NTs and their potential role in resistance to nucleoside drugs and discuss the potential use of genetic polymorphism analyses for NTs to address drug resistance.

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New antimetabolites in cancer chemotherapy and their clinical impact

Cited by 137 publications

References 45 publications

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Hsp90 Inhibition Depletes Chk1 and Sensitizes Tumor Cells to Replication Stress

Plasma pharmacokinetics and oral bioavailability of 3,4,5,6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

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