Human pharmacokinetics of WR-2721

Shaw, Leslie M.; Turrisi, Andrew T.; Glover, Donna J.; Bonner, Hugh; Norfleet, A.Lorraine; Weiler, Clare; Kligerman, Morton M.

doi:10.1016/0360-3016(86)90203-8

Cited by 79 publications

(27 citation statements)

References 10 publications

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“…The degree of resistance to amifostine conferred by p53 protein was modest, in the range of 1.5 -2-fold, and the biologic relevance of such relatively small degrees of resistance is poorly understood. Amifostine triggered apoptotic cell death at concentrations that are only slightly above the plasma concentrations achieved in clinical studies (Shaw et al, 1986(Shaw et al, , 1988, indicating that this observation may have clinical relevance.…”

Section: Discussionmentioning

confidence: 78%

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

et al. 2003

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To determine the role of p53 protein on the cellular effects of amifostine, we used molecularly engineered HCT116 colon cancer cells in which the p53 gene was inactivated by targeted homologous recombination or p53 protein was degraded by high-level expression of papillomavirus E6 protein. Amifostine induced a G1 arrest and protected against paclitaxel toxicity in p53-proficient but not in p53-deficient cells. In the absence of p53 protein, amifostine enhanced the cytotoxicity of paclitaxel. In addition, treatment of HCT116 cells with amifostine alone resulted in apoptotic cell death. Compared with p53-deficient cells, p53-proficient cells exhibited low-level resistance to amifostine-induced apoptosis. Amifostine induced the expression of p53 protein in p53-proficient cells and the expression of p21 protein in both p53-proficient and -deficient cells. These findings indicate that amifostine-induced G1 arrest and cytoprotection are mediated via a pathway that is dependent on p53 protein and that amifostine-induced expression of p21 protein is not sufficient to sustain a G1 arrest or to mediate cytoprotection. In addition, these findings identify p53 protein as a mechanism of resistance to amifostine-induced apoptosis.

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Section: Discussionmentioning

confidence: 78%

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

et al. 2003

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“…Similar plasma concentrations were observed for total WR-1065, whereas free WR-1065 in blood was undetectable. Thus, despite the application of nonclinical doses (i.e., usually infused as 910 mg/m 2 over 15 min or 200 mg/m 2 over 3 min; equivalent to about 8 mol/min/kg for both regimens), drug levels of amifostine and total WR-1065 in dogs were within the range of plasma concentrations observed for these drug species in cancer patients (Shaw et al, 1986b;Korst et al, 1997). In contrast, after a 740 or 910 mg/m 2 i.v.…”

Section: Discussionmentioning

confidence: 94%

Regional Pharmacokinetics of Amifostine in Anesthetized Dogs: Role of the Liver, Gastrointestinal Tract, Lungs, and Kidneys

Levi¹,

Knol²,

Ensminger³

et al. 2002

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.

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“…The rapid and preferential accumulation of WR-1065 in bone marrow and other normal tissues is attributed to the higher alkaline phosphatase activity in non-neoplastic cells. [22][23][24] Controlled clinical trials have confirmed the effectiveness of this agent in ameliorating the hematologic and organ toxicities of radiation and chemotherapy. 20,25 Given the broad myeloprotective activity of amifostine in preclinical investigations, this agent might also have intrinsic trophic effects on hematopoietic progenitors.…”

Section: Introductionmentioning

confidence: 99%

Amifostine stimulates formation of multipotent and erythroid bone marrow progenitors

et al. 1998

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Amifostine (WR-2721, Ethyol) is a phosphorylated aminothiol that affords broad cytoprotection from the myelosuppressive effects of antineoplastics. To further characterize its hematopoietic activities, we investigated the effects of amifostine and its dephosphorylated metabolite, WR1065, on the in vitro growth of human bone marrow progenitors. Preincubation exposure to amifostine or WR1065 stimulated the growth of colony-forming units granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) and erythroid bursts (BFU-E) from bone marrow mononuclear cells in a dose-dependent fashion. Over the concentration range tested (0.1-1000 M), pretreatment with the aminothiols enhanced formation of CFU-GEMM up to five-fold and BFU-E nine-fold, compared to a three-fold increase in myeloid colony recovery. In CD34؉ selected cells, preincubation with amifostine increased formation of CFU-GEMM up to 38-fold and produced macroscopic colonies, exceeding colony number in cultures initiated with optimal concentrations of interleukin-1 (IL-1), IL-3, or kit ligand (KL). When compared with recombinant human cytokines, amifostine enhanced IL-1 and IL-3 induced colony formation, although its stimulatory effect was less than additive. In contrast, pretreatment with amifostine antagonized the stimulatory effects of KL, whereas synergy was observed with concurrent exposure. Ex vivo expansion studies showed that amifostine alone supported and augmented the production of myeloid progenitors in secondary cultures. Similarly, under cytokine-deficient conditions, amifostine promoted cell survival and delayed apoptosis as measured by nucleosome generation. These data indicate that amifostine is a novel multipotent hematopoietic stimulant that augments the formation and survival of bone marrow progenitors.

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Human pharmacokinetics of WR-2721

Cited by 79 publications

References 10 publications

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

Regional Pharmacokinetics of Amifostine in Anesthetized Dogs: Role of the Liver, Gastrointestinal Tract, Lungs, and Kidneys

Amifostine stimulates formation of multipotent and erythroid bone marrow progenitors

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