MedLine Search: Phenylacetate
Legacy MedLine Search
This MedLine Search of the technical medical literature is from the early days of CancerGuide so it may not include the latest research. The articles referenced are still relevant but more recent ones may also be available. For more information on the incredibly powerful and freely available MedLine database see my Article on MedLine.
In all cases I have selected the references that looked most interesting to me. These are searches with a point of view! There could be references on this same subject that I didn’t include that you would have. For both of these reasons as well as the age of the search, you may want to consider doing your own search on this subject after looking at mine.
Finally, keep in mind that the abstracts presented here are only summaries of the actual articles. If you want to delve deeper you may want to get some of these articles from a Medical Library or an online document delivery service, as is provided with all MedLine accesses (usually for a fairly substantial fee).
SAT APR 29,1995 1:55 PM PaperChase provides 8,759,457 references -- all references found in the following databases of the National Library of Medicine and the National Cancer Institute*. You are searching all four databases simultaneously. Database Indexing Began Updated Current through MEDLINE 1966 weekly June 1995 Update, Part 4 HEALTH 1975 monthly May 1995 Update AIDSLINE 1980 monthly May 1995 Update *CANCERLIT 1980 monthly April 1995 Update LIST REFERENCES LIST REFERENCES A) PHENYLACETATE 85 D) NEOPLASMS 1155489 B) PHENYLACETATES 3994 E) NEOPLASMS /DT 126224 C) *SUM AB 4015 F) *ON C&E; 38 *****CANCER RESEARCH***** (REFERENCE 1 OF 10) 94185002 Thibault A Cooper MR Figg WD Venzon DJ Sartor AO Tompkins AC Weinberger MS Headlee DJ McCall NA Samid D et al A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer. In: Cancer Res (1994 Apr 1) 54(7):1690-4 Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose- limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease. Institutional address: Clinical Pharmacology Branch National Cancer Institute NIH Bethesda Maryland 20892. (REFERENCE 2 OF 10) 94147404 Samid D Ram Z Hudgins WR Shack S Liu L Walbridge S Oldfield EH Myers CE Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. In: Cancer Res (1994 Feb 15) 54(4):891-5 Phenylacetate, a deaminated metabolite of phenylalanine, has been implicated in damage to immature brain in phenylketonuria. Because primary brain tumors are highly reminiscent of the immature central nervous system, these neoplasms should be equally vulnerable. We show here that sodium phenylacetate can induce cytostasis and reversal of malignant properties of cultured human glioblastoma cells, when used at pharmacological concentrations that are well tolerated by children and adults. Treated tumor cells exhibited biochemical alterations similar to those observed in phenylketonuria-like conditions, including selective decline in de novo cholesterol synthesis from mevalonate. Because gliomas, but not mature normal brain cells, are highly dependent on mevalonate for production of sterols and isoprenoids vital for cell growth, sodium phenylacetate would be expected to affect tumor growth in vivo while sparing normal tissues. Systemic treatment of rats bearing intracranial gliomas resulted in significant tumor suppression with no apparent toxicity to the host. The data indicate that phenylacetate, acting through inhibition of protein prenylation and other mechanisms, may offer a safe and effective novel approach to treatment of malignant gliomas and perhaps other neoplasms as well. Institutional address: Clinical Pharmacology Branch National Cancer Institute National Institutes of Health Bethesda Maryland 20892. *****EXPERIENTIA***** (REFERENCE 3 OF 10) 72098727 Neish WJ Phenylacetic acid as a potential therapeutic agent for the treatment of human cancer. In: Experientia (1971 Jul) 27(7):860-1 [No Abstract Available] *****JOURNAL OF THE NATIONAL CANCER INSTITUTE***** (REFERENCE 4 OF 10) 92381739 Smigel K Non-toxic drug being tested to treat cancer and anemias [news] In: J Natl Cancer Inst (1992 Sep 16) 84(18):1398 [No Abstract Available] *****PROCEEDINGS / ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR***** (REFERENCE 5 OF 10) 95604089 Wood CG Lee C Grayhack JT Kozlowski JM Phenylacetate and phenylbutyrate promote cellular differentiation in human prostate cancer systems (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1994) 35:A2404 1994 Our laboratory has studied agents such as all-trans-retinoic acid (RA), extra cellular matrix (ECM), and dihydrotestosterone (DHT), which are capable of inducing prostate cancer differentiation, marked by decreased cell proliferation and increased prostate specific antigen (PSA) secretion, in the cell line LNCaP. In this study, we examine the effects of two novel tumor differentiation inducing agents, sodium phenylacetate (PA) and phenylbutyrate (PB). LNCaP and PC-3 cells were incubated in media containing charcoal stripped fetal bovine serum (cFBS). PA or PB, pH 7.0, was added at concentrations of 1, 5, or 10 mM. To a subset of wells, DHT was added at concentrations of 10(-12), 10(-10), or 10(-7) M. The effect of PA with RA was assessed at concentrations of 0.01, 0.1, 1, or 10 uM RA. Cell counts were assessed via Coulter counter and PSA was determined by the Hybritech assay. At concentrations of 5 and 10 mM, PA and PB inhibited proliferation by 50-75% in both cell lines at all concentrations of DHT (p less than 0.05). RA was additive and sometimes synergistic with PA in LNCaP, with inhibition of cell proliferation and increased PSA secretion from 10-100 fold in the absence of androgen (p less than 0.05). RA had no effect on PC-3. PA, at 5-10 mM, enhanced PSA secretion in LNCaP at all concentrations of DHT studied (p less than 0.05). PA and PB are potent agents capable of promoting a differentiated phenotype in aggressive prostate cancer systems. Their effect may complement other known differentiation inducing agents, resulting in more effective treatment strategies. Further studies will examine the effect of PA and PB on other markers of tumor differentiation. Institutional address: Dept. of Urology Northwestern University Medical School Chicago IL 60611 (REFERENCE 6 OF 10) 95604125 Shack S Prasanna P Hudgins WR Liu L Myers CE Samid D Experimental therapies for malignant gliomas: targeting the mevalonate pathway of cholesterol synthesis (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1994) 35:A2440 1994 Malignant gliomas are highly dependent on the mevalonate (MVA) for synthesis of cholesterol and intermediates critical to cell replication. Targeting MVA synthesis and/or utilization would be expected to inhibit tumor growth without damaging normal brain tissues, in which the MVA pathway is minimally active. Human glioblastoma cells were found to be uniquely vulnerable to lovastatin (LOV) and sodium phenylacetate (PA), inhibitors of the key regulatory enzymes HMG-coA reductase and MVA-PP decarboxylase, respectively. At IC50 concentrations, LOV (0.2 uM) and PA (4 mM) induced cytostasis and phenotypic reversion; 0.5-1 uM LOV caused cellular changes consistent with apoptosis. Combining LOV and PA at these pharmacological, nontoxic concentrations resulted in synergistic antitumor activity, suggesting an effective and safe new approach to treatment of malignant gliomas and perhaps other neoplasms as well. Both LOV and PA are in clinical trials at the NCI. Institutional address: Clinical Pharmacology Branch NCI Bethesda MD 20892 (REFERENCE 7 OF 10) 94602912 Thibault A Cooper MR Figg WD Tompkins A Samid D Myers CE A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1994) 35:A1226 1994 Phenylacetate (PA) induces terminal differentiation of HL60 cells and has preclinical activity against prostate cancer (PC) and glioblastoma multiforme (GBM). A phase I trial of PA was conducted in 17 patients (pts) with advanced solid tumors (PC:9, primary CNS:7, mesothelioma:1). Each pt received a single iv bolus followed by a 14- day continuous iv infusion (CIVI). 21 cycles of therapy were administered at 4 CIVI dose levels. PA displayed nonlinear pharmacokinetics (parameters, mean +/- SD: Km=105 + 45 g/ml, Vmax=24 +/- 5 mg/kg/hr and Vd=19 +/- 3 L). Conversion to phenylacetylglutamine, the major urinary metabolite, accounted for 99% of PA elimination. Dose-limiting toxicity, seen only during CIVI complicated by drug accumulation (PA concentration, mean +/- SD: 950 +/- 300 ug/ml), consisted of emesis and reversible CNS depression. Three pts with PC had stable PSA levels for greater than 2 months. One had improved bone pain. Two pts with GBM have sustained functional improvement for more than 6 months. In summary, PA given by CIVI has antineoplastic activity against PC and CNS tumors. Institutional address: Clinical Pharmacology Branch NCI Bethesda MD 20892 (REFERENCE 8 OF 10) 93693214 Stockhammer G Johnson R Lieberman F Phenylacetate inhibits proliferation of brain tumor-derived cell lines in vitro (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1993) 34:A2263 Phenylacetate (PA) inhibits proliferation and induces differentiation in promyelocytic leukemia cells (Samid et al, Cancer Res 52:1988, 1992). We tested the effect of PA on the proliferation of neuroectodermal tumor-derived cell lines. Human astrocytoma (U-251), medulloblastoma (DAOY, D-283), and rat malignant glioma (RG-2) cell lines were placed in 96 well microtiter plates with 2500 cells/100 ul of MEM + 15% fetal calf serum/well and incubated in concentrations of PA ranging from 0 to 20 mM. Cell proliferation was measured using a 4- hr [3H]thymidine uptake assay at 24-hr intervals for 7 days. All 4 cell lines demonstrated dose-dependent inhibition of proliferation. The ID50 for the human cell lines was in the 8 mM range; RG-2 cells responded only at the 20 mM concentration. Growth inhibition was not accompanied by changes in cell morphology. Autoradiographs of D-283 cell Western immunoblots demonstrated transforming growth factor beta (TGFB) 1 and 2 immunoreactivity, both before and after treatment with 10 mM PA. Affinity labeling with 125I-TGFB showed D-283 cells express TGFB-receptor subtypes 1, 2 and 3. PA inhibits proliferation of human malignant astrocytoma and medulloblastoma-derived cell lines at concentrations potentially achievable in patients. Whether PA interacts with a TGFB-regulatory pathway requires further study. Institutional address: Memorial Sloan-Kettering Cancer Center New York NY 10021 (REFERENCE 9 OF 10) 93693199 Samid D Shack S Liu L Hudgins B Prasanna P Danielpour D Qian S Myers CE Phenylacetate and related nontoxic differentiation inducers in treatment of prostate, brain and skin cancer (Meeting abstract). In: Proc Annu Meet Am Assoc Cancer Res (1993) 34:A2248 Phenylacetate, a common metabolite of phenylalanine, was recently discovered to be a novel differentiation inducer affecting hematopoietic cancer cells in vitro at nontoxic, pharmacologic concentrations. We now describe the effect of phenylacetate and derivatives on human solid tumors, including prostatic carcinoma, glioblastomas, and malignant melanoma. Treatment resulted in selective cytostasis and phenotypic reversion, as indicated by the restored anchorage-dependence, reduced invasiveness and loss of tumorigenicity in athymic mice. Molecular analyses of brain and hormone-refractory prostate cancer cells revealed marked decline in the production and secretion of TGF beta 2, a protein implicated in growth control, angiogenesis and immunosuppression. Treated prostatic cells exhibited decreased proteolytic activity mediated by urokinase- plasminogen activator, a molecular marker of disease progression in man. Phase I clinical trials with phenylacetate and its prodrug, phenylbutyrate, are being scheduled. Mechanisms of action and development of active analogs are described. Institutional address: NCI Bethesda MD 20892 (REFERENCE 10 OF 10) 92685654 Samid D Shack S Myers CE PHENYLACETATE IN SUPPRESSION OF HUMAN PROSTATE ADENOCARCINOMA CELL GROWTH AND INVASION (MEETING ABSTRACT) In: Proc Annu Meet Am Assoc Cancer Res (1992) 33:A3121 1992 Prostate cancer that no longer responds to hormonal therapy presents a major challenge in clinical oncology. Considering the increased glutamine dependence of malignant cells, we examined the efficacy of phenylacetate (PA), a plasma component known to deplete glutamine in humans. Treatment of hormone-refractory human prostate carcinoma cell lines PC3 and DU145 with pharmacologically attainable nontoxic concentrations of PA resulted in selective growth arrest and reversal of malignancy (ie, loss of invasiveness and tumorigenicity in athymic mice). Interestingly, PA enhanced the antitumor effects of suramin, a drug known to be active in patients with advanced disease. The data suggest that PA, used alone or in combination with other antitumor agents, may offer an effective and safe approach to treatment of androgen-insensitive prostate carcinoma. Institutional address: Clinical Pharmacology Branch NCI Bethesda MD 20892