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
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
Institutional address:
     Clinical Pharmacology Branch
     National Cancer Institute
     Maryland 20892.
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
     Maryland 20892.
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]
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]
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
     IL 60611
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
     MD 20892
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
     MD 20892
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
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:
     MD 20892
Samid D  Shack S  Myers CE
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
     MD 20892