UI - 12015757
AU - Abraham J; Bakke S; Rutt A; Meadows B; Merino M; Alexander R; Schrump D;
Bartlett D; Choyke P; Robey R; Hung E; Steinberg SM; Bates S; Fojo T
A phase II trial of combination chemotherapy and surgical resection for
the treatment of metastatic adrenocortical carcinoma: continuous
infusion doxorubicin, vincristine, and etoposide with daily mitotane as
a P-glycoprotein antagonist.
SO - Cancer 2002 May 1;94(9):2333-43
AD - Medicine Branch, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland 20892, USA.
BACKGROUND: Adrenocortical carcinoma (ACC) is rare, nearly always fatal,
and to the authors' knowledge has few nonsurgical treatment options.
Based on in vitro studies demonstrating the efficacy of mitotane as a
P-glycoprotein (Pgp) antagonist, and expression of high levels of Pgp in
ACC, the authors conducted a study of infusional doxorubicin,
vincristine, and etoposide with oral mitotane +/- surgical resection in
patients with metastatic ACC. METHODS: Thirty-six patients with
metastatic ACC received daily oral mitotane (mean, 4.6 g/day) and
96-hour infusional doxorubicin (10 mg/m(2)/day), etoposide (75
mg/m(2)/day), and vincristine (0.4 mg/m(2)/day). Four responding
patients (11%) underwent surgery. RESULTS: Thirty-five patients were
evaluable; all had metastatic disease. Eleven patients had not undergone
resection of the primary tumor. Approximately 53% of patients had
functional tumors. A total of 190 cycles were administered to 36
patients. Responses were observed in 8 patients (22%): 1 complete, 4
partial, and 3 minor responses. The mean duration of response was 12.4
months. Using a landmark method, the median survival of patients who did
not respond to chemotherapy was 11.6 months from a point 4 months after
the initiation of therapy, whereas that of 8 patients who demonstrated a
response to chemotherapy was 34.3 months from that same landmark. High
levels of Pgp expression were documented in nine of nine tumors.
Mitotane levels > 10 microg/mL, previously shown to antagonize Pgp in
vitro, were achieved in 25 of 36 patients (69%). However, rhodamine
efflux from CD56-positive cells was not impaired, suggesting poor in
vivo Pgp inhibition. The predominant Grade 3/4 toxicity (according to
the Common Toxicity Criteria of the National Cancer Institute) was
neutropenia in 66% of cycles; however, fever occurred in only 3% of
cycles. Daily mitotane was associated with Grade 1/2 nausea, diarrhea,
fatigue, and neuropsychiatric changes in 31 of 36 patients (86%).
CONCLUSIONS: Using a combination regimen of daily mitotane with
infusional doxorubicin, vincristine, and etoposide in patients with
metastatic ACC, responses were observed in 22% of patients. The
superiority of this combination over single-agent mitotane is uncertain.
The side effects of mitotane made treatment difficult. More effective
Pgp antagonists are needed. Copyright 2002 American Cancer Society.DOI
UI - 11994389
AU - Kuhn JM; Lefebvre H; Duparc C; Pellerin A; Luton JP; Strauch G
Cosecretion of estrogen and inhibin B by a feminizing adrenocortical
adenoma: impact on gonadotropin secretion.
SO - J Clin Endocrinol Metab 2002 May;87(5):2367-75
AD - European Institute for Peptide Research, Department of Endocrinology,
INSERM, U-413, University Hospital Rouen, 76031 Rouen, France.
We describe the first reported case of a feminizing adrenocortical
adenoma cosecreting estrogens and inhibin B. A 39-yr-old man, with no
previous history of disease and free of treatment, complained of
gynecomastia without any clinical abnormality. Plasma E2 and T were 496
pmol/liter and 8.7 nmol/liter, respectively. Testicular echography was
normal, and abdominal computed tomography scan showed a 28-mm right
adrenal tumor. hCG (5000 IU, im) induced a rise in plasma T levels (20.7
nmol/liter) without any change in plasma E2 levels. Basal plasma LH and
FSH levels were undetectable. GnRH (100 microg, i.v.) induced an
increase in plasma LH levels without a change in plasma FSH levels. The
mean plasma inhibin B level was 330 +/- 45 pg/ml (normal range, 94-327).
Pulsatile GnRH administration (20 microg/pulse every 90 min for 3 d)
stimulated LH secretion, whereas FSH secretion remained blunted. The
patient underwent surgery to remove a 12-g adrenal adenoma. Six months
later, plasma E2 and T levels were normalized. LH showed a spontaneous
pulsatile pattern, and the mean plasma FSH level was 4.8 U/liter. The
secretion of both gonadotropins was stimulated during a pulsatile GnRH
administration performed in the same manner as before surgery. The mean
plasma inhibin B level was 210 +/- 25 pg/ml. Immunohistochemical studies
revealed the presence of aromatase in clusters of tumor cells.
Incubation of tumor sections with anti-beta(B)-inhibin antibody revealed
intense staining in groups of cells that were also labeled with
anti-alpha-inhibin antibody. These data show that the tumor cosecreted
E2 and inhibin B, which were both responsible for inhibition of
gonadotropin secretion. Tumor secretions appeared to be much more potent
in suppressing FSH than LH levels.
UI - 11869873
AU - Johansson MK; Sanderson JT; Lund BO
Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid
steroidogenesis in the H295R human adrenocortical carcinoma cell line.
SO - Toxicol In Vitro 2002 Apr;16(2):113-21
AD - Department of Environmental Toxicology, Uppsala University, Norbyv. 18A,
SE-752 36 Uppsala, Sweden. firstname.lastname@example.org
The formation of steroids in the H295R human adrenocortical carcinoma
cell line was analysed by HPLC or RIA, and based on these data the
apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in
this cell line were calculated. The environmental pollutant
3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP)
inhibitors ketoconazole, metyrapone and aminoglutethimide were studied
for their effects on the steroid formation. Metyrapone (IC50) of 1
microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to
inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all
enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5
microM). Aminoglutethimide was examined only for effects on CYP11A
activity and was shown to inhibit pregnenolone formation (20 microM: 61
+/- 4% of control). The possibility of studying all CYP enzymes in the
corticosteroidogenesis makes this cell line a valuable test system to
examine effects of chemicals, such as suspected endocrine disruptors, on
the human glucocorticoid hormone synthesis. The inhibition of cortisol
formation by 3-MeSO2-DDE supports an interaction with the active site of
CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In
mice, this interaction led to metabolic activation and a high
adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity
of 3-MeSO2-DDE in humans are needed.
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