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 Posted: Mon Nov 17, 2008 6:50 am Post subject: Regulation of growth of prostate cancer cells selected in th |
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http://www.ncbi.nlm.nih.gov/pubmed/16998813?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedarticles&logdbfrom=pubmed
Regulation of growth of prostate cancer cells selected in the presence of
interleukin-6 by the anti-interleukin-6 antibody CNTO 328.
Steiner H, Cavarretta IT, Moser PL, Berger AP, Bektic J, Dietrich H, Zaki
MH, Nakada M, Hobisch A, Nemeth JA, Culig Z.
Department of Urology, Innsbruck Medical University, Innsbruck, Austria.
BACKGROUND: Interleukin-6 (IL-6) is a multifunctional regulator of
cellular events in prostate cancer. LNCaP-IL-6+ cells selected in the
presence of IL-6 were taken for assessment of effects of the chimeric
monoclonal anti-IL-6 antibody CNTO 328. METHODS: Cell viability was
assessed after treatment with CNTO 328 by the ATP assay. Expression of
Bcl-2 and Bax and activation of signaling pathways were evaluated by
Western analysis. Nude mice were inoculated with LNCaP-IL-6+ cells and
treated with CNTO 328. The tumors were analyzed by immunohistochemistry
for expression of Ki-67, tissue transglutaminase, and vascular endothelial
growth factor. RESULTS: CNTO 328 caused a statistically significant
inhibition of cell viability. The protein levels of Bcl-2 and the
phosphorylation of ERK1/2 mitogen-activated protein kinases were decreased
by the anti-IL-6 antibody. Treatment with CNTO 328 yielded an increase in
the phosphorylation of signal transducers and activators of transcription
factor 3. The mean tumor volume in animals inoculated with LNCaP-IL-6+
cells and treated with CNTO 328 was insignificantly lower than that in
animals treated with the control antibody. There was a statistically
significant decrease in the percentage of Ki-67-positive cells in CNTO
328-treated tumors. CONCLUSION: CNTO 328 has a potential in prostate
cancer therapy and could be further tested in various combination
experimental treatments.
PMID: 16998813 [PubMed - indexed for MEDLINE]
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* Review http://www.ncbi.nlm.nih.gov/pubmed/152391328
#Review Interleukin-6 regulation of prostate cancer cell growth.
http://www.ncbi.nlm.nih.gov/pubmed/15239138
Links
CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced
cachexia in nude mice.
Zaki MH, Nemeth JA, Trikha M.
Oncology Research, Centocor, Inc., Malvern, PA 19355-1307, USA.
IL-6 is a multifunctional cytokine implicated in several cancers. IL-6
is a growth factor for certain tumors and contributes to drug resistance,
cachexia and bone resorption. Cachexia is characterized by progressive
weight loss and depletion of host reserves of adipose tissue and skeletal
muscle. We have developed CNTO 328 (cCLB8), a human-mouse chimeric MAb to
IL-6 (K(d) approx. 10(-12) M) that inhibits IL-6 function. A phase I study
with CNTO 328 in multiple myeloma patients demonstrated that the antibody
was safe and had a circulating half-life of approximately 17 days. Since
IL-6 is implicated in cachexia, we hypothesized that CNTO 328 could
inhibit tumor-induced cachexia. We used 2 human tumor-induced cachexia
models in nude mice. In the first model, human melanoma cells were
inoculated in female nude mice. Control treated animals lost 19% (+/-7.7%)
body weight from day 0 to day 31, whereas CNTO 328 (10 mg/kg)-treated
animals lost only 1.5% (+/-1.3%) body weight from day 0 to day 31 (p =
0.023). In the second cachexia model, human prostate tumor cells were
injected into male nude mice. By day 29, control treated animals lost 6%
(+/-3.5%) body weight, whereas CNTO 328 (10 mg/kg)-treated animals gained
7% (+/-4%) body weight (p = 0.01). Since CNTO 328 blocks human IL-6 but
not mouse IL-6, the data indicate that tumor cell-secreted IL-6 directly
contributes to body weight loss, highlighting the potential role for CNTO
328 as an anticachectic agent.
PMID: 15239138 [PubMed - indexed for MEDLINE
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* Regulation of growth of prostate cancer cells selected in the
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[Prostate. 2006]
* Involvement of human interleukin 6 in experimental cachexia induced
by a human uterine cervical carcinoma xenograft. [Clin Cancer Res. 1995]
* ReviewTreatment of malignancy-associated hypercalcemia and cachexia
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Oncol. 2003]
http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/15521
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings
(Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 15521
Abstract
Preliminary results of a phase I study: A chimeric monoclonal anti IL-6
antibody CNTO 328 in combination with docetaxel in patients with hormone
refractory prostate cancer
G. R. Hudes, D. Nanus, M. Qi, U. Prabhakar, R. Corringham, Q. Jiao and M.
Eisenberger
Fox Chase Cancer Center, Philadelphia, PA; New York Presbyterian Hospital,
Cornell University, New York, NY; Centocor Inc, Malvern, PA; Sidney Kimmel
Cancer Center, Johns Hopkins Univ, Baltimore, MD
15521
Background: High serum levels of pro-inflammatory cytokine IL-6 may impact
the progression and survival of metastatic hormone refractory prostate
cancer (HRPC). CNTO328, an anti IL-6 monoclonal antibody, inhibited
prostate tumor growth in several preclinical xenograft mouse models.
Methods: This Phase 1, open label study evaluates the safety,
pharmacokinetics (PK), and pharmacodynamics of CNTO328 at three dose
levels (6mg/kg q2 weeks, 9mg/kg q3 weeks and 12mg/kg q3 weeks) in
combination with docetaxel (75mg/m2 q3 weeks) in men with metastatic HPRC.
C-reactive protein (CRP), a surrogate biomarker of serum IL-6, and
circulating tumor cells (CTC) are evaluated.
Results: Eight patients with a median baseline PSA value of 56.8 ng/ml
(range 13.6- 436.9 ng/ml) were treated in the first cohort (6 mg/kg
CNTO328 q2 weeks in combination with docetaxel 75 mg/m2 q3 weeks). At
baseline, 6 patients (75%) had detectable CRP and 6 patients had
detectable CTCs. The median number of CNTO328 doses and docetaxel cycles
administered was 6 (CNTO328: range 3 to 11 doses; docetaxel: range 3 to 13
cycles). No first-cycle DLT was observed for this combination.
Three patients discontinued treatment due to docetaxel-related grade 3
adverse events (deep vein thrombosis, hyperbilirubinemia, and nail
changes) after 6, 11, and 13 cycles of docetaxel, respectively. Serum CRP
decreased to below detectable levels 7 days after the first dose of
CNTO328 in all patients with measurable values at baseline and remained
undetectable throughout treatment.
Two patients with post-treatment CTC values showed CTC reduction from 82
to1, and 127 to1, respectively.
Six of 8 patients had = 50% PSA reductions and all had stable or improved
bone scans and/or CT scans.
PK of CNTO328 and docetaxel, alone and in combination, will be presented.
Conclusions: Thus far, anti-IL6 therapy with CNTO328 at 6mg/kg q2 weeks in
combination with docetaxel 75mg/m2 q3 week has been feasible and
tolerable. Complete suppression of CRP and PSA reduction provide evidence
of biological and anti-tumor activity of this approach and support further
testing.
Author Disclosure [see web page]
http://en.wikipedia.org/wiki/Anti-IL-6_chimeric_monoclonal_antibody
Anti-IL-6 chimeric monoclonal antibody
From Wikipedia, the free encyclopedia
Jump to: navigation, search
Anti-IL-6 chimeric monoclonal antibody is a chimeric (made from human and
mouse proteins) monoclonal antibody being studied in the treatment of
advanced kidney cancer and other types of cancer. Monoclonal antibodies
are made in the laboratory and can locate and bind to substances in the
body, including cancer cells. Anti-IL-6 chimeric monoclonal antibody works
by blocking inflammation and tumor growth. Also called CNTO 328 and cCLB8.
[edit] External links
* Anti-IL-6 chimeric monoclonal antibody entry in the public domain
NCI Dictionary of Cancer Terms
This article includes text from the U.S. National Cancer Institute>s
public domain Dictionary of Cancer Terms |
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