Aplidin hinders angiogenesis and the growth of anaplastic thyroid cancer
Released : Feb 07, 2006 4:39 PM
Aplidin (APLD) hinders angiogenesis and the growth of anaplastic thyroid cancer (ATC).
According to a study from the United States, "ATC is one of the most aggressive and highly lethal human cancers. Median survival after diagnosis is 4-6 months despite available radiotherapy and chemotherapy."
"Additional treatments are needed for ATC. Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulus, which is expressed by ATC. Previously, anti-VEGF antibody was used to block VEGF-dependent angiogenesis in ATC xenografts. This treatment induced partial (56%) but not complete tumor regression," noted A.M. Straight and colleagues, Uniformed Services University of the Health Sciences.
"APLD is a marine derived antitumor agent currently in phase II clinical studies. Multiple activities of this compound have been described which likely contribute to its antiproliferative effect. Notably, APLD has been shown to have antiangiogenic properties which include: inhibition of VEGF secretion, reduction in the synthesis of the VEGF receptor (FLT-1), and blockade of matrix metalloproteinase production by endothelial cells."
Scientists wrote, "we hypothesized that APLD, with its broad spectrum of action and antiangiogenic properties, would be a potentially effective drug against ATC. Thirty BALB/c nu/nu mice were injected with ATC cells (ARO-81, 1X106) and allowed to implant for 3 weeks."
"Animals were randomized to receive daily intraperitoneal injections of vehicle, low dose (0.5 mg/kg/day), or high dose (1.0 mg/kg/day) APLD. After 3 days, the animals were killed and the tumors were removed, weighed, and divided for RNA and protein analyses. APLD significantly reduced ATC xenograft growth (low dose, 20% reduction, p=.01; high dose, 40% reduction, p<.001)," investigators reported.
"This was associated with increased levels of apoptosis related proteins polyadenosylribose polymerase 85 (PARP-85, 75% increase, p=.024) and caspase 8 (greater than five-fold increase, p=.03). APLD treatment was further associated with lost or reduced expression of several genes that support angiogenesis to include: VEGF, hypoxia inducible factor 1 (HIF-1), transforming growth factor-beta (TGF-beta), TGF beta receptor 2 (TGF beta R2), melanoma growth stimulating factor 1 (GRO1), cadherin, and vasostatin."
Study authors concluded, "this data supports the hypothesis that APLD may be an effective adjunctive therapy against ATC. The demonstrated molecular impact against angiogenic related genes specifically supports future strategies combining APLD with VEGF interacting agents."
Straight and colleagues published the results of their research in Cancer Chemotherapy and Pharmacology (Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother Pharmacol, 2006;57(1):7-14).
For additional information, contact G.L. Francis, Uniformed Service University of Health Science, Dept. Pediatrics, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
The publisher of the journal Cancer Chemotherapy and Pharmacology can be contacted at: Springer, 233 Spring Street, New York, NY 10013, USA.
Keywords: Bethesda, Maryland, United States, Angiogenesis, Aplidin, Chemotherapy, Endocrinology, Pharmaceutical Research, Oncology, Anaplastic Thyroid Cancer, Genetics, Vascular Endothelial Growth Factor, Matrix Metalloproteinase.
This article was prepared by World Disease Weekly editors from staff and other reports. Copyright 2006, World Disease Weekly via NewsRx.com.
Copyright 2006 World Disease Weekly via NewsRx.com
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Nov 2005 :
Plitidepsin has a cytostatic effect in human undifferentiated (anaplastic) thyroid carcinoma.
Bravo SB, Garcia-Rendueles ME, Seoane R, Dosil V, Cameselle-Teijeiro J, Lopez-Lazaro L, Zalvide J, Barreiro F, Pombo CM, Alvarez CV
Department of Physiology, School of Medicine, University of Santiago de Compostela, Madrid, Spain.
Undifferentiated (anaplastic) thyroid carcinoma is a highly aggressive human cancer with very poor prognosis. Although there have been a few studies of candidate treatments, the fact that it is an infrequent tumor makes it very difficult to design clinical trials. A strong association has been observed between undifferentiated thyroid carcinoma and TP53 mutations in numerous molecular genetic and expression studies. Plitidepsin (Aplidin, PharmaMar, Madrid, Spain) is a novel anticancer compound obtained from a sea tunicate. This compound has been reported to induce apoptosis independently of TP53 status. We investigated the actions of plitidepsin in human thyroid cancer cells. In initial experiments using primary cultured cells from a differentiated (papillary) carcinoma, we found that 100 nmol/L plitidepsin induced apoptosis, whereas lower doses were cytostatic. Because our aim was to study the effects of plitidepsin at clinically relevant concentrations, subsequent experiments were done with a dosage regimen reflecting plasma concentrations observed in previously reported clinical trials: 100 nmol/L for 4 hours, followed by 10 nmol/L for 20 hours (4(100)/20(10) plitidepsin). This plitidepsin dosage regimen blocked the proliferation of a primary undifferentiated/anaplastic thyroid carcinoma culture obtained in our laboratory and of a commercial cell line (8305C) obtained from an undifferentiated thyroid carcinoma; however, it did not induce apoptosis. The proportion of cells in the G(1) phase of the cell cycle was greatly increased and the proportion in the S/G(2)-M phases greatly reduced, suggesting that plitidepsin blocks G(1)-to-S transition. Levels of the cyclin D1/cyclin-dependent kinase 4/p21 complex proteins were decreased and, in line with this, the levels of unphosphorylated Rb1 increased. The decrease in cell cycle proteins correlated with hypoacetylation of histone H3. Finally, we did experiments to assess how rapidly tumor cells return to their initial pretreatment proliferative behavior after 4(100)/20(10) plitidepsin treatment. Cells from undifferentiated tumors needed more than 3 days to recover logarithmic growth, and after 7 days, cell number was still significantly lower than in control cultures. 4(100)/20(10) plitidepsin inhibited the growth in soft agar. Together, our data show that plitidepsin is able to block in vitro cell cycle progression at concentrations similar to serum concentrations observed in vivo, and that this effect is persistent for several days after plitidepsin removal. Whether plitidepsin will prove to be clinically useful in the treatment of undifferentiated thyroid cancers remains to be established. However, our results raise the possibility that plitidepsin might be effective alone or in combination with radiotherapy and/or other drug treatments.