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At least 19 recordsLinked to original sources

PubMed2004

Antitumor effects of peroxisome proliferator activate receptor gamma ligands on anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma is an aggressive neoplasm and resistant to all sorts of treatment due to its rapid growth and invasive potential. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor modulating variety of biological properties, such as regulating of adipogenesis, inhibition of cancer cell proliferation or differentiation of tumor cells. The purpose of this study was to evaluate the possibility for the therapeutic effect of PPARgamma ligands against anaplastic thyroid tumor in vitro. Expressions of the PPARc gene and protein were examined in 5 human anaplastic carcinoma cell lines (MSA, IAA, ROA, K119 and KOA-2). We next evaluated the effects of PPARgamma ligands (Thiazolidinedione, Prostaglandin J2 and RS1303) on proliferation, differentiation, apoptosis and invasion. Five cell lines showed higher level of the PPARc gene and protein expression than papillary thyroid carcinoma. PPARgamma ligands inhibited cell proliferation by inducing apoptosis instead of differentiation in dose-dependent manner. PPARgamma ligands also down regulated the invasive potential of 5 cell lines. The inhibitory effect of proliferation or invasion was prominent in 3 cell lines, which exhibited higher expression level of the PPARc gene or protein. Our results indicated that PPARgamma ligands modify malignant potential of anaplastic carcinoma cell lines altering growth or invasive properties, suggesting that PPARgamma could be potentially the novel molecular target for human thyroid anaplastic carcinoma.

Antineoplastic Agents↗

PubMed1998

Does surgery improve the survival of patients with advanced anaplastic thyroid carcinoma?

Anaplastic thyroid carcinoma is one of the most lethal neoplasms, with poor prognosis being reported by most authors. The benefits of surgery for most cases of advanced disease remain controversial. In this study we asked the following question: Does surgical intervention alter outcomes for patients with advanced anaplastic thyroid carcinoma? Forty-six patients with advanced anaplastic thyroid carcinoma were analyzed. There were 20 patients with advanced localized disease (group 1), 15 of whom received surgery. Of the other 26 patients with evidence of distant metastases (group 2), 13 received surgery. For group 1 patients, the mean survival was 12.8 months versus 8.6 months in the surgical and nonsurgical subgroups (p = 0.46). For group 2 patients, the mean survival was 3.5 months versus 2.8 months in the surgical and nonsurgical subgroups (p = 0.72). These data suggest that surgery does not improve survival for patients with advanced anaplastic thyroid carcinoma. In conclusion, the mean survival showed no significant differences between surgical and nonsurgical patients (p = 0.43). This study suggests that surgical resection does not improve the survival of patients with advanced anaplastic thyroid carcinoma.

Age Factors↗

PubMed2004

Epidermal growth factor receptor as a novel therapeutic target in anaplastic thyroid carcinomas.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies, with a median survival of up to 6 months. Such a bad prognosis under the present treatment procedures suggests the need for novel approaches in the management of this disease. Since some epidermal growth factor receptor (EGFR) inhibitors are now in clinical trials and few data are available concerning EGFR expression in anaplastic thyroid carcinomas, we tried to estimate a possible overexpression of this receptor in a larger tumor series. Twenty-five ATCs, including 3 ATCs with poorly differentiated thyroid carcinoma (PDTC) parts, were immunohistochemically investigated with a mouse monoclonal antibody directed against EGFR (EGFR pharmDX kit). The tumors revealed primarily a distinct membranous staining pattern, and in several tumor cells an additional cytoplasmic reactivity could be observed. The anaplastic carcinomas presented with 5 of 25 (20%) without EGFR reaction, 10 of 25 (40%) with reactivity, and 10 of 25 (40%) with overexpression of the receptor. All ATCs with PDTC parts (100%) showed EGFR overexpression. Cytoplasmic reactivity was observed in 56% of all ATCs. A significant correlation was calculated for EGFR overexpression and cytoplasmic staining (P = 0.036). Concerning receptor overexpression, ATCs were significantly different from ATCs with PDTC parts (P = 0.023). For the first time, we present EGFR overexpression in ATC in a larger tumor series, demonstrating that EGFR overexpression is a common finding in ATC. For at least one-third of all anaplastic thyroid carcinomas, EGFR seems to be a promising agent for the targeted molecular therapy of these extraordinarily aggressive tumors.

Aged↗

PubMed2005

Potential activity of paclitaxel, vinorelbine and gemcitabine in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) has a rapidly fatal course in the mostly elderly patients with a median survival after diagnosis of 4-12 months. Activity of commonly used chemotherapy (doxorubicin) is low, thus more active compounds need to be introduced into the therapeutic concept of ATC. Recently, based on preclinical data Ain et al. conducted a clinical phase II study with paclitaxel 96 h infusion in ATC achieving a promising response rate of 53%. To further improve therapeutic options in ATC, we evaluated the activity of topotecan, oxaliplatin, vinorelbine, gemcitabine and paclitaxel in comparision to cisplatin and doxorubicin (1 and 96 h drug exposure) alone or in combination in the ATC cell lines SW1736 and 8505C. IC50 values were determined by the sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity (RAA) and drug interaction was analyzed using a parametric response surface approach (Greco model) of the Loewe additivity. Duration of drug effect was estimated by regrowth kinetics. We found paclitaxel, vinorelbine and gemcitabine active in ATC with RAA (1 h drug exposure) ranging from 86 to 454, 15 to 17 and 31 to 140, respectively. The activity of doxorubicin and cisplatin was moderate with RAA ranging from 1.4 to 2.2 and 0.2 to 0.3, respectively. Combined drug exposure of gemcitabine/paclitaxel and gemcitabine/vinorelbine was synergistic with a Loewe index > 0. However, these results did not reach statistical significance with p > 0.05. At clinically relevant drug concentrations paclitaxel, gemcitabine and vinorelbine but not oxaliplatin exerted a sustained growth inhibition after cessation of drug exposure for the complete assay time of 15 days. In conclusion, paclitaxel, gemcitabine and vinorelbine but not topotecan or oxaliplatin appeared to be active in anaplastic thyroid carcinoma based on RAA or growth delay at clinically relevant drug concentrations. Combinations of vinorelbine/gemcitabine and paclitaxel/gemcitabine exerted a trend to synergy. Thus, further evaluation of paclitaxel, vinorelbine and gemcitabine alone or in combination with ATC seems warranted.

Antineoplastic Agents↗

PubMed2000

Anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive tumor characterized by rapid growth that causes death soon after diagnosis. Optimal treatment is debatable because of inherent difficulties investigating a rare malignancy associated with a survival of only months. Nevertheless, there is evidence that a multimodality approach consisting of surgery, chemotherapy, and radiotherapy is the preferred approach when the disease is localized. Eradication by complete surgical resection with total thyroidectomy, although often not feasible, followed or preceded by concurrent doxorubicin-based chemotherapy and hyperfractionated external beam radiation has been occasionally used and can rarely be associated with long-term survival. Surgical extirpation with radical organ resection is associated with high morbidity, and, although an aggressive surgical approach is reasonable in selected patients, organ preservation should be the goal in a disease with high recurrence and death rates. Any modality used in isolation usually fails to control local and regional ATC. In otherwise healthy patients who can tolerate aggressive therapy, chemoradiation and surgery may also be warranted for palliating incurable disease in the neck, which can cause death by asphyxiation.

Antineoplastic Agents↗

PubMedDate not supplied

Integrated therapeutic strategies for anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a very rare neoplasm with an aggressive course. The prognosis has not changed in the last decades and the median survival does not exceed six months. Only few patients with incidental limited ATC will be cured. Different therapeutic options have been explored but the results are disappointing. At present, new drugs and new timing for proper treatment are under investigation. In this short review we have summarized these recent developments.

Carcinoma↗

PubMed2000

Variable expression of keratins and nearly uniform lack of thyroid transcription factor 1 in thyroid anaplastic carcinoma.

Thyroid anaplastic (undifferentiated) carcinomas (TACs) comprise a morphologically heterogeneous group of tumors, which can arise in the background of differentiated papillary or follicular carcinoma. The thyroid epithelial differentiation varies in these tumors and has not been completely characterized. In this study, we immunohistochemically analyzed different variants TACs from 35 patients by using antibodies specific to 9 different keratin polypeptides, epithelial membrane antigen, thyroid transcription factor I (TTF-1), and thyroglobulin. These tumors were histologically divided into 3 categories: squamoid-cohesive (SC, 13 tumors), spindle cell sarcomatous (SS, 8 cases) and intermediate group, including tumors with giant cells and solid epithelioid components (GC, 18 tumors); 4 tumors had 2 components. The patients ages ranged from 40 to 89 years, with a mean age in all groups of 70 years. TTF-1 was present in only 2 of 9 of the SC tumors, and absent in all other TACs, but was present in entrapped differentiated components. Thyroglobulin was absent in all but 1 case. A complex keratin (K) pattern of stratified epithelia was typically seen in the SC tumors with extensive K7, K8, K17, K18, and K19, and variable K13 and K14 expression; EMA was also present. K16 was limited to squamous pearls in 1 tumor, and K10 was absent. The GC carcinomas typically had K8 and K18, whereas the expression of K7 was variable and that of K14, K17, and K19 sporadic; EMA was variably present in half of the cases. The keratins in spindle cell sarcomatous tumors were usually limited to K7, K8, and K18, often in limited numbers of cells. EMA was present in 1 case only. These results indicate a complex pattern of keratins in squamoid and giant cell TACs, similar to papillary carcinoma and suggesting the possibility of relationship. There was a progressive loss of epithelial differentiation and keratins in sarcomatoid TACs. Loss of TTF-1 is a nearly uniform feature of TAC and disallows the use of this marker to pinpoint a thyroid origin of these tumors.

Adenocarcinoma, Follicular↗

PubMed1999

Comparative genomic hybridization defines frequent loss on 16p in human anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the malignant tumors with the poor prognosis that is thought to arise from well-differentiated thyroid cancer (DTC). To investigate the molecular mechanism of ATC, we studied genomic alterations of eight ATC cell lines and three DTC cell lines by means of the comparative genomic hybridization (CGH) method. Loss of 16p was observed in five of eight ATC cell lines (62. 5%), but none of the three DTC cell lines showed loss of this chromosome arm. It is notable that loss of 18q [7/8 of ATC (87.5%), 2/3 of DTC (67%)] and gain of 20q [5/8 of ATC (62.5%), 3/3 of DTC (100%)] were frequently seen in both histologic types. Our results suggest that there is a gene in 16p that is closely associated with transformation from well-differentiated thyroid cancer to anaplastic cancer.

Carcinoma↗

PubMed1999

Anaplastic thyroid carcinoma survival.

Anaplastic thyroid carcinoma is a rare, highly malignant tumor of elderly people. The purpose of this retrospective study was to characterize the patient population and to detect a potential subgroup with better prognosis or any intervention that would be useful. From 1967 through 1994 a total of 33 anaplastic thyroid carcinomas were operated on at the Second Department of Surgery, Helsinki University Central Hospital. There were 26 females and 7 males with mean age of 66.0 years (range 36-89 years). At the time of diagnosis 16 of 33 patients had distant metastases, and 32 of 33 of the tumors had invaded the thyroid capsule. Disease-specific survival was 9.7% (95% confidence interval from 2.0% to 25.9%) at 1 year using the product limit survival analysis. In the stepwise Cox proportional hazards regression model, local resectability (p = 0.0002), presence of distant metastases at diagnosis (p = 0.0014), radiotherapy (p = 0.014), and radioiodine ablation (p = 0.039) were independent prognostic factors. We concluded that even though statistically significant, independent, prognostic factors can be found the survival of the patients with the best prognostic characteristics is still poor. Only one patient, who had an anaplastic carcinoma focus within an encapsulated follicular thyroid carcinoma, survived in this series. At present there seems to be no surgical treatment that would be efficient for treating symptomatic anaplastic thyroid carcinoma.

Adult↗

PubMed2006

Derangement of the E-cadherin/catenin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid cancer arises, or transforms, from pre-existing differentiated thyroid cancer. E-cadherin functions as a cell-cell adhesion molecule that complexes with catenin proteins for function. The objective of this study was to evaluate the change in E-cadherin/beta-catenin expression in the transformation of differentiated to anaplastic thyroid carcinoma. METHODS: A tissue microarray was constructed from 12 anaplastic thyroid tumors and their adjacent associated differentiated foci. Immunohistochemistry was used to evaluate tumor expression of E-cadherin and beta-catenin. RESULTS: There was decreased expression of E-cadherin and beta-catenin by the anaplastic tumors when compared with the differentiated thyroid tumors from which they evolved. The expression of E-cadherin and beta-catenin was 92% and 67%, respectively, by the differentiated thyroid carcinoma, and 17% and 50%, respectively, by the anaplastic tumors. CONCLUSIONS: This report shows that derangement of the E-cadherin/catenin complex is associated with the transformation of differentiated into anaplastic thyroid carcinoma.

Aged↗

PubMed2002

The important role of operations in the management of anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma is a rare and highly lethal neoplasm. We investigated whether operations have an impact on the survival of patients who have anaplastic carcinoma without distant metastasis. METHODS: Between 1989 and 1999, 40 consecutive patients with anaplastic carcinoma, without distant metastasis at the time of presentation or during local treatment, were reviewed. The cumulative survival rates and 1-year survival rates were compared. RESULTS: Eleven patients had a small focus of anaplastic carcinoma in a differentiated carcinoma, and 29 patients had ordinary anaplastic thyroid carcinoma. Surgical debulking was performed in 26 patients. Radiotherapy was used for 31 patients and chemotherapy for 19 patients. The 1-year survival rates of the patients with incidental anaplastic carcinoma, ordinary anaplastic carcinoma who underwent operations, and ordinary anaplastic carcinoma who did not undergo operations were 73%, 60%, and 21%, respectively. A significantly higher cumulative survival rate was observed in patients with incidental anaplastic carcinoma than in those with ordinary anaplastic carcinoma. A significantly better outcome was obtained by surgical debulking of ordinary anaplastic carcinoma. CONCLUSIONS: Patients with incidental anaplastic carcinoma tended to have a good outcome, but some had a poor prognosis. Surgical debulking improved the outcome of patients with ordinary anaplastic carcinoma.

Carcinoma↗

PubMed2005

Mitogenic effects of the up-regulation of minichromosome maintenance proteins in anaplastic thyroid carcinoma.

CONTEXT: Anaplastic thyroid carcinomas (ATC) are among the most aggressive human malignancies and are characterized by high mitotic activity. Minichromosome maintenance proteins (MCM) 2-7 are required to initiate eukaryotic DNA replication, and their overexpression has been associated with dysplasia and malignancy. OBJECTIVE: In an attempt to cast light on the mechanisms governing ATC, we evaluated MCM5 and MCM7 expression in human normal, papillary (PTC), and anaplastic thyroid samples, as well as in primary culture cells and transgenic mouse models. RESULTS: MCM5 and MCM7 expression was high in 65% of ATC and negligible in normal thyroid tissue and papillary thyroid carcinomas. In ATC, high MCM5 and MCM7 expression was paralleled by high levels of MCM2 and MCM6. An analysis of human ATC primary cell cultures and of a transgenic mouse model of ATC confirmed these findings. An increased transcription rate accounted for MCM7 up-regulation, because the activity of the MCM7 promoter was more than 10-fold higher in ATC cells compared with normal thyroid cells. Adoptive overexpression of wild-type p53, but not of its inactive (R248W and R273H) mutants, strongly down-regulated transcription from the MCM7 promoter, suggesting that p53 knock-out contributes to MCM7 up-regulation in ATC. Treatment with small inhibitory duplex RNAs, which decrease MCM7 protein levels, reduced the rate of DNA synthesis in ATC cells. CONCLUSION: MCM proteins are overexpressed in ATC and sustain the high proliferative capacity of ATC cells.

Animals↗

PubMed2005

Overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) as a novel gene responsible for anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is one of the most fulminant human malignancies. However, the molecular carcinogenic mechanisms of ATC are understood poorly. Recently, the authors performed a cyclic DNA (cDNA) microarray analysis with 11 anaplastic thyroid carcinoma cell lines (ACLs) and discovered several novel responsible genes for ACLs and ATC. From the extended list, they focused on hypothetical and anonymous genes and investigated a novel gene, named the overexpressed in anaplastic thyroid carcinoma-1 (OEATC-1) gene. METHODS: To investigate the role of the OEATC-1 gene in ATC carcinogenesis, first, the expression levels of OEATC-1 in ACLs, in various types of carcinoma cell lines, and in normal human tissues were examined with reverse transcriptase-polymerase chain reaction analysis. To explore the effect of OEATC-1 in ATC development, a cell-growth assay was performed with KTA2 cells under OEATC-1 gene silencing using small-interfering RNA (siRNA). RESULTS: OEATC-1 was overexpressed significantly in ACLs and in other types of carcinoma cell lines with various expression levels. Conversely, in normal human tissues, OEATC-1 was expressed weakly in placenta, kidney, spleen, thymus, small intestine, and thyroid gland. To evaluate the effects of OEATC-1 on tumor cell growth, gene silencing was caused by transfecting the plasmid-generating siRNA effect to KTA2 cells. Consequently, the silencing of OEATC-1 significantly suppressed the cell growth compared with controls. CONCLUSIONS: The current results indicated that OEATC-1 may have some oncogenic or cell growth-promoting function in ACL. OEATC-1 is considered a novel responsible gene in ATC.

Carcinoma↗

PubMed2004

Prognostic factors of anaplastic thyroid carcinoma.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is a relatively rare but very aggressive malignancy, which usually results in death a few months after diagnosis. However, some patients survive for a long time, and the purpose of this study was to identify the prognostic factors of ATC. METHODS: We retrospectively analyzed the records of 19 patients diagnosed with ATC in our institution between 1984 and 2002. RESULTS: The median survival was 9.4 months, with a range of 0.6-76.3 months, and the 1-, 2-, and 5-year survival rates were 21%, 11%, and 5%, respectively. The mean tumor size was 5.7 cm, with a range of 3.6-10.5 cm, and complete resection was achieved in 4 patients. The prognostic factors according to univariate analysis were complete resection and small tumor size of less than 5 cm ( P = 0.005 and 0.047). However, according to multivariate analysis, complete resection was the only prognostic factor for ATC ( P = 0.015). No association was found between survival and acute symptoms, chemotherapy, radiation therapy, extrathyroidal invasion, distant metastasis, age, or leukocytosis. CONCLUSION: At present, while there is no successful treatment regimen for ATC, only patients who undergo complete resection at a very early stage have any chance of long-term survival.

Adult↗

PubMed2001

Effect of primary treatment on survival in anaplastic thyroid carcinoma.

AIMS: Anaplastic thyroid carcinoma (ATC) is a fatal disease despite combined treatment consisting of chemotherapy, radiotherapy and surgery. The optimal sequence of treatment modalities is not known. The purpose of our retrospective non-randomized study was to find out whether timing of the treatment modality had any influence on survival, and to find out if primary surgery prolongs survival in comparison to primary chemotherapy and/or radiotherapy. METHODS: From our database of 162 patients with ATC treated at the Institute of Oncology Ljubljana from 1972-98, 79 patients (26 men, 53 women; age: 40-86 years, mean age 65 years) were included in this retrospective study. The 83 patients with distant metastases on admission, with the survival shorter than one month or patients without any treatment were excluded. The 79 patients were classified into (1) primary surgery group (n=26) and (2) primary chemotherapy and/or radiotherapy group (n=53), including the 12 patients in whom surgery was performed after chemotherapy and/or radiotherapy. The survival of both groups was compared by log-rank test and group characteristics by ANOVA and(2 test using SPSS program. RESULTS: In comparison to the primary surgery group, the patients from the primary chemotherapy and/or radiotherapy group were older and had faster growing, and larger tumours, which were not confined to the thyroid, and more frequently had regional metastases. There was no difference in the survival of the two groups (P=0.17). Survival for longer than one year was observed in 25% of patients with primary surgery and in 21% of patients with primary chemotherapy and/or radiotherapy. The best results (50% survival at one year) were obtained in patients in whom the tumour was surgically removed after primary chemotherapy and radiotherapy. CONCLUSION: This study suggests that the timing of the treatment modalities has an impact on survival and that treatment should start with chemotherapy and/or radiotherapy, with surgery to follow if possible.)

Adult↗

PubMed2001

Butyrate alters the expression and activity of cell cycle components in anaplastic thyroid carcinoma cells.

Anaplastic thyroid carcinoma (ATC) is the most malignant and aggressive form of thyroid cancer. Most patients die within months of diagnosis, primarily due to the absence of effective chemotherapeutic strategies. Identifying alternative therapies is necessary to increase long-term survival. Butyrate elicits a number of responses from cancer cells both in vitro and in vivo including growth repression, cell cycle arrest, differentiation, and apoptosis. Even though many types of cancer cells have been studied, little is known of the response of ATC cells to this drug. In this study, we report that butyrate induces differential cell cycle arrest (arrest in G1 and G2/M phases) in an ATC cell line that correlates with changes in the expression, phosphorylation, and activity of key components of the cell cycle machinery. Exposure to butyrate increases the expression of the cyclin-dependent kinase inhibitors, p21/Cip1 and p27/Kip1, decreases the expression of cyclin A and cyclin B, inhibits the phosphorylation of the retinoblastoma protein (pRb), and decreases the activity of cdk1 and cdk2-associated kinases. These results suggest that butyrate may be useful in the clinical treatment of ATC.

Butyrates↗

PubMed2006

2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells.

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.

2-Methoxyestradiol↗

PubMed2005

Plitidepsin has a cytostatic effect in human undifferentiated (anaplastic) thyroid carcinoma.

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.

Adult↗