scholarly journals Cytotoxic Activity of Camptothecin and Paclitaxel in Newly Established Continuous Human Medullary Thyroid Carcinoma Cell Lines

2004 ◽  
Vol 89 (5) ◽  
pp. 2397-2401 ◽  
Author(s):  
K. Kaczirek ◽  
M. Schindl ◽  
A. Weinhäusel ◽  
C. Scheuba ◽  
C. Passler ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Cell Lines ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Medullary Thyroid ◽  
Cell Counts ◽  
In Vitro Investigation ◽  
Ic50 Values

At the time of diagnosis, more than one quarter of patients with medullary thyroid carcinoma (MTC) has distant metastases. Only few of these patients can be cured by surgery. Standard chemotherapy is characterized by low response rates and short response time. The establishment of eight human MTC cell lines provides a new basis for in vitro investigation of cytotoxic drugs. Camptothecin (CPT) and paclitaxel, which never have been investigated in the treatment of MTC, were tested for their cytotoxic profile in comparison with the clinically ineffective dacarbazine. Eight MTC cell lines were established from seven patients with MTC. IC50 values were calculated from dose-response relationships using cell counts and a formazan dye assay (WST-1). IC50 values were 3.5 ± 1.2 nmol/liter for CPT and 8.2 ± 1.9 nmol/liter for paclitaxel. Dacarbazine showed no reduction of cell proliferation at concentrations 10-fold higher than clinically achievable. Given peak plasma concentrations of 65 ± 20 nmol/liter for CPT and 1 μmol/liter for paclitaxel, these promising in vitro results provide a basis for the performance of clinical trials in patients with advanced MTC.

Study on the degradation rule of calcitonin in vitro in patients with medullary thyroid carcinoma

2018 ◽  
Vol 507 (1-4) ◽  
pp. 106-109 ◽  
Author(s):  
Guoping Ou ◽  
Qiaolun Chen ◽  
Wanli Liu ◽  
Xiaohui Li ◽  
Shulin Chen ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Medullary Thyroid

Effect of S9788 on the efficiency of doxorubicin in vivo and in vitro in medullary thyroid carcinoma xenograft

1996 ◽  
Vol 7 (3) ◽  
pp. 321-330 ◽  
Author(s):  
C Massart ◽  
J Gibassier ◽  
M Raoul ◽  
A Denais ◽  
S Maugendre ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Medullary Thyroid ◽  
Carcinoma Xenograft

Molecular mechanism(s) of resistance to vandetanib in medullary thyroid carcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15628-e15628
Author(s):  
Brittany Glassberg ◽  
Sophia Khan ◽  
Alex Pemov ◽  
Robert Hawley ◽  
Brigitte C. Widemann ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Tyrosine Kinase ◽  
Cell Line ◽  
Rna Sequencing ◽  
Medullary Thyroid Carcinoma ◽  
Cell Lines ◽  
Resistant Cell ◽  
Knock Out ◽  
Medullary Thyroid ◽  
Genome Wide

e15628 Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C cells of the thyroid. Pediatric cases of this cancer are associated with the diagnosis of multiple endocrine neoplasia, which is caused by a mutation in the rearranged during transfection ( RET) gene. Vandetanib, an oral receptor tyrosine kinase inhibitor, is approved for the treatment of patients with progressive MTC. While there is a response rate of 50%, the majority of patients eventually develop resistant disease. The goal of this work is to understand genetic and epigenetic underpinnings of sensitivity and resistance to vandetanib, and develop novel synergistic combination therapies in medullary thyroid carcinoma. Methods: The TT cell line (RET mutation p.C634W) was cultured in increasing concentrations of vandetanib in order to generate a vandetanib resistant cell line. Both vandetanib-sensitive and vandetanib-resistant lines were evaluated. Each line underwent exome sequencing, RNA sequencing, and methylation array analysis. In parallel we performed Genome-wide CRISPR knock-out and CRISPR activation of both cell lines using the TKO Version 3 Library, consisting of 71,090 gRNAs targeting 18,000 genes, and the Calabrese P65-HSF activation Library, using 56,762 guides for 18,000 genes. Results: Both whole exome and RNA sequencing demonstrate increased expression of RET C634W in both cell lines, to a significantly greater extent in the drug-resistant line than in the sensitive line. RNA sequencing demonstrates differential expression of transcripts between the vandetanib-sensitive and vandetanib-resistant cell lines, including multidrug-resistance 1 (which confers drug resistance in other cancers) and autotaxin (promotes cell survival). Genome-wide CRISPR knock-out showed enrichment of genes necessary for growth suppression by vandetanib, including MACROD2, GORASP2, and MAP3K genes. Gene set enrichment analysis of the CRISPR knock-out data showed enrichment of the proteasome pathway as a potential candidate of growth suppression by vandetanib, which was validated via exposure of the cell lines to bortezomib (IC50 = 3.62nM), a molecularly targeted proteasome-inhibitor. Conclusions: DNA mutations and epigenetic modification confer resistance of medullary thyroid carcinoma to tyrosine kinase inhibition. Adding further therapeutic agents to target these genetic alterations is a potential strategy for overcoming resistance.

Sign in / Sign up

Export Citation Format

Share Document