Advertisement

Topics

Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo.

08:00 EDT 1st June 2019 | BioPortfolio

Summary of "Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo."

We showed recently that ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) exhibit potent antiproliferative activities against a broad spectrum of soft tissue sarcoma and gastrointestinal stromal tumor (GIST) cell lines in vitro. The molecular mechanism of action was owing to inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to the accumulation of tumor cells in the M-phase and induction of apoptosis. Given that more than 50% of the patients with GISTs develop resistance to imatinib (IM) over the 2 years of IM-based therapy, we examined whether EAPCs exhibit activity against IM-resistant GISTs in vitro and in vivo. A real-time antiproliferation assay illustrated the potent antiproliferative activities of EAPCs against IM-sensitive and IM-resistant GISTs. This was in agreement with the colony formation assay, which revealed potent antiproliferative activities of EAPCs against IM-resistant GISTs, being much stronger when compared with IM and doxorubicin, a topoisomerase II inhibitor. Next, we tested the efficacy of EAPCs in the xenograft model of GISTs, exhibiting secondary IM resistance owing to RTK switch (loss of c-KIT/gain of FGFR2α). A total of 30 5- to 8-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with IM-resistant GIST-T1-R cells (100 μl of 1×10 GIST T-1R cells/ml suspension, in Dulbecco's PBS). Mice were randomized as control (untreated), IM (50 mg/kg), EAPC-20 (10 mg/kg) or EAPC-24 (10 mg/kg) and were treated orally for 10 days. IM has a minor inhibitory effect on tumor size, thus revealing GIST resistance to IM. In contrast, both of EAPCs effectively reduced the tumor size. This was associated with an increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, both EAPCs significantly reduced the proliferative activity of tumor cells in the central zones of tumors as measured by positivity for Ki-67 staining. More importantly, in EAPC-24-treated GISTs, the histological response was mainly characterized by the induction of necrosis, whereas EAPC-20 induced the signs of intratumoral fibrosis and myxoid degeneration. Collectively, our data suggest that EAPC-20 and EAPC-24 are the perspective antitumor agents that exhibit antiproliferative and cytotoxic activity against GISTs exhibiting secondary resistance to IM.

Affiliation

Journal Details

This article was published in the following journal.

Name: Anti-cancer drugs
ISSN: 1473-5741
Pages: 475-484

Links

DeepDyve research library

PubMed Articles [10819 Associated PubMed Articles listed on BioPortfolio]

Andrographolide and its potent derivative exhibit anticancer effects against imatinib-resistant chronic myeloid leukemia cells by downregulating the Bcr-Abl oncoprotein.

Chronic myelogenous leukemia (CML) is clinically treated with imatinib, which inhibits the kinase activity of the Bcr-Abl oncoprotein. However, imatinib resistance remains a common clinical issue. And...

Clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure gastrointestinal stromal tumour.

The majority of available data on the clinical efficacy of sunitinib in patients with imatinib-resistant or -intolerant gastrointestinal stromal tumours (GISTs) are from studies of western populations...

Tyrosine kinase inhibitor imatinib modulates the viability and apoptosis of castrate-resistant prostate cancer cells dependently on the glycolytic environment.

The tyrosine kinase inhibitor imatinib has been used in prostate cancer treatment with outcomes that did not follow the in vitro findings. The glycolytic environment has been shown to influence the ef...

Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia.

Although Imatinib and other tyrosine kinase inhibitors (TKIs) have excellent results, the appearance of resistance is a problem in chronic myeloid leukaemia (CML). PI3K/AKT/mTOR pathway is activated b...

Carfentrazone-ethyl resistance in an Amaranthus tuberculatus population is not mediated by amino acid alterations in the PPO2 protein.

To date, the only known mechanism conferring protoporphyrinogen IX oxidase (PPO)-inhibitor resistance in waterhemp (Amaranthus tuberculatus) is a glycine deletion in PPO2 (ΔG210), which results in cr...

Clinical Trials [5415 Associated Clinical Trials listed on BioPortfolio]

Study of AMN107 With Imatinib in Gastrointestinal Stromal Tumors (GIST)

This study is an open-label, multicenter, Phase I dose-escalation study of the combination of AMN107 and imatinib (STI571) in patients with imatinib-resistant GIST. This study is designed ...

A Study to Investigate the Safety and Efficacy of AT13387, Alone or in Combination With Imatinib, in Patients With GIST

The purpose of this study is to investigate if an investigational drug called AT13387 is active against Gastrointestinal Stromal Tumor (GIST) that is resistant to other treatments, and to ...

A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Blood Related Cancers

The purpose of this trial is to assess the efficacy, safety, tolerability, biologic activity, and pharmacokinetics of AMN107 in six groups of patients with one of the following conditions:...

Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate

The purpose of this multicenter, single-arm, Simon two-stage, phase II trial is to determine the efficacy and safety of everolimus in combination with Imatinib mesylate in patients with pr...

Mouthwash With Chlorhexidine 0.12%/Ethyl Alcohol 7% Compared to Ethyl Alcohol 7%

Clinical triple-blind randomized controlled trial to assess the use of two different mouthwashes to reduce the oral colonization by gramnegative bacteria in patients with chemotherapy indu...

Medical and Biotech [MESH] Definitions

Porphyrins with four methyl and four ethyl side chains attached to the pyrrole rings.

Porphyrins with four methyl, two ethyl, and two propionic acid side chains attached to the pyrrole rings.

A pyrimidine and thiazole derived ANTINEOPLASTIC AGENT and PROTEIN KINASE INHIBITOR of BCR-ABL KINASE. It is used in the treatment of patients with CHRONIC MYELOID LEUKEMIA who are resistant or intolerant to IMATINIB.

A gas that condenses under slight pressure. Because of its low boiling point ethyl chloride sprayed on skin produces an intense cold by evaporation. Cold blocks nerve conduction. Ethyl chloride has been used in surgery but is primarily used to relieve local pain in sports medicine.

Organic compounds having ethyl groups bound to an oxygen atom

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topic

Assays
An assay is an analytic procedure for qualitatively assessing or quantitatively measuring the presence or amount or the functional activity of a target entity.  This can be a drug or biochemical substance or a cell in an organism or organic sample. ...


Searches Linking to this Article