Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

Моисеева, Н. И.; Laletina, Lidia; Fetisov, Timur; Makhmudova, Leyla F; Manikaylo, Angelika E; Fomina, Liliya Y; Burov, D. A.; Lesovaya, Ekaterina A.; Bokhyan, Beniamin; Zinovieva, Victoria Y; Vilkova, Alice S; Мехеда, Л В; Козлов, Н. А.; Scherbakov, Alexander M.; Kirilin, Evgeny; Belitsky, Gennady A.; Yakubovskaya, Marianna G.; Кирсанов, Кирилл И.

doi:10.3390/ijms23063183

Cited by 8 publications

(3 citation statements)

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“…In addition, this test can be used both in a search and selection of prognostic biomarkers and in a study of resistance mechanisms in STS cells. We have already shown the effectiveness of the CSRA approach in the analysis of STS multidrug resistance caused by ATP-binding cassette transporters and apoptosis inactivation [6,8]. Thus, CSRA application in the study and management of STSs will contribute to a more rapid progress of knowledge in this field.…”

Section: Discussionmentioning

confidence: 95%

“…Currently, there are no clinically used molecular markers that predict responses to therapy and survival in STSs. The data obtained from some STS cell lines [5] are not in full agreement with the results of tumor analysis of STS patients [6]. Although the mutation rate is low in STS [7], a number of studies have revealed a relationship between the development of resistance to Dox and the presence of mutations in the apoptosis activation pathway [8].…”

Section: Introductionmentioning

confidence: 99%

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Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy

Fetisov,

Khazanova,

Shtompel

et al. 2023

IJMS

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Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy

Fetisov,

Khazanova,

Shtompel

et al. 2023

IJMS

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“…15 P-gp has been implicated in chemoresistance. [20][21][22] Therefore, the antitumor activity of unesbulin is not expected to diminish with longterm use.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma

Van Tine,

Ingham,

Attia

et al. 2024

JCO

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PURPOSE This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. RESULTS Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. CONCLUSION Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

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Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming

Mattioli,

Ilari,

Colotti

et al. 2023

Molecular Aspects of Medicine

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Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

Cited by 8 publications

References 48 publications

Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy

Perspectives of Cell Sensitivity/Resistance Assay in Soft Tissue Sarcomas Chemotherapy

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma

Doxorubicin and other anthracyclines in cancers: Activity, chemoresistance and its overcoming

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