Modulation of Multidrug-Resistant Tumors by Dexverapamil

Keilhauer, Gerhard; Romerdahl, Cynthia A.; Küpper, H.; Schlick, E.

doi:10.1159/000218480

Cited by 3 publications

(3 citation statements)

References 11 publications

(11 reference statements)

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“…Cancer cells can develop resistance to multiple therapeutic drugs, which is the major challenge for the effective treatment of cancer patients. However, dexverapamil, a calcium channel blocker, modulates multidrug resistance in tumors ( Keilhauer et al, 1994 ). Although EM is a mild slowly progressive endometrial disease, it exhibits tumor-identical distinguishing characteristics, including lump formation, metastasis, invasion, and relapse.…”

Section: Discussionmentioning

confidence: 99%

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis

Cui

Bhandari

Qin

et al. 2021

Front. Mol. Biosci.

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Endometriosis (EM) is a chronic neuroinflammatory disorder that is associated with pain and infertility that affects ∼10% of reproductive-age women. The pathophysiology and etiology of EM remain poorly understood, and diagnostic delays are common. Exploration of the underlying molecular mechanism, as well as novel diagnostic biomarkers and therapeutic targets, is urgently needed. Inflammation is known to play a key role in the development of lesions, which are a defining feature of the disorder. In our research, the CIBERSORT and WGCNA algorithms were used to establish a weighted gene co-expression network and to identify macrophage-related hub genes using data downloaded from the GEO database (GSE11691, 7305). The analysis identified 1,157 differentially expressed genes (DEGs) in EM lesions, of which five were identified as being related to M2 macrophages and were validated as differentially expressed by qRT-PCR and immunohistochemistry (IHC). Of these putative novel biomarker genes, bridging integrator 2 (BIN2), chemokine receptor 5 (CCR5), and macrophage mannose receptor 1 (MRC1) were upregulated, while spleen tyrosine kinase (SYK) and metalloproteinase 12 (ADAM12) were downregulated in ectopic endometria vs. normal endometria. Meanwhile, 23 potentially therapeutic small molecules for EM were obtained from the cMAP database, among which topiramate, isoflupredone, adiphenine, dexverapamil, MS-275, and celastrol were the top six molecules with the highest absolute enrichment values. This is our first attempt to use the CIBERSORT and WGCNA algorithms for the identification of novel Mϕ2 macrophage-related biomarkers of EM. Our findings provide novel insights into the impact of immune cells on the etiology of EM; nevertheless, further investigation of these key genes and therapeutic drugs is needed to validate their effects on EM.

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Section: Discussionmentioning

confidence: 99%

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis

Cui

Bhandari

Qin

et al. 2021

Front. Mol. Biosci.

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“…The in vitro concentrations of verapamil necessary to overcome MDR are in general too toxic (> 6 M ≈ > 3,000 ng/ml) in vivo. Verapamil is usually prescribed as a racemic mixture (R-and L-verapamil), but the pharmacological properties of its isomers are different [7]. L-verapamil is 10 times more cardioactive as measured by A-V prolongation.…”

Section: Introductionmentioning

confidence: 99%

Alteration in Epirubicin Pharmacokinetics and Metabolism by Dexverapamil: Results from a Phase II Study in Patients with Metastatic Breast Cancer

Mross¹,

Kröger²,

Herbst³

et al. 1999

Oncol Res Treat

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Background: To study the effect of the resistance-modifying agent (RMA) dexverapamil on the pharmacokinetics and metabolism of epirubicin. Methods: Nine women with metastatic breast cancer who received epirubicin (120 mg/m 2 ) as a 0.25-hour infusion without dexverapamil during the first treatment cycle and with dexverapamil (12 × 300 mg p. o. every 6 h) during the third treatment cycle were monitored with frequent plasma samples up to 48 h postinfusion. Epirubicin and its metabolites and dexverapamil and its main metabolite nordexverapamil were measured using a reverse-phase high-pressure liquid chromatography assay. Results: The concomitant administration of dexverapamil resulted in an increase in mean (±SD) epirubicin clearance from 1,408 (610) ml/min/m 2 to 2,004 (1,696) ml/min/m 2 , a decrease in epirubicin exposure (area under the curve (AUC)) from 2,968 (1,219) mg × h/ml to 1,901 (494) mg × h/ml, and an increase of the volume of distribution at steady state from 1,436 (1,231) l/m 2 to 2,425 (1,340) l/m 2 . The mean residence time and the elimination half-life were not different. There was a significant increase of epiglucuronide and the 7-deoxy-aglycones. At the time of epirubicin administration mean dexverapamil and nordexverapamil plasma levels were 790±409 and 755 ± 274 ng/ml, respectively. Conclusion: Dexverapamil had a significant effect on the pharmacokinetics and metabolism of epirubicin. However, other than observed in previous studies of RMAs and cytotoxic drugs, dexverapamil did not increase but reduce the AUC of epirubicin and had no effect on its toxicity. These data suggest that the type of pharmacologic interaction between RMAs and cytotoxic drugs can differ depending on the particular compounds used in combination.

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“…Based on histological studies indicating that most gastro intestinal cancers constitutively express the MDR1 phenotype which might be related to their inherent refractoriness to conventional anticancer agents [10,11] and according to the promising therapeutic index of the second-generation modula tor dexverapamil (DVPM) [12], we have recently initiated a phase-II study of DVPM and doxorubicin in colorectal cancer and a disease-oriented phase-I study of DVPM and epirubicin in advanced pancreatic cancer [13,14]. All patients involved in these two studies were prospectively evaluated for cardiovas-463 cular and other systemic side effects.…”

Section: Introductionmentioning

confidence: 99%

Tolerance of the Novel Chemosensitizer Dexverapamil in Combination with Anthracycline Chemotherapy: a Prospective Toxicity Analysis in Advanced Gastrointestinal Cancer

et al. 1995

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Background: A prospective clinical study was performed to determine the incidence and severity of cardiovascular and other systemic toxicities associated with the novel chemosensitizer dexverapamil (DVPM) combined with anthracycline chemotherapy. Patients and Methods: Sixteen patients with advanced colorectal cancer and 20 patients with pancreatic cancer were analyzed in this study. Treatment consisted of oral DVPM 1,000-1,400 mg/day for 3 days and intravenous doxorubicin 75 mg/m² on day 2 (colorectal cancer) or epirubicin 90-120 mg/m² on day 2 plus Gm-CSF support from day 5-15 (pancreatic cancer). Treatment cycles were repeated every 3-4 weeks. Toxicity was monitored clinically, radiologically, with laboratory tests, ECG, and serial echocardiographic determinations of the left ventricular ejection fraction (LVEF). Results: The most common DVPM-related cardiovascular side effect was transient hypotension (mean arterial BP < 70 mm Hg), which occurred in 24/36 patients (67%). It was rarely symptomatic, however, and never required pressure support. Sinus bradycardia (heart rate < 50 beats/min) was noted in 9 patients (25%), and 9 patients experienced transient heart block with only one exceeding grade I. All cardiovascular reactions either resolved spontaneously or within 2-3 h following temporary discontinuation of DVPM. As opposed to racemic verapamil, the mean LVEF was not decreased during subsequent measurements, and PR interval was the only cardiovascular parameter which demonstrated a significant correlation with the cumulative dose of DVPM (p = 0.0035). Other DVPM-related side effects were uncommon and mild, and there appeared to be no potentiation of organic toxicities known to occur with anthracyclines except for myelosuppression. Conclusions: Because of the mild and reversible toxicity patterns, both cardiovascular and noncardiovascular, we conclude that DVPM can be safely coadministered with anthracyclines at this dose and schedule, making it a promising candidate for in vivo reversal of multidrug resistance.

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Modulation of Multidrug-Resistant Tumors by Dexverapamil

Cited by 3 publications

References 11 publications

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis

Alteration in Epirubicin Pharmacokinetics and Metabolism by Dexverapamil: Results from a Phase II Study in Patients with Metastatic Breast Cancer

Tolerance of the Novel Chemosensitizer Dexverapamil in Combination with Anthracycline Chemotherapy: a Prospective Toxicity Analysis in Advanced Gastrointestinal Cancer

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