A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

DiPaola, Robert S.; Chen, Yu Hui; Stein, Mark N.; Vaughn, David J.; Patrick‐Miller, Linda; Carducci, Michael A.; Roth, Bruce J.; White, Eileen; Wilding, George

doi:10.1186/1479-5876-8-20

Cited by 17 publications

(12 citation statements)

References 15 publications

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“…Bcl-2 is an antiapoptotic protein that is overexpressed in multiple tumors including prostate cancer, thereby conferring resistance to therapies that induce apoptosis, such as ADT [3, 4]. Based upon preclinical data suggesting that the efficacy of ADT could be enhanced by combing ADT with AT-101, we undertook the current single arm phase II study in men with newly diagnosed hormone sensitive metastatic disease in order to determine if the combination could improve upon a novel clinical endpoint in this disease setting, the rate of patients achieving an undetectable PSA after 7 months of ADT and AT-101.…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies in prostate cancer tissue demonstrated that Bcl-2 is over-expressed in most patients with castration-resistant prostate cancer (CRPC) [3, 4]. In animal models, Bcl-2 is responsible for drug resistance to chemotherapy and ADT, and modulation of Bcl-2 improves sensitivity [5, 6].…”

Section: Introductionmentioning

confidence: 99%

“…In animal models, Bcl-2 is responsible for drug resistance to chemotherapy and ADT, and modulation of Bcl-2 improves sensitivity [5, 6]. To date, several strategies have been employed to inhibit Bcl-2 including use of a clinical bcl-2 antisense or modulation of bcl-2 expression with the combination of interferon and cis-retinoic acid [3, 4, 7, 8]. AT-101 [R-(–)-gossypol acetic acid; Ascenta Therapeutics, Inc.] is an enantiomer of racemic gossypol, a natural substance found in cottonseeds.…”

Section: Introductionmentioning

confidence: 99%

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A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

Stein

Hussain

Stadler

et al. 2016

Clinical Genitourinary Cancer

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Background We conducted a phase II study in men with castration sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer. Methods Patients with metastatic prostate cancer scheduled to start, or recently (within 6 weeks) initiated ADT, were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide started 6 weeks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28-day cycle. The primary endpoint of the study was percentage of patients with undetectable PSA (less than or equal to 0.2) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between CHD1 and drug sensitivity, FISH with confocal microscopy was assessed in a subgroup of patients. Results Fifty-five patients enrolled, median age 61 years, median PSA of 27.6 ng/dL, and 72% had a Gleason score > 8. Three patients had visceral metastases and the remaining patients had bone or nodal metastasis. An undetectable PSA was achieved in 31% of patients. Twelve patients experienced serious adverse events (SAEs), and seven were considered related to study therapy. The majority of related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible with a non-significant association with therapeutic sensitivity in a small number of patients. Conclusion The combination of ADT and AT-101 did not meet the pre-specified level of activity for further development of this combination

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

Stein

Hussain

Stadler

et al. 2016

Clinical Genitourinary Cancer

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“…Retinoids can decrease expression of Bcl-2, and the combination of 13-cis retinoic acid and interferon enhanced the effect of paclitaxel chemotherapy, resulting in that this combination can be safely administered in phase I studies [48]. Interactions between polyamines and retinoids can regulate retinoid-induced apoptosis in Jurkat cells [23]; similarly, retinoic acid activates transglutaminase that conjugates with putrescine, probably leading to a simultaneous inhibition of DNA synthesis in PH-animals [49, 50].…”

Section: Discussionmentioning

confidence: 99%

Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

2016

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BackgroundThe pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH), by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism.MethodsThis study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar) treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC), and polyamine levels, were determined.ResultsPre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids.ConclusionsPutrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased retinoid levels induced by α-tocopherol. Therefore interactions between polyamines and retinol, mediated by the oxidant status, should be taken into consideration in the development of new therapeutic strategies for pathologies occurring with liver cell proliferation.

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“…Furthermore, mitoxantrone may induce cell senescence [19]. Side effects of mitoxantrone include leukemia [20], cardiotoxicity [21], anemia [21] and thrombosis [22,23,24,25,26,27]. …”

Section: Introductionmentioning

confidence: 99%

Mitoxantrone-Induced Suicidal Erythrocyte Death

Arnold

Bissinger

Läng

2014

Cell Physiol Biochem

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Background/Aims: Mitoxantrone, a cytotoxic drug used for the treatment of malignancy and multiple sclerosis, is at least in part effective by triggering apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a type of suicidal cell death. Hallmarks of eryptosis are cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signalling involved in eryptosis include Ca²⁺-entry, ceramide formation and oxidative stress. Methods: Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, formation of reactive oxidant species (ROS) from 2′,7′-dichlorodihydrofluorescein-diacetate fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 48 hours exposure to mitoxantrone was followed by significant decrease of forward scatter (≥ 5 μg/ml mitoxantrone) and increase of annexin-V-binding (≥ 10 μg/ml mitoxantrone), effects paralleled by significant increases of ROS formation (25 μg/ml mitoxantrone) and ceramide abundance (25 μg/ml mitoxantrone). The effect of mitoxantrone was not significantly modified by nominal absence of extracellular Ca²⁺ but significantly blunted by the antioxidant N-acetylcysteine (1 mM). Conclusions: Mitoxantrone triggers cell membrane scrambling, an effect not requiring entry of extracellular Ca²⁺ but at least partially due to formation of ROS and ceramide.

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A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899

Cited by 17 publications

References 15 publications

A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

Mitoxantrone-Induced Suicidal Erythrocyte Death

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