A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer

Witte, Robert S.; Hsieh, Peggy; Elson, Paul; Oken, Martin M.; Trump, Donald L.

doi:10.1007/bf00180819

Cited by 20 publications

(13 citation statements)

References 21 publications

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“…Although this drug has activity as a single agent in hematologic malignancies (40,41), it did not reduce the size of established solid tumors in clinical studies (42,43). Our report might provide an explanation for the lack of benefit of homoharringtonine in solid tumors.…”

Section: Discussionmentioning

confidence: 62%

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

et al. 2007

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Malignant epithelial cells with metastatic potential resist apoptosis that normally occurs upon loss of anchorage from the extracellular matrix, a process termed ''anoikis.'' Resistance to anoikis enables malignant cells to survive in an anchorage-independent manner, which leads to the formation of distant metastases. To understand the regulation of anoikis, we designed, automated, and conducted a high-throughput chemical screen for anoikis sensitizers. PPC-1 anoikisresistant prostate cancer cells were seeded in hydrogel-coated ultralow binding plates for suspension conditions and standard tissue culture plates to promote adhesion. After seeding, cells were treated with aliquots from a library of previously characterized small molecules, and viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, assay. From this chemical screen, we identified anisomycin that induced apoptosis in suspension conditions, but was not toxic to these cells grown under adherent conditions. Anisomycin sensitized cells to anoikis by decreasing levels of the caspase-8 inhibitor FLIP and subsequently activating the death receptor pathway of caspase activation. Although anisomycin activated c-Jun-NH 2 -kinase and p38, these kinases were not functionally important for the effect of anisomycin on anoikis and FLIP. Rather, anisomycin decreased FLIP and sensitized cells to anoikis by inhibiting its protein synthesis. Finally, we showed that anisomycin decreased distal tumor formation in a mouse model of prostate cancer metastases. Thus, a novel chemical screen identified anisomycin as an anoikis sensitizer that acts by decreasing FLIP protein synthesis. Our results suggest that FLIP is a suppressor of anoikis and inhibiting FLIP protein synthesis may be a useful antimetastatic strategy. [Cancer Res 2007;67(17):8307-15]

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Section: Discussionmentioning

confidence: 62%

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

et al. 2007

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“…29,33 Several phase 2 studies in patients with a wide variety of solid tumors demonstrated the lack of efficacy of HHT in that setting. [34][35][36][37] However, significant activity was reported in phase 1/2 clinical trials in patients with AML in which HHT was administered as a continuous infusion. [38][39][40][41][42] In a compound analysis of 3 phase 1/2 trials in which 117 patients with refractory AML received HHT at doses from 5 mg/m 2 to 7 mg/m 2 daily by continuous infusion, 14 of 91 assessable patients (15%) attained a complete response (CR), and 1 patient achieved a partial response (PR).…”

Section: Phase 2 Studies Of Intravenous Hht In CMLmentioning

confidence: 99%

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Quintás‐Cardama

Kantarjian²,

Cortés

2009

Cancer

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Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon-a therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib-resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinibresistant CML, including those who carry the tyrosine kinase inhibitor-insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state-ofthe-art treatment algorithms for CML.

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“…The results suggested that HHT was inactive in patients with malignant glioma. 70 Witte et al 71 treated 48 previously untreated patients with advanced, unresectable renal carcinoma with amonafide (17 patients), caracemide (17 patients), or HHT (14 patients). No objective responses were observed.…”

Section: Phase II Studies In Solid Tumorsmentioning

confidence: 99%

“…No objective responses were observed. 72 More recently, Witte et al treated 24 previously untreated patients with advanced colorectal carcinoma with either caracemide (11 patients) or HHT (13 patients). No objective responses were observed in either treatment cohort.…”

Section: Phase II Studies In Solid Tumorsmentioning

confidence: 99%

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Homoharringtonine

Kantarjian

Talpaz

Santini

et al. 2001

Cancer

168

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A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer

Cited by 20 publications

References 21 publications

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

A Chemical Screen Identifies Anisomycin as an Anoikis Sensitizer That Functions by Decreasing FLIP Protein Synthesis

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Homoharringtonine

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