A phase II open-label trial of apomine (SR-45023A) in patients with refractory melanoma

Lewis, Karl D.; Thompson, John A.; Weber, Jeffrey S.; Robinson, William A.; O’Day, Steven; Lutzky, Jose; Legha, Sewa S.; Floret, Simon; Ruvuna, Francis; González, René

doi:10.1007/s10637-005-4544-y

Cited by 9 publications

(7 citation statements)

References 10 publications

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“…A patient with metastatic melanoma experienced stabilization of disease while on Apomine. Apomine was also investigated in a Phase II study in patients with refractory melanoma [9]. While marginally active, Apomine was found to be well tolerated and was not myelosuppressive, which would make it a possible candidate for combination therapy with myelosuppressive agents.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

et al. 2006

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Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well understood. Previous work has demonstrated that Apomine induces cell death by activation of caspase-3 in several cancer cell types. However, we have demonstrated that Apomine induces cell death in the A375 human melanoma cell line through a novel membrane-mediated mechanism that is independent of caspase-3 activation. This mechanism of membrane lysis may apply to other bisphosphonates and may be an important mechanism for overcoming resistance to apoptosis. Interestingly, Apomine-mediated cell death in the A375 and UACC 3093 human melanoma cell lines is also independent of N-Ras farnesylation, which was a previously described mechanism of action for Apomine in other cancer cell types. These data suggest that Apomine induces cell death through a novel plasma membrane-mediated cytolytic pathway, independent of caspase-3 activation and N-Ras farnesylation.

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Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

et al. 2006

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“…24 It reached an open-label, nonrandomized phase II trial in 2001 for the treatment of metastatic melanoma. 25 Additionally, several other BP tetraethylesters have shown promising anticancer activity in vitro in studies with multiple tumor cell lines. 26,27 The stability of different BP esters has been investigated in vitro to evaluate their resistance toward enzymatic hydrolysis (Table 1).…”

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confidence: 99%

Structural Requirements for Bisphosphonate Binding on Hydroxyapatite: NMR Study of Bisphosphonate Partial Esters

Puljula

Turhanen

Vepsäläinen

et al. 2015

ACS Med. Chem. Lett.

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Eighteen different bisphosphonates, including four clinically used bisphosphonate acids and their phosphoesters, were studied to evaluate how the bisphosphonate structure affects binding to bone. Bisphosphonates with weak bone affinity, such as clodronate, could not bind to hydroxyapatite after the addition of one ester group. Medronate retained its ability to bind after the addition of one ester group, and hydroxy-bisphosphonates could bind even after the addition of two ester groups. Thus, several bisphosphonate esters are clearly bone binding compounds. The following conclusions about bisphosphonate binding emerge: (1) a hydroxyl group in the geminal carbon takes part in the binding process and increases the bisphosphonate's ability to bind to bone; (2) the bisphosphonate's ability to bind decreases when the amount of ester groups increases; and (3) the location of the ester groups affects the bisphosphonate's binding ability.

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“…Due to these highly promising data, and keeping in mind the broad clinical experience already existing for the use of bisphosphonates, they are currently being investigated as possible anticancer drugs in serveal large clinical trials [148]. For example, ZA is in phase II clinical trial for the treatment of refractory prostate cancer [149] and apomine is under investigation in patients with refractory melanoma [150].…”

Section: Anticancer Effects Of Bisphosphonatesmentioning

confidence: 99%

Targeting the Mevalonate Pathway for Improved Anticancer Therapy

Fritz¹

2009

CCDT

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The mevalonate pathway is important for the generation of isoprene moieties thereby providing the basis for the biosynthesis of molecules required for maintaining membrane integrity, steroid production and cell respiration. Additionally, isoprene precursors are indispensable for the prenylation of regulatory proteins such as Ras and Ras-homologous (Rho) GTPases. These low molecular GTP-binding proteins play key roles in numerous signal transduction pathways stimulated upon activation of cell surface receptors by ligand binding. Thus, Ras/Rho proteins eventually regulate cell proliferation, tumor progression and cell death induced by anticancer therapeutics. Lipid modification of Ras/Rho proteins at their C-terminal CAAX-box is essential for their correct intracellular localization and function. Therefore, pharmacological inhibition of the isoprene metabolism is anticipated to impact the manifold biological functions attributed to Ras/Rho proteins. Here, the pros and cons of compounds that interfere with the mevalonate pathway for cancer treatment are summarized and discussed.

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A phase II open-label trial of apomine (SR-45023A) in patients with refractory melanoma

Cited by 9 publications

References 10 publications

Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

Cytotoxic activity of Apomine is due to a novel membrane-mediated cytolytic mechanism independent of apoptosis in the A375 human melanoma cell line

Structural Requirements for Bisphosphonate Binding on Hydroxyapatite: NMR Study of Bisphosphonate Partial Esters

Targeting the Mevalonate Pathway for Improved Anticancer Therapy

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