Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours

Crul, Mirjam; Rosing, Hilde; Klerk, G.J.M. de; Dubbelman, R.; Traiser, M; Reichert, Sonia; Knebel, Norbert; Schellens, Jan H.M.; Beijnen, Jos H.; Huinink, W.W. ten Bokkel

doi:10.1016/s0959-8049(02)00127-2

Cited by 152 publications

(102 citation statements)

References 17 publications

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“…Most of the tested cell lines exhibited moderate response to perifosine with IC 50 s ranging from 8 to 15 Amol/L (Fig. 1A), which are within the clinically achievable and safe peak plasma concentrations of 12 to 15 Amol/L (25,26). The p53 and PTEN mutation status in the NSCLC cell lines tested did not correlate with sensitivity to perifosine, suggesting that perifosine inhibits cell growth independently of p53 and PTEN mutation status (Fig.…”

Section: Effects Of Perifosine On Cell Survival and Apoptosis In Nsclmentioning

confidence: 82%

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The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway

Elrod

Yue

et al. 2007

Molecular Cancer Therapeutics

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The Akt inhibitor, perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of cancer. The mechanisms by which perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of perifosine on the induction of apoptosis and its underlying mechanisms in human non -small cell lung cancer (NSCLC) cells. Perifosine, at clinically achievable concentration ranges of 10 to 15 Mmol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells. Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly, enforced activation of Akt attenuated perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for perifosine-induced apoptosis. Despite the activation of both caspase-8 and caspase-9, perifosine strikingly induced the expression of the tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) receptor, death receptor 5, and downregulated cellular FLICE-inhibitory protein (c-FLIP), an endogenous inhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-X L , PUMA, and survivin. Silencing of either caspase-8 or death receptor 5 attenuated perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP small interfering RNA sensitized cells to perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to perifosine. Collectively, these data indicate that activation of the extrinsic apoptotic pathway plays a critical role in perifosine-induced apoptosis. Moreover, perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of perifosine in combination with TRAIL in the treatment of NSCLC.

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Section: Effects Of Perifosine On Cell Survival and Apoptosis In Nsclmentioning

confidence: 82%

“…1A), which are within the clinically achievable and safe peak plasma concentration ranges (i.e., 10 -15 Amol/L; refs. 25,26), suggesting the potential of perifosine in the treatment of NSCLCs.…”

Section: Discussionmentioning

confidence: 99%

The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway

Elrod

Yue

et al. 2007

Molecular Cancer Therapeutics

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“…Our data furthermore present evidence that phosphorylation of La T301 is essential for polyribosome association in glial progenitor cells. In this study, we specifically used the alkylphospholipids perifosine as an inhibitor of the Akt pathway, because it is currently in clinical trials of several tumor types, including gliomas (Crul et al, 2002). It is worth noting that the regulation of translational efficiencies of many critical mRNAs will be one of the molecular outcomes of therapy targeting Akt activity in gliomas and probably other tumor types as well.…”

Section: Discussionmentioning

confidence: 99%

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

et al. 2008

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The Akt signaling pathway activity increases as normal tissue progresses to malignant transformation, and regulates the translation of specific messenger RNAs (mRNAs) through multiple mechanisms. We have identified one such mechanism of Akt-dependent translation control as involving the lupus autoantigen La. La is an RNA-associated protein that contains multiple trafficking elements to support the interaction with RNAs in different subcellular locations. We show here that the La protein is a direct target of the serine/threonine protein kinase Akt on threonine 301, and La nuclear export in mouse glial progenitors, as well as its association with polysomes is modulated by Akt activity. Using a functional approach to determine the network of genes affected by La in the cytoplasm by microarray analysis of polysome-bound mRNAs, we found that La binds 34% of the polysome bound mRNAs and regulates the expression of a specific pool of mRNAs under KRas/Akt activation. Therefore, La appears to be an important contributor to Aktmediated translational regulation of these transcripts in murine glial cells.

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“…51,52 Two recent phase II trials of perifosine in CaP have been reported. A California Cancer Consortium trial in 25 patients with biochemical recurrence following definitive therapy demonstrated biological and chemical activity, with 23% of patients having a decrease in PSA, although none were 450%.…”

Section: Perifosinementioning

confidence: 99%

Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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Akt is a serine/threonine kinase mediating multiple intracellular pathways involved in prostate cancer (CaP) biology. Increased understanding of the molecular mechanisms of Akt activation and signaling have led to the development of an increasing number of Akt inhibitors. These biologic agents demonstrate activity against a wide range of cancers in preclinical studies. Clinical studies of Akt inhibition in CaP are in progress, including agents such as celecoxib, perifosine and genistein. How best to integrate Akt inhibitors with standard CaP therapy or select patients most likely to benefit is the subject of ongoing research.

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Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours

Cited by 152 publications

References 17 publications

The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway

The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and activation of the extrinsic apoptotic pathway

Akt phosphorylation of La regulates specific mRNA translation in glial progenitors

Inhibition of Akt pathways in the treatment of prostate cancer

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