VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia

Biscardi, Monica; Caporale, Roberto; Balestri, Francesca; Gavazzi, S.; Jimeno, J.; Grossi, Alberto

doi:10.1093/annonc/mdi311

Cited by 50 publications

(36 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aplidin has previously been described as an antiangiogenic compound Biscardi et al, 2005). In vitro and in vivo, Aplidin inhibited the neovascularisation associated with MM disease.…”

Section: Discussionmentioning

confidence: 94%

“…The results of these studies show that Aplidin reduces secretion of VEGF from MOLT-4 human leukaemia cells in vitro and has been shown to reduce the expression of VEGFR-1 in the same cell line Biscardi et al, 2005).…”

mentioning

confidence: 85%

“…Aplidin was initially selected for its enhanced cytotoxicity against different tumour cell lines and its lower myelotoxicity. Aplidin is an extremely potent inducer of apoptosis, with concentrations that caused 50% inhibition of tumour growth (IC 50 ) in vitro in a low nanomolar range, and it also exhibits strong antitumor activity in xenograft models (Urdiales et al, 1996;Erba et al, 2002;Broggini et al, 2003;Biscardi et al, 2005). In different haematological malignancies, such as acute lymphoblastic leukaemia, acute myeloid leukaemia and lymphoma, the drug is cytotoxic on primary human cells and cell lines, even on leukaemic cells carrying cytogenetic abnormalities that have poor prognostic implications (Bresters et al, 2003;Erba et al, 2003;Gajate et al, 2003).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Caers

Raeve³

et al. 2008

Br J Cancer

View full text Add to dashboard Cite

Aplidin s is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC 50 of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 mg kg À1 daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (Po0.001), while BM invasion with myeloma cells was decreased by 35% (Po0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.

show abstract

“…Aplidin has previously been described as an antiangiogenic compound Biscardi et al, 2005). In vitro and in vivo, Aplidin inhibited the neovascularisation associated with MM disease.…”

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 85%

mentioning

confidence: 99%

See 1 more Smart Citation

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Caers

Raeve³

et al. 2008

Br J Cancer

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

“…In addition, plitidepsin has shown antiangiogenic activity in several preclinical models through inhibition of the expression of several angiogenic genes, including the vascular endothelial growth factor (VEGF) and its receptor (VEGFR-1; refs. [12][13][14][15]. Plitidepsin activity has been studied in vitro and in vivo against several different models at concentrations as low as in the nanomolar range (16).…”

mentioning

confidence: 99%

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

Mateos

Cibeira

Richardson

et al. 2010

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m 2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks. Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population. Clin Cancer Res; 16(12); 3260-9. ©2010 AACR.Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin's lymphoma. In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. The disease primarily affects aged individuals, with a median age of 60 years at diagnosis. Despite recent advances in the treatment of multiple myeloma and the availability of novel agents, few patients, if any, can be considered cured, as the vast majority will eventually relapse (1). Thus, new active agents without known cross-resistance with other well-established anti-multiple myeloma agents are needed.Plitidepsin is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans and is currently produced by chemical synthesis. The doselimiting toxicities (DLT) at the phase II recommended dose of 5.0 mg/m 2 over a 3-hour i.v. infusion every two weeks (2-7) included myalgia, muscular weakness, transient and reversible transaminases increase, and fatigue both in patients with solid tumors and in those

show abstract

Potential Novel Therapeutics: Some Biological Aspects of Marine‐derived Bioactive Peptides

Liyanage

Jayawardana

Kodithuwakku

2013

Marine Proteins and Peptides

View full text Add to dashboard Cite

VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia

Abstract: APL harbors a strong in vitro antileukemic activity at a concentration achievable in patients at non-myelotoxic doses. Our data also support the notion of an impact on VEGF secretion. Clinical studies with this new marine-derived compound in relapsed/resistant leukemia are underway.

Cited by 50 publications

References 21 publications

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

Potential Novel Therapeutics: Some Biological Aspects of Marine‐derived Bioactive Peptides

Contact Info

Product

Resources

About