Pegylated liposomal doxorubicin: Proof of principle using preclinical animal models and pharmacokinetic studies

Vail, David M.; Amantea, Michael; Colbern, Gail; Martin, Francis J.; Hilger, Ralf A.; Working, Peter K.

doi:10.1053/j.seminoncol.2004.08.002

Cited by 164 publications

(101 citation statements)

References 48 publications

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“…The major difference is, while only one tumor in the previous study was HCC, we enrolled only HCC, which might have a different response to hyperthermia and PLD. HCC has a poorer response to PLD than other tumors, which might explain the results in this study [18,19]. Another difference was that the tumors in this study were small, so that RFA might destroy them completely.…”

Section: Discussioncontrasting

confidence: 42%

Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin

et al. 2010

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Purpose Synergy between radiofrequency ablation (RFA) and chemotherapy was demonstrated for liver malignancy. We assess the efficacy of intravenous pegylated liposomal doxorubicin (PLD) for RFA in patients with small hepatocellular carcinoma (HCC). Methods This study was designed as a non-randomized control trial. Patients received either PLD (20 mg) intravenously before RFA, or standard RFA alone. Computed tomography was performed immediately and 4 weeks after RFA to obtain ablative diameter, area and volume for each tumor. The changes in ablation size were analyzed by paired images for each tumor. All patients were followed up regularly. Results A total of 24 patients with 29 HCCs, including 12 patients with 16 tumors (mean 2.2 cm ± 0.9) in the PLD and RFA group, and 12 patients with 13 tumors (2.4 cm ± 0.5) in the RFA alone group, were enrolled. The ablative diameter, area and volume significantly decreased 4 weeks after RFA. The ablative volume decrease was significantly greater for the RFA alone group than for the combination group (26.1 vs. 12.1%, p = 0.018). The 3-year cumulative tumor progression and survival rates did not differ significantly between the two groups. Conclusion Intravenous PLD before RFA reduced contraction of ablative volume and might have no impact on tumor progression and survival in patients with small HCC after RFA.

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Section: Discussioncontrasting

confidence: 42%

Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin

et al. 2010

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“…Studies on PLD in different tumours, although insufficient to define an ideal dose schedule, indicate that lower doses (35 mg sqm e1 ) are as effective as higher doses as long as dose intensity is maintained at !10 mg sqm e1 per week. 19 We have previously investigated the activity of this low-dose frequent schedule, which mimics a metronomic administration with the aim of increasing activity and lowering toxicity, in heavily pretreated advanced breast cancer patients. We obtained a clinical benefit (defined as objective responses þ SD lasting !24 weeks) in 33% of patients, with a favourable toxicity profile.…”

Section: Discussionmentioning

confidence: 99%

Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer

et al. 2011

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a b s t r a c tAim: To evaluate the role of pegylated liposomal doxorubicin with low-dose metronomic cyclophosphamide as primary systemic treatment in locally advanced breast cancer. Patients and Methods: The activity and safety of intravenous pegylated liposomal doxorubicin 20 mg sqm À1 biweekly for eight courses in combination with metronomic cyclophosphamide 50 mg day À1 orally were evaluated in 29 patients with locally advanced breast cancer who were not suitable to receive a standard chemotherapy due to age or co-morbidities or who asked for a regimen with low incidence of toxic effects irrespective of age.Results: The rate of breast-conserving surgery was 44.8%. Eighteen patients (62.1%) achieved a partial response (including one pathological complete response), 10 (34.5%) a stable disease and one patient experienced a progressive disease. Treatment was well tolerated, with no grade 4 toxicities, and with grade 3 skin toxicity in three patients and handefoot syndrome in four patients. Conclusion: The regimen was well tolerated but with limited activity in the preoperative setting. Other options (e.g., endocrine therapy in estrogen receptor -positive disease) should be considered in locally advanced breast cancer patients who are not suitable to receive a standard chemotherapy.

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“…Liposomes are spherical nanoparticles containing a phospholipid bilayer surrounding an aqueous core. Addition of a poly(ethylene glycol) (PEG)-coating delays uptake by the mononuclear phagocyte system (MPS), resulting in prolonged circulation time and enhanced tumour accumulation due to the enhanced permeability and retention effect (Vail et al, 2004;Minchinton and Tannock, 2006). Furthermore, liposomes can be specifically targeted by coupling peptide ligands or antibodies to the outer surface.…”

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confidence: 99%

Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma

et al. 2008

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Vascular disrupting agents (VDAs) are able to affect selectively tumour endothelial cell morphology resulting in vessel occlusion and widespread tumour cell necrosis. However, single-agent antitumour activity of VDAs is typically limited, as tumour regrowth occurs rapidly following drug treatment. To improve the therapeutic effectiveness of VDAs, we investigated liposomal targeting using ZD6126 as a model VDA. ZD6126 is a phosphate-prodrug of the tubulin-binding vascular disrupting agent ZD6126 phenol. ZD6126 was encapsulated into long circulating PEG-liposomes for passive targeting and PEG-liposomes conjugated with peptide ligands containing the RGD-motif for active targeting to a v -integrins on tumour endothelial cells. ZD6126 could be stably encapsulated, and liposomes displayed minimal leakage in vitro (o10% in 3 weeks). In vivo, upon intravenous injection, free ZD6126 was rapidly converted into ZD6126 phenol, which was cleared from the circulation within minutes. In contrast, ZD6126 encapsulated into either RGD-targeted or PEG liposomes showed prolonged blood circulation times (t 1/2 ¼ 10 h), and ZD6126 phenol exposure was also prolonged (t 1/2 ¼ 8 h). Both liposomal formulations displayed tumour accumulation plus hepatosplenic uptake by local macrophages. The altered pharmacokinetics and tissue distribution profiles of both liposomal ZD6126 formulations resulted both in single-dose and multiple-dose regimes, in improved therapeutic efficacy in established murine B16.F10 melanomas compared with free ZD6126. The passively and actively targeted liposomes showed equal antitumour efficacy, indicating that delivery of ZD6126 to the tumour tissue may suffice to disrupt tumour blood vessels without the need for specific targeting to the tumour endothelium.

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Pegylated liposomal doxorubicin: Proof of principle using preclinical animal models and pharmacokinetic studies

Cited by 164 publications

References 48 publications

Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin

Radiofrequency ablation of small hepatocellular carcinoma with intravenous pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer

Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma

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