Pegylated liposome-encapsulated doxorubicin and cisplatin in the treatment of head and neck xenograft tumours

Harrington, KJ; Rowlinson-Busza, Gail; Ps, Uster; Js, Stewart

doi:10.1007/s002800000128

Cited by 54 publications

(74 citation statements)

References 30 publications

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“…In comparable analyses, Harrington et al (2000) have demonstrated that also liposomes hold significant potential for combination with radiotherapy. They combined both PEGylated liposomal doxorubicin and PEGylated liposomal cisplatin with both single dose (4.5 and 9 Gy) and fractionated (3 Â 3 Gy) radiotherapy, and they showed that animals treated with carrierbased radiochemotherapy survived for significantly longer periods of time than did animals treated with standard radiochemotherapy.…”

Section: Discussionmentioning

confidence: 90%

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Subr²,

et al. 2008

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Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio-and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and g-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.

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Section: Discussionmentioning

confidence: 90%

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Subr²,

et al. 2008

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“…Tumour volume was estimated as described previously. 25 Briefly, three orthogonal diameters corresponding to the length, breadth and height (d1, d2 and d3) were measured using Vernier calipers and the tumour volume was calculated from the formula: V ¼ p/6 Â d1 Â d2 Â d3. The tumour volume on the day of injection of the therapeutic agent was designated as the initial volume or Vo.…”

Section: Establishment Of Xenograft Tumoursmentioning

confidence: 99%

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

et al. 2007

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Escherichia coli nitroreductase (NTR) converts the prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) into a bifunctional alkylating agent that causes DNA crosslinks. In this study, the ability of NTR to enhance the combined effects of CB1954 and radiation has been tested in vitro and in vivo. Stably transduced ovarian cancer cells (SKOV3-NTR) that are sensitive to CB1954 (IC 50 ¼ 0.35 mM) demonstrated enhanced cytotoxicity when treated with CB1954 and single-fraction irradiation. The NTR-CB1954 system mediated a bystander effect in combination with radiation on transfer of conditioned medium from SKOV3-NTR, but not SKOV3, cells to SW480 target cells. The ability of CB1954 to enhance radiationinduced cytotoxicity in SKOV3-NTR (but not SKOV3) cells was also demonstrated by fluorescence-activated cell sorting (FACS) with dual staining for propidium iodide/fluorescein diacetate, 4 0 ,6-diamidino-2-phenylindole dichloride staining of apoptotic cells and measurement of double-stranded DNA breaks by FACS and confocal microscopy for gH2AX foci. Adenoviral delivery of NTR, under constitutive cytomegalovirus or tissue-specific CTP1 promoters, increased the in vitro cytotoxicity of CB1954 plus radiation in MTT and clonogenic assays. Finally, adenoviral delivery of NTR plus CB1954 enhanced the effect of fractionated radiotherapy (12 Gy in four fractions) in SW480 xenograft tumours in nude mice.

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“…Liposome delivery offers the prospect of reducing or circumventing each of these problems by targeting delivery of the radiosensitiser preferentially to the tumour tissue and avoiding local and distant normal tissue deposition of the drug. We have recently provided proof of principle for this strategy using RT and liposomal doxorubicin and cisplatin in a KB tumour xenograft model (Harrington et al, 2000b). However, since each of those agents has been shown to have a demonstrable antitumour effect in this model (Harrington et al, 2000c), it was difficult to be clear that they were acting as true radiosensitisers.…”

Section: Discussionmentioning

confidence: 99%

Targeted radiosensitisation by pegylated liposome-encapsulated 3′, 5′-O-dipalmitoyl 5-iodo-2′-deoxyuridine in a head and neck cancer xenograft model

et al. 2004

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5-Iodo-20 -deoxyuridine (IUdR) is an effective radiosensitiser but its clinical development has been limited by toxicity. Prolonged intravenous infusions of IUdR are necessary for optimal tumour uptake but cause dose-limiting myelosuppression. The lack of selective tumour uptake can lead to radiosensitisation of adjacent normal tissues and enhanced local radiation toxicity. Liposomal IUdR delivery offers selective targeting of tumour tissues and avoidance of local and systemic toxicity. In these studies, we report the development of a pegylated liposome containing a lipophilic IUdR derivative (3 0 , 5 0 -O-dipalmitoyl-5-iodo-2 0 -deoxyuridine) for use in a head and neck cancer xenograft model. Initial studies confirmed the ability of IUdR to sensitise two head and neck cancer cell lines to single fractions of radiotherapy (SFRT) and this effect was seen to correlate with the thymidine replacement index in KB cells. In vivo delivery of single doses of either unencapsulated IUdR or pegylated liposomal IUdR (PLIUdR) to nude mice bearing KB xenograft tumours did not enhance the effect of SFRT delivered 16 h later. When PLIUdR was delivered by a protracted administration schedule to a dose of 48 mg kg À1 over 7 days, it enhanced the effect of both 4.5 Gy SFRT and fractionated radiotherapy. PLIUdR was at least as effective as unencapsulated IUdR delivered by multiple intravenous injections or continuous subcutaneous infusion. Immunohistochemistry with a specific anti-IUdR monoclonal antibody confirmed greater levels of tumour staining in tumours from animals treated with PLIUdR compared with those treated with unencapsulated IUdR.

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Pegylated liposome-encapsulated doxorubicin and cisplatin in the treatment of head and neck xenograft tumours

Abstract: Both PLED and PLEC were shown to exert significant activity against head and neck xenograft tumours, with PLED showing particular efficacy.

Cited by 54 publications

References 30 publications

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

Targeted radiosensitisation by pegylated liposome-encapsulated 3′, 5′-O-dipalmitoyl 5-iodo-2′-deoxyuridine in a head and neck cancer xenograft model

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