Reduction in Toxicity of Doxorubicin by Liposomal Entrapment

Sells, R. A.; Owen, R R; New, R. R. C.; Gilmore, I T

doi:10.1016/s0140-6736(87)93011-x

Cited by 24 publications

(9 citation statements)

References 3 publications

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“…Although the recent expansion of nanotechnology has led to the emergence of different strategies, such as the use of drugloaded liposomes (3)(4)(5), stealth liposomes (6,7), polymeric nanospheres with equivalent stealth properties (8), polymeric nanocapsules (9), and solid lipid nanoparticles (10), a major obstacle to the success of chemotherapy in many cancers remains to be multidrug resistance (MDR).…”

Section: Introductionmentioning

confidence: 99%

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Garcion

Lamprecht

Heurtault

et al. 2006

Molecular Cancer Therapeutics

172

107

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By focusing on rat glioma, we elucidated whether new lipid nanocapsules (LNC) were able to improve anticancer hydrophobic drug bioavailability while also overcoming multidrug resistance. Blank LNCs and LNCs loaded with the antineoplastic agent paclitaxel were formulated by an emulsion inversion phase process. Expression of efflux pumps by rat glioma cells was assessed by reverse transcription-PCR, Western blot, and immunohistochemistry, and their activity was followed using the tracer 99 Tc m -methoxyisobutylisonitrile. Modalities of LNC action were addressed by using confocal microscopy detection of fluorescently labeled LNCs, fluorescence-activated cell sorting, high-performance liquid chromatography measurement of paclitaxel release, and analysis of tumor cell growth. This revealed an interaction between LNCs and efflux pumps that resulted in an inhibition of multidrug resistance in glioma cells, both in culture and in cell implants in animals. LNCs were able to target the intracellular compartment of glioma cells, a mechanism that was abrogated by using intracellular cholesterol inhibitors but not by clathrin-coated pit or caveolae uptake inhibitors. This result can be correlated to the LNC inhibitory effects on efflux pump activity that is itself known to be stimulated by intracellular cholesterol. In parallel, we showed that paclitaxel-loaded LNCs were active reservoirs from which paclitaxel could be released. Finally, we established that paclitaxel-loaded LNCs were more efficient than the commercially available paclitaxel formulation (Taxol) for clinical use, thus reducing tumor expansion in vitro and in vivo. Considering the physiologically compatible nature of LNC excipients, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.

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Section: Introductionmentioning

confidence: 99%

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Garcion

Lamprecht

Heurtault

et al. 2006

Molecular Cancer Therapeutics

172

107

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“…They administered liposome-encapsulated DOX to 6 patients with hepatic metastases from gastrointestinal adenocarcinomas and recorded one objective response and absence of the typical doxorubicin induced toxicity. 25 This led to several phase I trials which found that the dose of a liposomeencapsulated doxorubicin could be driven up significantly higher compared to free DOX. 26 The maximal dose reached with this formulation was 120 mg/m 2 given every 3 weeks; however this was associated with substantial bone-marrow suppression, particularly neutropenia, as well as stomatitis and alopecia.…”

Section: Phase I and Ii Development Of Pldmentioning

confidence: 99%

Pegylated liposomal doxorubicin in ovarian cancer

Strother

Matei

2009

TCRM

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Abstract:The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.

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“…A formulation of daunorubicin encapsulated in liposomal particles (liposomal daunorubicin, DaunoXome®) has an interesting pharmacokinetic profile: increased delivery to leukemic cells, decreased susceptibility to the membrane efflux pump, and reduced extra-hematological toxicity [18][19][20][21][22][23]. We have combined HDARAC, fludarabine and DaunoXome® in a salvage regimen to be applied in a multicenter study for rescuing primary refractory and relapsed AML adult patients.…”

Section: Introductionmentioning

confidence: 99%

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome®) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

Camera¹,

Rinaldi²,

Palmieri³

et al. 2008

Ann Hematol

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International audienceA large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory ( = 16), or relapsed ( = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible

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Reduction in Toxicity of Doxorubicin by Liposomal Entrapment

Cited by 24 publications

References 3 publications

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Pegylated liposomal doxorubicin in ovarian cancer

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome®) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

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