In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy

Tardi, Paul; Johnstone, Sharon A.; Harasym, Natashia; Xie, Sherwin; Harasym, Troy O.; Zisman, Natalia; Harvie, Pierrot; Bermudes, David; Mayer, Lawrence D.

doi:10.1016/j.leukres.2008.06.028

Cited by 318 publications

(238 citation statements)

References 36 publications

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“…1A). Although combination treatments can provide many advantages, the degree of synergism/antagonism between drugs in combination treatments can vary significantly with the drug ratio (2,11). Hence, to determine the optimal drug loading of each therapeutic into the nanoparticle, it is essential to first determine the ratio of free drugs that will yield the maximum synergy in vitro.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, by incorporating two or more drugs into the same nanoparticle, their rate of release, biodistribution, and metabolism can be controlled so that the optimal synergistic ratio can be attained at the tumor site for improved therapeutic efficacy (11). Thus, utilizing nanoparticles as drug delivery vehicles for combinatorial therapeutics can have a significant impact on patient outcomes.…”

Section: Introductionmentioning

confidence: 99%

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Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Ashley

Quinlan

Schroeder

et al. 2016

Molecular Cancer Therapeutics

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Here, we report the synthesis and evaluation of dual drugloaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug-loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug-loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug-loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Ashley

Quinlan

Schroeder

et al. 2016

Molecular Cancer Therapeutics

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“…; V) are nanotherapeutics really effective, or do they only lower toxicity? Shouldn't we consider integrating nanotherapeutics in combined modality regimens (Figure 2D-F; [32][33][34][35][36][37])? ; VI) how important is solid tumor treatment from a clinical point of view?…”

Section: Therapeutic Nanomedicinementioning

confidence: 99%

“…from different types of sarcomas (R), thereby enabling patient preselection and (more) personalized nano-chemotherapeutic treatments. Images are adapted, with permission, from [30,[32][33][34][38][39][40][41][42][50][51][52]. Rationale for image-guided and personalized nanomedicine.…”

Section: Theranostic Nanomedicinementioning

confidence: 99%

Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

Rizzo

Theek

Storm

et al. 2013

Current Opinion in Biotechnology

305

188

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In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-) physiological processes. In addition, ever more efforts have been undertaken to combine diagnostic and therapeutic properties within a single nanomedicine formulation. These so-called nanotheranostics are able to provide valuable information on drug delivery, drug release and drug efficacy, and they are considered to be highly useful for personalizing nanomedicine-based (chemo-) therapeutic interventions.

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“…CPX-351 is a liposomal-based experimental drug that results in the delivery of a 5:1 ratio of cytarabine to anthracycline that is maintained for up to 24 h in the bone marrow and blood of leukemia bearing mice and has been shown to result in optimal synergy between these two drugs in preclinical models [35]. The initial experience of CPX-351 in the treatment of 48 patients with relapsed or refractory MDS/AML defined the MTD at 101 U/m 2 when given on days 1, 3, and 5 of an induction cycle, and nine out of the 43 patients with AML achieved a CR.…”

Section: Cpx 351mentioning

confidence: 99%

Novel agents in acute myeloid leukemia

Ungewickell

Medeiros

2012

Int J Hematol

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Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, longterm survivors represent only 10-15 % of all AML patients older than 60 years of age and \10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

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In vivo maintenance of synergistic cytarabine:daunorubicin ratios greatly enhances therapeutic efficacy

Cited by 318 publications

References 36 publications

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

Novel agents in acute myeloid leukemia

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