Personalizing Colon Cancer Therapeutics: Targeting Old and New Mechanisms of Action

Kline, Christina Leah B.; El‐Deiry, Wafik S.

doi:10.3390/ph6080988

Cited by 19 publications

(12 citation statements)

References 309 publications

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“…Our findings of differentiation were similar, but unlike the Santos study with irinotecan, the differentiation persisted months after treatment was discontinued. SN38 is the major active metabolite of irinotecan and inactivates topoisomerase 1 (29), so the effects in both the Santos study and ours are presumably mediated by the same mechanism. However, the durability of the differentiation in our study is presumably related to the higher intratumoral concentrations of SN38 we achieved (Table 1) and/or the protracted duration of exposure afforded by NP delivery.…”

Section: Discussionmentioning

confidence: 51%

Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma

et al. 2015

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Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. We formulated ultrasmall-sized ( < 100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). Alternative dosing schedules of SN38-TS NPs were compared to irinotecan. Comparison of SN38-TS NPs (2 doses) with irinotecan (20 doses) showed equivalent efficacy but no cures. Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and “cures” were obtained in all NP arms. SN38-TS NP delivery resulted in 200x the amount of SN38 in NB tumors at 4 hr post-treatment, compared to SN38 detected for the irinotecan arm; no toxicity was seen with NPs. We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity.

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Section: Discussionmentioning

confidence: 51%

Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma

et al. 2015

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“…those with the DPYD*2A SNP), encapsulation and delivery of FdUMP could give this chemotherapy treatment better efficacy without increasing the risk of toxicities (52, 53). Similarly, patients with low activity of cytidine deaminase, the enzyme that catabolizes dFdC to difluorodeoxyuridine, can develop severe adverse effects from dFdC treatment (54).…”

Section: Discussionmentioning

confidence: 99%

Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer

Loc

Linton

Wilczynski

et al. 2017

Nanomedicine: Nanotechnology, Biology and Medicine

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Drug resistant cancers like pancreatic ductal adenocarcinoma (PDAC) are difficult to treat, and nanoparticle drug delivery systems can overcome some of the limitations of conventional systemic chemotherapy. In this study, we demonstrate that FdUMP and dFdCMP, the bioactive, phosphorylated metabolites of the chemotherapy drugs 5-FU and gemcitabine, can be encapsulated into calcium phosphosilicate nanoparticles (CPSNPs). The non-phosphorylated drug analogs were not well encapsulated by CPSNPs, suggesting the phosphate modification is essential for effective encapsulation. In vitro proliferation assays, cell cycle analyses and/or thymidylate synthase inhibition assays verified that CPSNP-encapsulated phospho-drugs retained biological activity. Analysis of orthotopic tumors from mice treated systemically with tumor-targeted FdUMP-CPSNPs confirmed the in vivo up take of these particles by PDAC tumor cells and release of active drug cargos intracellularly. These findings demonstrate a novel methodology to efficiently encapsulate chemotherapeutic agents into the CPSNPs and to effectively deliver them to pancreatic tumor cells.

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“…Based on the findings they call for further studies to investigate physiological and or genetic differences underlying heterogeneity in 5-FU levels during dose optimisation. This paper and the comparative study by Kline and El-Deiry 223 are the only two full papers that used My5-FU for dose adjustment. The paper describes AUCs and adjustments well, but does not report overall results needed for data extraction such as mean 5-FU dose and frequency of dose adjustment.…”

Section: Gamelin Ec Danquechinmentioning

confidence: 99%

Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion

Freeman

Connock

Cummins³

et al. 2015

Health Technol Assess

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Background5-Fluorouracil (5-FU) is a chemotherapy used in colorectal, head and neck (H&N) and other cancers. Dose adjustment is based on body surface area (BSA) but wide variations occur. Pharmacokinetic (PK) dosing is suggested to bring plasma levels into the therapeutic range to promote fewer side effects and better patient outcomes. We investigated the clinical effectiveness and cost-effectiveness of the My5-FU assay for PK dose adjustment to 5-FU therapy.ObjectivesTo systematically review the evidence on the accuracy of the My5-FU assay compared with gold standard methods [high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS)]; the effectiveness of My5-FU PK dosing compared with BSA; the effectiveness of HPLC and/or LC-MS compared with BSA; the generalisability of published My5-FU and PK studies; costs of using My5-FU; to develop a cost-effectiveness model.Data sourcesWe searched MEDLINE, EMBASE, Science Citation Index and other databases between January and April 2014.MethodsTwo reviewers independently screened titles and abstracts with arbitration and consensus agreement. We undertook quality assessment. We reconstructed Kaplan–Meier plots for progression-free survival (PFS) and overall survival (OS) for comparison of BSA and PK dosing. We developed a Markov model to compare My5-FU with BSA dosing which modelled PFS, OS and adverse events, using a 2-week cycle over a 20 year time horizon with a 3.5% discount rate. Health impacts were evaluated from the patient perspective, while costs were evaluated from the NHS and Personal Social Services perspective.ResultsA total of 8341 records were identified through electronic searches and 35 and 54 studies were included in the clinical effectiveness and cost-effectiveness reviews respectively. There was a high apparent correlation between My5-FU, HPLC and LC-MS/mass spectrometer but upper and lower limits of agreement were –18% to 30%. Median OS were estimated as 19.6 [95% confidence interval (CI) 17.0 to 21.0] months for PK versus 14.6 (95% CI 14.1 to 15.3) months for BSA for 5-FU + folinic acid (FA); and 27.4 (95% CI 23.2 to 38.8) months for PK versus 20.6 (95% CI 18.4 to 22.9) months for BSA for FOLFOX6 in metastatic colorectal cancer (mCRC). PK versus BSA studies were generalisable to the relevant populations. We developed cost-effectiveness models for mCRC and H&N cancer. The base case assumed a cost per My5-FU assay of £61.03. For mCRC for 12 cycles of a oxaliplatin in combination with 5-fluorouracil and FA (FOLFOX) regimen, there was a quality-adjusted life-year (QALY) gain of 0.599 with an incremental cost-effectiveness ratio of £4148 per QALY. Probabilistic and scenario analyses gave similar results. The cost-effectiveness acceptability curve showed My5-FU to be 100% cost-effective at a threshold of £20,000 per QALY. For H&N cancer, again, given caveats about the poor evidence base, we also estimated that My5-FU is likely to be cost-effective at a threshold of £20,000 per QALY.LimitationsQuality and quantity of evidence were very weak for PK versus BSA dosing for all cancers with no randomised controlled trials (RCTs) using current regimens. For H&N cancer, two studies of regimens no longer in use were identified.ConclusionsUsing a linked evidence approach, My5-FU appears to be cost-effective at a willingness to pay of £20,000 per QALY for both mCRC and H&N cancer. Considerable uncertainties remain about evidence quality and practical implementation. RCTs are needed of PK versus BSA dosing in relevant cancers.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Personalizing Colon Cancer Therapeutics: Targeting Old and New Mechanisms of Action

Cited by 19 publications

References 309 publications

Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma

Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma

Effective encapsulation and biological activity of phosphorylated chemotherapeutics in calcium phosphosilicate nanoparticles for the treatment of pancreatic cancer

Fluorouracil plasma monitoring: systematic review and economic evaluation of the My5-FU assay for guiding dose adjustment in patients receiving fluorouracil chemotherapy by continuous infusion

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