Immunohistochemical Analysis of Human Equilibrative Nucleoside Transporter-1 (hENT1) Predicts Survival in Resected Pancreatic Cancer Patients Treated with Adjuvant Gemcitabine Monotherapy

Morinaga, Soichiro; Nakamura, Yoshiyasu; Watanabe, Takeshi; Mikayama, Hiroshi; Takahashi, Hiroshi; Yamamoto, Naoto; Shiozawa, Manabu; Amaki, Makoto; Ohkawa, S.; Konishi, Yoichi; Miyagi, Yohei

doi:10.1245/s10434-011-2054-z

Cited by 55 publications

(57 citation statements)

References 10 publications

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“…Ultimately, we identified 5 patients with high hENT1 staining and 7 patients with low hENT1 staining (Supplemental Figure 8). Although the semiquantitative nature of hENT1 intensity scoring limits this methodology, the final classification was similar to previous work (15,17). In this manner, we found that hENT1 score significantly correlated with normalized gemcitabine incorporation ( Figure 3A).…”

Section: Figuresupporting

confidence: 84%

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Koay

Truty²,

Cristini³

et al. 2014

J. Clin. Invest.

162

156

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Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.Trial registration. Clinicaltrials.gov NCT01276613.

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Section: Figuresupporting

confidence: 84%

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Koay

Truty²,

Cristini³

et al. 2014

J. Clin. Invest.

162

156

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“…117,168 Therefore, reduced expression of nucleoside transporters on tumor cells causes tumor cell resistance to gemcitabine. 123,169 For example, it was reported that high hENT1 expression in resected specimen of patients with PDAC who received postoperative gemcitabine therapy is correlated with increased overall survival, [170][171][172][173] whereas low hENT1 expression was linked to gemcitabine resistance and shorter overall survival. 109,123,169 In addition, low levels of hENT1 expression were also detected in tumors in gallbladder adenocarcinoma patients who respond poorly to gemcitabine.…”

Section: Increasing Cellular Uptake Of Gemcitabinementioning

confidence: 99%

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Chen¹,

Zheng²,

Shi³

et al. 2018

IJN

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Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine.

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“…Of these articles, 23 were excluded after a review of their titles and key words; then, abstracts and full texts were reviewed, and another 23 articles were excluded. Eleven clinical studies met our inclusion criteria for this meta-analysis (Spratlin et al, 2004;Giovannetti et al, 2006;Farrell et al, 2009;Marechal et al, 2009Marechal et al, , 2012Fujita et al, 2010;Kim et al, 2011a;Kondo et al, 2012;Morinaga et al, 2012;Murata et al, 2012;Nakagawa et al, 2013). The flow chart of the study selection process is shown in Figure 1.…”

Section: Baseline Characteristics Of Included Studiesmentioning

confidence: 99%

“…In vitro studies also showed that high hENT1 gene expression was significantly associated with increased chemosensitivity to gemcitabine (Mori et al, 2007;Michalski et al, 2008). Several previous studies have indicated that high hENT1 protein/mRNA expression was associated with increased overall survival (OS) and disease-free survival (DFS) (Farrell et al, 2009;Marechal et al, 2012;Morinaga et al, 2012). However, there are also some contradictory data in the literature concerning the prognostic value of hENT1 in predicting gemcitabine chemosensitivity for pancreatic cancer patients (Fujita et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Human Equilibrative Nucleoside Transporter 1 Predicts Survival in Patients with Pancreatic Cancer Treated with Gemcitabine: A Meta-Analysis

Zhu

Lao

et al. 2014

Genetic Testing and Molecular Biomarkers

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Immunohistochemical Analysis of Human Equilibrative Nucleoside Transporter-1 (hENT1) Predicts Survival in Resected Pancreatic Cancer Patients Treated with Adjuvant Gemcitabine Monotherapy

Cited by 55 publications

References 10 publications

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Transport properties of pancreatic cancer describe gemcitabine delivery and response

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Human Equilibrative Nucleoside Transporter 1 Predicts Survival in Patients with Pancreatic Cancer Treated with Gemcitabine: A Meta-Analysis

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