The Experts below are selected from a list of 99 Experts worldwide ranked by ideXlab platform

Zhengrong Cui - One of the best experts on this subject based on the ideXlab platform.

  • just getting into cells is not enough mechanisms underlying 4 n stearoyl Gemcitabine solid lipid nanoparticle s ability to overcome Gemcitabine resistance caused by rrm1 overexpression
    Journal of Controlled Release, 2013
    Co-Authors: Piyanuch Wonganan, Saijie Zhu, Dharmika S P Lansakarap, Melisande Holzer, Michael A Sandoval, Mangalika Warthaka, Zhengrong Cui
    Abstract:

    Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl Gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired Gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome Gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the Gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, Gemcitabine Triphosphate (dFdCTP), and thus more potent against Gemcitabine-resistant tumor cells than 4-(N)-GemC18 or Gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them.

  • The effect of the acid-sensitivity of 4-(N)-stearoyl Gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression.
    Biomaterials, 2012
    Co-Authors: Saijie Zhu, Dharmika S.p. Lansakara-p, Piyanuch Wonganan, Hannah L. O’mary, Zhengrong Cui
    Abstract:

    Chemoresistance is a major issue for most Gemcitabine-related chemotherapies. The overexpression of ribonucleotide reductase subunit M1 (RRM1) plays a key role in Gemcitabine resistance. In this study, we synthesized a new highly acid-sensitive amphiphilic micelle material by conjugating hydrophilic polyethylene glycol with a hydrophobic stearic acid derivative (C18) using a hydrazone bond, which was named as PHC-2. A lipophilic prodrug of Gemcitabine, 4-(N)-stearoyl Gemcitabine (GemC18), was loaded into micelles prepared with PHC-2, a previously synthesized less acid-sensitive PHC-1, and their acid-insensitive counterpart, PAC. GemC18 loaded in acid-sensitive micelles can overcome Gemcitabine resistance, and GemC18 in the highly acid-sensitive PHC-2 micelles was more cytotoxic than in the less acid-sensitive PHC-1 micelles. Mechanistic studies revealed that upon cellular uptake and lysosomal delivery, GemC18 in the acid-sensitive micelles was released and hydrolyzed more efficiently. Furthermore, GemC18 loaded in the highly acid-sensitive PHC-2 micelles inhibited the expression of RRM1 and increased the level of Gemcitabine Triphosphate (dFdCTP) in Gemcitabine resistant tumor cells. The strategy of delivering lipophilized nucleoside analogs using highly acid-sensitive micelles may represent a new platform technology to increase the antitumor activity of nucleoside analogs and to overcome tumor cell resistance to them.

Robert S Benjamin - One of the best experts on this subject based on the ideXlab platform.

  • phase ii clinical investigation of Gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on Gemcitabine Triphosphate accumulation
    Journal of Clinical Oncology, 2001
    Co-Authors: Shreyaskumar Patel, Varsha Gandhi, Jan Jenkins, Nicholas Papadopolous, Andrew M Burgess, Carl Plager, William Plunkett, Robert S Benjamin
    Abstract:

    PURPOSE: To evaluate the efficacy, toxicity, and optimal dose rate of Gemcitabine in adult patients with advanced soft tissue sarcomas (STS) by comparing levels of Gemcitabine Triphosphate (GTP) in peripheral-blood mononuclear cells (PBMCs) of patients receiving two different dose rates. PATIENTS AND METHODS: Fifty-six assessable patients with STS (17 gastrointestinal [GI] leiomyosarcomas and 39 other histologies) were treated on a two-arm phase II study. Gemcitabine was given at 1 g/m2 as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and reassessment of tumor. Subsequent cycles were given at 1 g/m2 weekly for 3 weeks followed by 1 week of rest. Nine patients underwent cellular pharmacologic studies at two different dose rates (1 g/m2 over a standard 30-minute infusion on week 1 and over pharmacologically based infusion of 150 minutes on week 2) to evaluate GTP levels in PBMCs. RESULTS: Seven partial responses were noted among 39 patients, for an overall response rate of 18% (95...

D I Jodrell - One of the best experts on this subject based on the ideXlab platform.

  • Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo
    British Journal of Cancer, 2014
    Co-Authors: T E Bapiro, K K Frese, A Courtin, J L Bramhall, B Madhu, N Cook, A Neesse, J R Griffiths, D A Tuveson, D I Jodrell
    Abstract:

    Background: The modest benefits of Gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS^G12D; p53^R172H; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. Methods: LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. Results: In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (Gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite Gemcitabine Triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine Triphosphate (CTP). In tumour homogenates in vitro , CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro , leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. Conclusions: GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo .

Saijie Zhu - One of the best experts on this subject based on the ideXlab platform.

  • just getting into cells is not enough mechanisms underlying 4 n stearoyl Gemcitabine solid lipid nanoparticle s ability to overcome Gemcitabine resistance caused by rrm1 overexpression
    Journal of Controlled Release, 2013
    Co-Authors: Piyanuch Wonganan, Saijie Zhu, Dharmika S P Lansakarap, Melisande Holzer, Michael A Sandoval, Mangalika Warthaka, Zhengrong Cui
    Abstract:

    Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl Gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired Gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome Gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the Gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, Gemcitabine Triphosphate (dFdCTP), and thus more potent against Gemcitabine-resistant tumor cells than 4-(N)-GemC18 or Gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them.

  • The effect of the acid-sensitivity of 4-(N)-stearoyl Gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression.
    Biomaterials, 2012
    Co-Authors: Saijie Zhu, Dharmika S.p. Lansakara-p, Piyanuch Wonganan, Hannah L. O’mary, Zhengrong Cui
    Abstract:

    Chemoresistance is a major issue for most Gemcitabine-related chemotherapies. The overexpression of ribonucleotide reductase subunit M1 (RRM1) plays a key role in Gemcitabine resistance. In this study, we synthesized a new highly acid-sensitive amphiphilic micelle material by conjugating hydrophilic polyethylene glycol with a hydrophobic stearic acid derivative (C18) using a hydrazone bond, which was named as PHC-2. A lipophilic prodrug of Gemcitabine, 4-(N)-stearoyl Gemcitabine (GemC18), was loaded into micelles prepared with PHC-2, a previously synthesized less acid-sensitive PHC-1, and their acid-insensitive counterpart, PAC. GemC18 loaded in acid-sensitive micelles can overcome Gemcitabine resistance, and GemC18 in the highly acid-sensitive PHC-2 micelles was more cytotoxic than in the less acid-sensitive PHC-1 micelles. Mechanistic studies revealed that upon cellular uptake and lysosomal delivery, GemC18 in the acid-sensitive micelles was released and hydrolyzed more efficiently. Furthermore, GemC18 loaded in the highly acid-sensitive PHC-2 micelles inhibited the expression of RRM1 and increased the level of Gemcitabine Triphosphate (dFdCTP) in Gemcitabine resistant tumor cells. The strategy of delivering lipophilized nucleoside analogs using highly acid-sensitive micelles may represent a new platform technology to increase the antitumor activity of nucleoside analogs and to overcome tumor cell resistance to them.

Shreyaskumar Patel - One of the best experts on this subject based on the ideXlab platform.

  • phase ii clinical investigation of Gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on Gemcitabine Triphosphate accumulation
    Journal of Clinical Oncology, 2001
    Co-Authors: Shreyaskumar Patel, Varsha Gandhi, Jan Jenkins, Nicholas Papadopolous, Andrew M Burgess, Carl Plager, William Plunkett, Robert S Benjamin
    Abstract:

    PURPOSE: To evaluate the efficacy, toxicity, and optimal dose rate of Gemcitabine in adult patients with advanced soft tissue sarcomas (STS) by comparing levels of Gemcitabine Triphosphate (GTP) in peripheral-blood mononuclear cells (PBMCs) of patients receiving two different dose rates. PATIENTS AND METHODS: Fifty-six assessable patients with STS (17 gastrointestinal [GI] leiomyosarcomas and 39 other histologies) were treated on a two-arm phase II study. Gemcitabine was given at 1 g/m2 as a 30-minute infusion weekly for up to 7 weeks followed by 1 week of rest and reassessment of tumor. Subsequent cycles were given at 1 g/m2 weekly for 3 weeks followed by 1 week of rest. Nine patients underwent cellular pharmacologic studies at two different dose rates (1 g/m2 over a standard 30-minute infusion on week 1 and over pharmacologically based infusion of 150 minutes on week 2) to evaluate GTP levels in PBMCs. RESULTS: Seven partial responses were noted among 39 patients, for an overall response rate of 18% (95...