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Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models.

ABSTRACT: Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC50 values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures were significantly lower when compared with gemcitabine hydrochloride (GemHCl) treated cultures. In acute toxicity study, liver enzyme level of aspartate aminotransferase (AST) of the control mice was not significantly different from AST levels of 4NSG and GemHCl treated mice. However, alanine aminotransferase (ALT) level of control mice (67 ± 5 mUnits/mL) was significantly lower compared with ALT levels of GemHCl (232 ± 28 mUnits/mL) and that of 4NSG (172 ± 22 mUnits/mL) (p < 0.0001). More importantly, ALT level of 4NSG was lower than ALT level of GemHCl (p < 0.05). Although ALT levels were elevated, pathological images of liver and kidney tissues of control, GemHCl and 4NSG treated mice revealed no architectural changes and no significant change in mice weight was observed during treatment. The bioavailability (AUC) of 4NSG was 3-fold high and significantly inhibited the tumor growth as compared with equivalent dose of GemHCl. Immunohistochemical staining revealed that 4NSG significantly inhibited the expression vascular endothelial growth factor (VEGF) receptor. The study is unique because it established, for the first time, enhanced anticancer activity of 4NSG against pancreatic patient-derived xenograft (PDX) mouse model and PPCL-46 cells compared with Gem. 4SGN enhanced pharmacokinetic profile and improved the therapeutic efficacy of the standard-of-care Gem. Lastly, 4GSN showed a remarkable tumor growth inhibition and revealed significant antiangiogenic activity in 4GSN treated pancreatic PDX tumor.

SUBMITTER: Inkoom A

PROVIDER: S-EPMC7522377 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models.

Inkoom Andriana A Ndemazie Nkafu N Affram Kevin K Smith Taylor T Zhu Xue X Underwood Patrick P Krishnan Sunil S Ofori Edward E Han Bo B Trevino Jose J Agyare Edward E

International journal of pharmaceutics: X 20200923

Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC<sub>50</sub> values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures w ...[more]

PMID: 33015617

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Project description:BACKGROUND:Meningiomas constitute one-third of all primary brain tumors. Although typically benign, about 20% of these tumors recur despite surgery and radiation, and may ultimately prove fatal. There are currently no effective chemotherapies for meningioma. We, therefore, set out to develop patient-derived orthotopic xenograft (PDOX) mouse models of human meningioma using tumor. METHOD:Of nine patients, four had World Health Organization (WHO) grade I tumors, five had WHO grade II tumors, and in this second group two patients also had recurrent (WHO grade III) meningioma. We also classified the tumors according to our recently developed molecular classification system (Types A, B, and C, with C being the most aggressive). We transplanted all 11 surgical samples into the skull base of immunodeficient (SCID) mice. Only the primary and recurrent tumor cells from one patient-both molecular Type C, despite being WHO grades II and III, respectively-led to the formation of meningioma in the resulting mouse models. We characterized the xenografts by histopathology and RNA-seq and compared them with the original tumors. We performed an in vitro drug screen using 60 anti-cancer drugs followed by in vivo validation. RESULTS:The PDOX models established from the primary and recurrent tumors from patient K29 (K29P-PDOX and K29R-PDOX, respectively) replicated the histopathology and key gene expression profiles of the original samples. Although these xenografts could not be subtransplanted, the cryopreserved primary tumor cells were able to reliably generate PDOX tumors. Drug screening in K29P and K29R tumor cell lines revealed eight compounds that were active on both tumors, including three histone deacetylase (HDAC) inhibitors. We tested the HDAC inhibitor Panobinostat in K29R-PDOX mice, and it significantly prolonged mouse survival (p < 0.05) by inducing histone H3 acetylation and apoptosis. CONCLUSION:Meningiomas are not very amenable to PDOX modeling, for reasons that remain unclear. Yet at least some of the most malignant tumors can be modeled, and cryopreserved primary tumor cells can create large panels of tumors that can be used for preclinical drug testing.

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Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models.

Publications

Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models.

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