A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging

Bornmann, Christian; Graeser, Ralph; Esser, N.; Ziroli, Vittorio; Jantscheff, Peter; Keck, Tobias; Unger, Clemens; Hopt, Ulrich T.; Adam, Ulrich; Schäechtele, Christoph; Massing, Ulrich; Dobschuetz, Ernst von

doi:10.1007/s00280-007-0482-z

Cited by 65 publications

(73 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antimetastatic effects of empty liposomes, as observed in the AsPC1 pancreatic cancer model (8), are supposedly a consequence of passive accumulation of liposomes in tumor tissue (8,22,23) due to the enhanced permeability and retention effect (24). We postulated an enzymatic hydrolysis of accumulated liposomes similar to PL in lipoproteins (12)(13)(14)(15), such as by PLA2-active tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…Using the highly metastatic murine melanoma cell line B16.F10 (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), incubated with LysoPC containing saturated FA residues (8), a striking uptake and membrane integration of the FAs of LysoPC into the melanoma cells was observed in vitro. This treatment also reduced the in vitro interaction of B16.F10 cells with platelets via P-selectin as well as the binding of tumor cell integrin VLA-4 to VCAM-1 (34).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

Jantscheff

Schlesinger

Fritzsche

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Lysophosphatidylcholine (LysoPC) is an important intermediate in degradation and biosynthesis of phosphatidylcholine (PC). Reduced plasma LysoPC levels observed in patients with advanced cancer indicate a deregulation of LysoPC metabolism in metastasis. Recent data showed strong antimetastatic effects of liposomes consisting of saturated PC in a murine pancreatic metastasis model. LysoPC, generated from saturated PC after accumulation of the liposomes in tumor tissue, might be contributing to these effects. Examining effects of high local concentrations of saturated LysoPC and investigating potential molecular mechanisms, fast removal of saturated LysoPC from medium by murine B16.F10 melanoma cells and radical shifts in tumor cell membrane fatty acid (FA) composition toward saturated FAs were observed in vitro. Scanning electron microscopy revealed remarkable morphologic surface changes of LysoPC-treated tumor cells, probably causing their impaired migratory ability on fibronectin. A LysoPC concentration exceeding a threshold of about 400 mmol/L, slightly above physiologic levels, strongly reduced VLA-4-mediated binding of B16.F10 cells to VCAM-1 as well as P-selectin-dependent interaction with activated platelets, although expression levels were not altered. These findings were reflected in a syngenic intravenous lung invasion model using repeatedly ex vivo LysoPC-treated (450 mmol/L) B16.F10 cells, resulting in significantly reduced lung metastasis-like lesions (À48.3%, P ¼ 0.006). Prior application of 50 IU unfractionated heparin further reduced lung invasion (À81.6%, P ¼ 0.043). Our work shows for the first time that saturated LysoPC in high concentrations reduces melanoma cell adhesion in vitro and hematogeneous dissemination in vivo by direct ex vivo tumor cell targeting.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

Jantscheff

Schlesinger

Fritzsche

et al. 2011

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…For our study, the PSApositive LNCaP prostate tumor cell line, transduced with a construct expressing a Luciferase-Neomycin resistance fusion protein, was implanted orthotopically into the prostates of SCID mice. When implanted orthotopically, this cell line metastasizes to local lymph nodes, lungs and other organs [14][15][16][17] thus drug effects on metastases can be investigated as well.…”

mentioning

confidence: 99%

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Graeser¹,

Chung

Esser³

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

The prostate-specific antigen (PSA) is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albuminbound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062-4066). In this work, we describe an albumin-binding prodrug, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO [EMC: e-Maleimidocaproic acid; DOXO 5 doxorubicin; X 5 amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water-solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA-positive tumors (LNCaP) demonstrated that the albumin-bound form of the prodrug was efficiently cleaved by PSA at the P 1 -P 0 1 scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was 100-fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 3 4 mg/kg caused significant weight loss and mortality (225%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 3 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (625%, **p 5 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (250%, SD 6 115%, *p 5 0.038). ' 2007 Wiley-Liss, Inc.Key words: doxorubicin; macromolecular prodrug; human serum albumin; PSA; orthotopic animal model; LNCaP; luciferase; in vivo bioluminescence Hormone refractory prostate cancer responds unfavorably to chemotherapy. The best results to date are achieved with Taxotere. 1 To improve prostate cancer therapy, tumor-specific delivery of anticancer agents to the primary tumor and metastases is a goal worth pursuing.For selectively releasing anticancer agents, the prostate-specific antigen (PSA) is especially attractive as a target protease because it is solely expressed in prostate tissue and prostate carcinoma in prostate cancer patients with high levels up to mg/g present in human prostate carcinoma. 2,3 PSA is a serine protease that belongs to the kallikrein gene family with chymotrypsin-like activity that is involved in the hydrolytic processing of semenogelins (cleavage of the semenal fluid proteins semenogelin I and II), which is required for liquefaction of seminal fluids. 2,3 Over...

show abstract

“…PANC-luc5 cells showed tumorigenicity in nude mice, and the tumors that developed produced intense light emission, proving the usefulness of this cell line for bioluminescent imaging experiments. Other researchers have also constructed luciferase-expressing cell lines derived from PANC-1 or other pancreatic carcinoma cell lines and used them for in vivo bioluminescent imaging [17][18][19][20].…”

Section: Discussionmentioning

confidence: 99%

In Vivo Bioluminescence Imaging of Pancreatic Cancer Xenografts in NOG Mice

Yoshimura¹,

Matsuda²,

Naito³

et al. 2013

J Carcinogene Mutagene

View full text Add to dashboard Cite

Implantation of human tumors in immunodeficient mice and in vivo bioluminescence imaging are powerful tools for cancer research. In the present study, we established a novel cell line, PANC-luc5, from PANC-1 pancreatic carcinoma cells transfected with the luciferase gene. We confirmed the usefulness of this cell line by transplanting it into three mouse strains with different immunodeficiency statuses; BALB/cA Jcl-nu/nu (Nude), Crlj:SHO-Prkdc scid Hr hr (SHO), and NOD/Shi-scid, IL-2γ null (NOG) mice. NOG mice were also inoculated with PANC-luc5 cells in either the tail vein or abdominal cavity, and monitored with in vivo bioluminescence imaging. Our results show that PANC-luc5 tumors orthotopically transplanted into NOG mice grew steadily and progressed to metastases, but those in Nude and SHO mice remained their original size with no metastasis throughout the experimental period. In the orthotopic and experimental metastasis models, in vivo bioluminescence imaging was used successfully to visualize tumor growth and metastasis of PANC-luc5 cells in NOG mice. In conclusion, in vivo bioluminescence imaging using orthotopic, intravenous, and intraperitoneal implantation of PANC-luc5 cells into NOG mice can be used to study the mechanisms of metastasis and to develop anti-pancreatic cancer drugs.

show abstract

A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging

Cited by 65 publications

References 23 publications

Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

Lysophosphatidylcholine Pretreatment Reduces VLA-4 and P-Selectin–Mediated B16.F10 Melanoma Cell Adhesion In vitro and Inhibits Metastasis-Like Lung Invasion In vivo

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

In Vivo Bioluminescence Imaging of Pancreatic Cancer Xenografts in NOG Mice

Contact Info

Product

Resources

About