Use of a novel cross-linking method to modify adenovirus tropism

Rogers, BE; Jt, Douglas; Ahlem, Clarence N.; Buchsbaum, Donald J.; Frincke, James M.; Curiel, DT

doi:10.1038/sj.gt.3300541

Cited by 70 publications

(48 citation statements)

References 7 publications

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“…17,31 In all six pancreatic cancer cell lines, there was an enhancement of AdLuc transduction, ranging from 2 -to 34-fold ( Fig 5). Addition of the FGF2 -Fab 0 conjugate resulted in a 2.5-to 4 -fold increase in adenoviral transduction in PANC -1 and ASPC -1 cells, a 10-to 13-fold increase in CAPAN -1, MIA -PaCa -2, and T3M4 cells, and a 34-fold increase in COLO -357 cells ( Fig 5 ).…”

Section: Fgfr -Targeted Gene Delivery Enhances Transduction Efficiencmentioning

confidence: 91%

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

et al. 2002

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Pancreatic ductal adenocarcinomas ( PDACs ) overexpress various cell -surface tyrosine kinase receptors, including the type I highaffinity fibroblast growth factor receptor ( FGFR -1 ). The purpose of this study was to determine whether FGFR -targeted gene therapy is feasible in this disorder. Accordingly, the effects of a conjugate consisting of fibroblast growth factor ( FGF ) -2 linked to a Fab 0 fragment against the adenovirus knob region were evaluated in human pancreatic cancer cell lines treated with an adenoviral vector containing the herpes simplex virus thymidine kinase ( AdTK ) gene. An adenoviral vector containing the firefly luciferase reporter gene ( AdLuc ) served to assess infection efficiency, and was initially tested in L6 rat myoblasts. In parental L6 cells that express exceedingly low levels of high -affinity FGFRs, transduction with AdLuc was enhanced 7 -to 10 -fold with the FGF2 -Fab 0 conjugate, whereas in L6 cells transfected to express FGFR -1, it was enhanced 39 -to 52 -fold. The pancreatic cancer cell lines expressed variable levels of the four high -affinity FGF receptors, and exhibited 2 -to 34 -fold increases in gene transduction in the presence of the FGF2 -Fab 0 conjugate. In the absence of FGF2 -Fab 0 there was no correlation between surface binding of FGF2 and AdLuc transduction efficiency, whereas in the presence of FGF2 -Fab 0 , enhanced AdLuc transduction efficiency correlated with greater surface binding of FGF2. In the absence of AdTK, all the cell lines were insensitive to ganciclovir, whereas after AdTK transduction, only ASPC -1 and PANC -1 cells were resistant to ganciclovir even in the presence of FGF2 -Fab 0 . Ganciclovir -mediated inhibition was dependent on the conjugate in CAPAN -1 and COLO -357 cells, but was independent of the conjugate in T3M4 and MIA -PaCa -2 cells. Real -time quantitative PCR of laser -captured cancer cells revealed high levels of various FGFR mRNA species in six of seven PDAC tumor samples. These findings indicate that transduction efficiency with FGF2 -Fab 0 in pancreatic cancer cells is independent of native adenoviral transduction efficiency and is greatest in cells that exhibit concomitant expression of various highaffinity FGFRs. In view of the overexpression of high -affinity FGFRs in the cancer cells in PDAC, our findings also suggest that the combined use of AdTK, ganciclovir, and FGF2 -Fab 0 may ultimately be a promising therapeutic approach in a subgroup of patients with PDAC.

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Section: Fgfr -Targeted Gene Delivery Enhances Transduction Efficiencmentioning

confidence: 91%

Targeting of suicide gene delivery in pancreatic cancer cells via FGF receptors

et al. 2002

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“…[163][164][165] Activity has also been described in preclinical trials using an antifiber-Fab FGF2 retargeting molecule that links adenovirus components to the FGF2 receptor on the malignant cell. [164][165][166][167][168] In some cases, retargeting has been shown to be more efficient than the native adenovirus pathway. 169 Retargeting with specificity to malignant …”

Section: Enhancement Of Oncolytic Viral Therapeutic Potencymentioning

confidence: 99%

Oncolytic viral therapies

2004

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Molecular research has vastly advanced our understanding of the mechanism of cancer growth and spread. Targeted approaches utilizing molecular science have yielded provocative results in the treatment of cancer. Oncolytic viruses genetically programmed to replicate within cancer cells and directly induce toxic effect via cell lysis or apoptosis are currently being explored in the clinic. Safety has been confirmed and despite variable efficacy results several dramatic responses have been observed with some oncolytic viruses. This review summarizes results of clinical trials with oncolytic viruses in cancer.

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“…In addition, the antiknob antibody has been conjugated to the basic fibroblast growth factor for targeting adenovirus to Kaposi's sarcoma cells in vitro. 4 This resulted in an enhanced level of gene transfer when compared with unmodified adenovirus, where less than 1% of the cells were transduced with adenovirus alone compared to Ͼ40% with the conjugate-modified adenovirus.…”

Section: Figure 3 Selective Infection Of Human Colorectal Cancer Cellmentioning

confidence: 99%

“…Targeting of adenoviruses to tumor cells may be accomplished by replacing the natural receptor binding affinity by a tumor-specific binding domain. Previously, it was shown that an antiknob antibody conjugated to a ligand directed against internalizing cellular receptors can re-route the entry of adenovirus to the folate receptor, 2 the EGF receptor, 3 the FGF receptor 4 or integrins. 5 In the present study, we sought to determine if a well-described pan-carcinoma antigen could be utilized to target adenoviral vectors to tumor cells using a bispecific antibody approach.…”

Section: Introductionmentioning

confidence: 99%