Noninvasive imaging of apoptosis and its application in cancer therapeutics
被引:63
作者:
Coppola, Julia M.
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Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
Coppola, Julia M.
[2
]
Ross, Brian D.
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Univ Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
Ross, Brian D.
[1
,2
]
Rehemtulla, Alnawaz
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Univ Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USAUniv Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
Rehemtulla, Alnawaz
[1
]
机构:
[1] Univ Michigan, Med Ctr, Dept Radiat Oncol, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA
Purpose: Activation of the apoptotic cascade plays an important role in the response of tumors to therapy. Noninvasive imaging of apoptosis facilitates optimization of therapeutic protocols regarding dosing and schedule and enables identification of efficacious combination therapies. Experimental Design: We describe a hybrid polypeptide that reports on caspase-3 activity in living cells and animals in a noninvasive manner. This reporter, ANLucBCLuc, constitutes a fusion of small interacting peptides, peptide A and peptide B, with the NLuc and CLuc fragments of luciferase with a caspase-3 cleavage site (DEVD) between pepANLuc (ANLuc) and pepBCLuc (BCLuc). During apoptosis, caspase-3 cleaves the reporter, enabling separation of ANLuc from BCLuc. A high-affinity interaction between peptide A and peptide B restores luciferase activity by NLuc and CLuc complementation. Using a D54 glioma model, we show the utility of the reporter in imaging of apoptosis in living subjects in response to various chemotherapy and radiotherapy regimens. Results: Treatment of live cells and mice carrying D54 tumor xenografts with chemotherapeutic agents such as temozolomide and perifosine resulted in induction of bioluminescence activity, which correlated with activation of caspase-3. Treatment of mice with combination therapy of temozolomide and radiation resulted in increased bioluminescence activity over individual treatments and increased therapeutic response due to enhanced apoptosis. Conclusion: The data provided show the utility of the ANLucBCLuc reporter in dynamic, noninvasive imaging of apoptosis and provides a rationale for use of this technology to optimize dose and schedule of novel therapies or to develop novel combination therapies using existing drugs.
机构:
US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
Cohen, MH
;
Johnson, JR
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US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
Johnson, JR
;
Pazdur, R
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US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
机构:
Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USAHarvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA
Danial, NN
;
Korsmeyer, SJ
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Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USAHarvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA
机构:
US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
Cohen, MH
;
Johnson, JR
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US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
Johnson, JR
;
Pazdur, R
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US FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USAUS FDA, Ctr Drug Evaluat & Res, Div Oncol Drug Prod, Rockville, MD 20857 USA
机构:
Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USAHarvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA
Danial, NN
;
Korsmeyer, SJ
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Harvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USAHarvard Univ, Howard Hughes Med Inst, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA