Liposomal Doxorubicin Increases Radiofrequency Ablation— induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways

Stephanie A SOLAZZO; Muneeb AHMED; S. Nahum GOLDBERG; Rachel SCHOR-BARDACH; Wei Yang; Geoffrey D GIRNUN; Syed RAHMANUDDIN; Tatyana LEVCHENKO; Sabina SIGNORETTI; Douglas R SPITZ; Vladimir TORCHILIN

doi:10.1148/radiol.09091196

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Liposomal Doxorubicin Increases Radiofrequency Ablation— induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways

Journal article

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Liposomal Doxorubicin Increases Radiofrequency Ablation— induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways

Stephanie A SOLAZZO, Muneeb AHMED, S. Nahum GOLDBERG, Rachel SCHOR-BARDACH, Wei Yang, Geoffrey D GIRNUN, Syed RAHMANUDDIN, Tatyana LEVCHENKO, Sabina SIGNORETTI, Douglas R SPITZ, …

Radiology, Vol.255(1), pp.62-74

2010

DOI: 10.1148/radiol.09091196

PMID: 20160000

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Abstract

Purpose To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. Materials and Methods Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated γH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]–modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed. Results By 4 hours after RF ablation alone, a 0.48-mm ± 0.13 (standard deviation) peripheral band with 57.0% ± 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm ± 0.18 band with 77.7% ± 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE–modified proteins, 8-OHdG, NT, and γH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm ± 0.09 band of 25.9% ± 7.4 positivity vs 0.59-mm ± 0.11 band of 62.9% ± 6.0 positivity, P < .001 for both comparisons). Conclusion Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis.

Tumors

Biological and medical sciences

Treatment. General aspects

Other treatments

Medical sciences

Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects)

Details

Title: Subtitle: Liposomal Doxorubicin Increases Radiofrequency Ablation— induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways
Creators: Stephanie A SOLAZZO - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
Muneeb AHMED - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
S. Nahum GOLDBERG - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
Rachel SCHOR-BARDACH - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
Wei Yang - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
Geoffrey D GIRNUN - Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Md, United States
Syed RAHMANUDDIN - Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, United States
Tatyana LEVCHENKO - Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, North-eastern University, Boston, Mass, United States
Sabina SIGNORETTI - Department of Pathology, Brigham and Women's Hospital, Boston, Mass, United States
Douglas R SPITZ - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa, United States
Vladimir TORCHILIN - Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, North-eastern University, Boston, Mass, United States
Resource Type: Journal article
Publication Details: Radiology, Vol.255(1), pp.62-74
DOI: 10.1148/radiol.09091196
PMID: 20160000
NLM abbreviation: Radiology
ISSN: 0033-8419
eISSN: 1527-1315
Publisher: Radiological Society of North America; Oak Brook, IL
Language: English
Date published: 2010
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984047888902771

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