Pretreatment 18F-FAZA PET Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine

Beck, Roswitha; Röper, Barbara; Carlsen, Janette; Huisman, Marc C.; Lebschi, Julia Aloisia; Andratschke, Nicolaus; Picchio, Maria; Souvatzoglou, Michael; Machulla, H.-J.; Piert, Morand

doi:10.2967/jnumed.106.038570

Cited by 96 publications

(67 citation statements)

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“…Hypoxia tracer uptake can be used to select suitable patients for hypoxia-targeted treatment regimes. The predictive value of such approaches using the cytotoxin tirapazamine has been shown in murine tumor models and humans (12,40). Likewise, novel antiangiogenic drugs blocking avb3 integrins or other established antiangiogenic drugs will likely predominantly diminish access to nutrients and energy for tumor cells downstream of 125 I-Gluco-RGD/ avb3 integrin-positive vasculature.…”

Section: Resultsmentioning

confidence: 99%

“…Tumor hypoxia was measured with 18 F-labeled azomycin arabinoside ( 18 F-FAZA), a second-generation hypoxia PET tracer displaying a more rapid clearance from normal tissues and, compared with 18 F-fluoromisonidazole, resulting in favorable tumor-to-background ratios in various tumor models (including EMT6 tumors) and humans (10)(11)(12)(13)(14). The angiogenic potential of these tumors was investigated with a glycosylated RGD-containing peptide ( 125 I-3-iodoDTyr 4 -cyclo(-Arg-Gly-Asp-DTyr-Lys(SAA)-), or 125 I-Gluco-RGD) that binds with high affinity and selectivity to the avb3 integrin on endothelial cells undergoing angiogenesis (15).…”

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confidence: 99%

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Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Picchio¹,

Beck²,

Haubner³

et al. 2008

J Nucl Med

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The hypoxia-inducible factor-1a (HIF-1a) activates angiogenesis in response to cellular hypoxia, suggesting a spatial correlation between angiogenesis and tissue hypoxia. Methods: Using digital autoradiography of coinjected 18 F-labeled azomycin arabinoside ( 8 F-FAZA) (assessing regional hypoxia) and a glycosylated RGD-containing peptide ( 125 I-3-iodo-DTyr 4 -cyclo(-Arg-Gly-AspDTyr-Lys(SAA)-), or 125 I-Gluco-RGD) (assessing angiogenesis via binding to avb3 integrin receptors on endothelial cells) performed on 22 EMT6 tumor xenografts, we investigated the intratumoral spatial distribution of these tracers. We applied a Bayesian bivariate image analysis using the mean tumor-tomuscle ratio as a discriminator, resulting in 4 groups: FAZA high/RGD high (Q1), FAZA low/RGD high (Q2), FAZA low/RGD low (Q3), and FAZA high/RGD low (Q4). In an additional 18 xenografts, the immunohistochemically derived HIF-1a protein distribution was compared with 18 F-FAZA autoradiography. Animals were divided into groups breathing either room air or carbogen (95% oxygen, 5% CO 2 ) for 4 h until sacrifice. Results: Under room air conditions, roughly 60% of the tumor surface displayed a spatial coupling of 18 F-FAZA and 125 I-Gluco-RGD uptake: either high (Q1) or low (Q3) uptake for both tracers, with Q1 indicating spatial association of hypoxia and angiogenesis and Q3 indicating adequate oxygenation without active angiogenesis. However, the remaining approximately 40% of the tumor surface showed discordant 18 F-FAZA and 125 I-Gluco-RGD uptake, indicating that hypoxia and angiogenesis are not necessarily spatially linked to each other and highlighting substantial intratumoral heterogeneity of the 18 F-FAZA and 125 I-Gluco-RGD uptake. Although carbogen breathing conditions significantly decreased the mean 18 F-FAZA tumor-to-muscle ratio, no significant changes were observed for 125 I-Gluco-RGD, indicating that an acute increase in tumor oxygenation did not influence avb3 integrin receptor expression. The HIF-1a-positive (HIF pos ) tumor cell fraction was not significantly influenced by breathing conditions and covered between 0% and 35% of the total tumor section surface. However, the HIF pos tumor section surface was much smaller than the tumor section surface of increased 18 F-FAZA uptake, suggesting that both markers are identifying distinctly different biologic processes associated with hypoxia. Conclusion: The study revealed a substantial spatial discordance of the 18 F-FAZA and 125 I-Gluco-RGD tumor distribution suggesting that hypoxia and angiogenesis are not necessarily spatially linked in malignancies. These results may prove essential in developing advanced targeted systemic chemotherapeutic approaches (such as combinations of hypoxiaactivated cytotoxins and antiangiogenic drugs) for hypoxic tumors.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Picchio¹,

Beck²,

Haubner³

et al. 2008

J Nucl Med

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“…In this issue of The Journal of Nuclear Medicine, Beck et al present a study on the role of another PET hypoxia agent in predicting response to TPZ in an animal model (19). The authors used 18 F-fluoroazamycin arabinoside ( 18 F-FAZA), a PET hypoxia tracer with properties similar to those of 18 F-FMISO.…”

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confidence: 99%

Beyond Detection: Novel Applications for PET Imaging to Guide Cancer Therapy

Rajendran

Mankoff²

2007

Journal of Nuclear Medicine

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“…Several radionuclide-labeled hypoxic markers, including F-18 fluoroazomycinarabinofuranoside, 11 F-18-misonidazole, 12,13 Cu-60-ATSM 14 and I-125-azomycin galactopyranoside, 15 have been developed. Tc-99 m butyleneamine oxime (BnAO, Tc-99m-HL91) displays good hypoxia selectivity.…”

Section: Introductionmentioning

confidence: 99%

“…11 Tumor growth was defined as the time in days for tumors to grow from 100 to 1000 mm 3 . The aGD was defined as the time in days for tumors to grow from 100 to 1000 mm 3 minus the average time in days for PBS-treated tumors to reach the same size.…”

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confidence: 99%

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model

Lee

Chiu

et al. 2012

Cancer Gene Ther

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Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100 mm 3 , pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500 mg kg À1 ) or the vehicle for 1 week. When tumor volumes reached 1000 mm 3 , autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens.

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Pretreatment 18F-FAZA PET Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine

Cited by 96 publications

References 35 publications

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Beyond Detection: Novel Applications for PET Imaging to Guide Cancer Therapy

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model

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Pretreatment 18F-FAZA PET Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine

Cited by 96 publications

References 35 publications

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by 18F-FAZA and 125I-Gluco-RGD Autoradiography

Beyond Detection: Novel Applications for PET Imaging to Guide Cancer Therapy

Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model

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Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography

Intratumoral Spatial Distribution of Hypoxia and Angiogenesis Assessed by ¹⁸F-FAZA and ¹²⁵I-Gluco-RGD Autoradiography