Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia Journal Article
| Authors: | McCall, K. C.; Humm, J. L.; Bartlett, R.; Reese, M.; Carlin, S. |
| Article Title: | Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia |
| Abstract: | Purpose: The behavior of copper-64-diacetyl-bis(N(4)- methylthiosemicarbazone) ( 64Cu-ATSM) in hypoxic tumors was examined through a combination of in vivo dynamic positron emission tomography (PET) and ex vivo autoradiographic and histologic evaluation using a xenograft model of head-and-neck squamous cell carcinoma. Methods and Materials: 64Cu-ATSM was administered during dynamic PET imaging, and temporal changes in 64Cu-ATSM distribution within tumors were evaluated for at least 1 hour and up to 18 hours. Animals were sacrificed at either 1 hour (cohort A) or after 18 hours (cohort B) postinjection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment subregions was conducted by immunohistochemical staining for markers of hypoxia (pimonidazole hydrochloride) and blood flow (Hoechst-33342). Results: Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (K i) constant was 12-fold that of muscle, whereas the distribution volume (V d) was 5-fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18-hour course of imaging. However, no spatial changes in 64Cu-ATSM distribution occurred in PET imaging at 20 minutes postinjection. Microscopic intratumoral distribution of 64Cu-ATSM and pimonidazole were not correlated at 1 hour or after 18 hours postinjection, nor was 64Cu-ATSM and Hoechst-33342. Conclusions: The oxygen partial pressures at which 64Cu-ATSM and pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Researchers have shown 64Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer. © 2012 Elsevier Inc. |
| Keywords: | immunohistochemistry; controlled study; unclassified drug; histopathology; microscopy; carcinoma, squamous cell; nonhuman; positron emission tomography; biological marker; biological markers; animals; animal tissue; animal experiment; animal model; in vivo study; tumor xenograft; xenograft model antitumor assays; hypoxia; correlation analysis; tumor targeting; drug accumulation; drug distribution; drug uptake; tissue distribution; tumors; head and neck neoplasms; rat; radiopharmaceutical agent; transplantation, heterologous; ex-vivo; in-vivo; pet imaging; radiography; pimonidazole; cell hypoxia; radioactive tracers; rats; rats, nude; kinetic analysis; blood flow; ex vivo study; distribution volume; organometallic compounds; thin layer chromatography; copper; thiosemicarbazones; autoradiography; nitroimidazoles; image reconstruction; muscle; muscles; blood oxygen tension; partial pressure; dynamic pet; pet images; head and neck squamous cell carcinoma; tumor microenvironment; head-and-neck squamous cell carcinoma; immunohistochemical staining; microenvironments; microscopic distribution; oxygen partial pressure; postinjection; spatial changes; temporal change; diacetyl bis[n(4) methylthiosemicarbazone] cu 64 |
| Journal Title: | International Journal of Radiation Oncology, Biology, Physics |
| Volume: | 84 |
| Issue: | 3 |
| ISSN: | 0360-3016 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2012-11-01 |
| Start Page: | e393 |
| End Page: | e399 |
| Language: | English |
| DOI: | 10.1016/j.ijrobp.2012.05.005 |
| PROVIDER: | scopus |
| PUBMED: | 22727887 |
| PMCID: | PMC3522091 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: IOBPD" - "Source: Scopus" |
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