作者: Mafalda Laranjo ; Maria Elisa Silva Serra ; Bárbara Oliveiros ; Joana Rio ; Ana Margarida Abrantes ; Maria Filomena Botelho ; António Manuel Rocha-Gonsalves ; Ana Cristina Gonçalves ; Ana Bela Sarmento-Ribeiro

Colorectal cancer is one of the most common malignancies in the Western world and is an example of a solid tumour in which hypoxia is a common feature and develops because of the inability of the vascular system to supply adequate amounts of oxygen to growing tumours. Hypoxia effects on tumour cell biology can be detected and characterized using different methods. The use of imaging with gamma-emitting radionuclides to detect hypoxic tissue was first suggested by Chapman in 1979 [N Engl J Med 301 (1979) 1429-1432]. (99m)Tc-4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime, also known as (99m)Tc-HL-91, has been among the most studied hypoxia markers. The objective of this study was to correlate the uptake of (99m)Tc-HL-91 and (99m)Tc-MIBI in colon cancer cells under normoxic and hypoxic conditions and to compare this information with some parameters such as oxidative stress and mitochondrial dysfunction of the cells analyzed by flow cytometry. Our results show that the in vitro (99m)Tc-HL-91 uptake is higher in hypoxic conditions, which is confirmed by the decreased uptake of (99m)Tc-MIBI. Flow cytometry results demonstrate that hypoxic conditions used are not enough to induce cellular death, but are responsible for the alterations in the intracellular redox environment, namely, increase of ROS production, proteic pimonidazol-derived adduct formation and alteration in the mitochondrial membrane permeability. Therefore, these results confirm that (99m)Tc-HL-91 is a radiopharmaceutical with favourable characteristics for detecting hypoxia.

2000-08-15·Cancer research

Scintigraphic imaging of the hypoxia marker (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; prognox): noninvasive detection of tumor response to the antivascular agent 5,6-dimethylxanthenone-4-acetic acid.

Article

作者: Wilson, W R ; Rutland, M D ; Siim, B G ; Laux, W T ; Palmer, B N

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) and combretastatin A4 phosphate (CA-4-P) markedly inhibit tumor blood flow in mice and are both currently in clinical trial. One of the challenges in clinical evaluation of antivascular agents is the monitoring of tumor blood flow inhibition in individual patients. This study investigates, using mouse models, whether a new marker for tissue hypoxia, (99m)technetium-labeled 2,2'-(1,4-diaminobutane)bis(2-methyl-3-butanone) dioxime (99mTc-labeled HL-91; Prognox)] has potential for the scintigraphic monitoring of tumor response to antivascular agents. Determination of radioactivity in dissected tissues 3 h after DMXAA (80 micromol/kg) or CA-4-P (227 micromol/kg) was injected indicated that both drugs inhibited blood flow (86RbCl uptake; 84 and 87%, respectively) and increased 99mTc-labeled HL-91 levels (350 and 300%, respectively) selectively in murine RIF-1 tumors. Planar imaging of 99mTc-labeled HL-91 3 h after DMXAA injection showed a dose-dependent increase in tumor levels above a threshold of 50 micromol/kg; this same threshold was observed for the inhibition of tumor blood flow (determined using Hoechst 33342). DMXAA also inhibited blood flow--and increased 99mTc-labeled HL-91 uptake--in MDAH-MCa-4 mouse mammary carcinomas and in NZMN10 human melanoma xenografts. Whether 99mTc-labeled HL-91 might also be useful as a biomarker for tumor cell killing was investigated by clonogenic assay of surviving cells 15 h after imaging 99mTc-labeled HL-91 in RIF-1 tumors. Log cell kill in individual tumors showed a statistically significant linear correlation (P < 0.001) with 99mTc-labeled HL-91 uptake after 60 micromol/kg (r2 = 0.79) and 70 micromol/kg (r2 = 0.44) but not at 80 micromol/kg DMXAA. The lack of correlation at high doses presumably reflects the insensitivity of the tumor-averaged 99mTc-labeled HL-91 signal to small regions in which tumor blood flow is preserved (which will limit log cell kill). The results indicate the potential of 99mTc-labeled HL-91 for the noninvasive imaging of tumor blood flow inhibition by antivascular drugs in humans.

1998-06-30·Circulation1区 · 医学

“Hot Spot” Detection of Ischemic Myocardium In Vivo by Gamma Camera Imaging

1区 · 医学

Article

作者: North, Timothy L. ; Okada, Robert D. ; Johnson, Gerald ; Archer, Colin M. ; Edwards, Barbara ; Nguyen, Kiem N. ; Liu, Zhonglin ; Kelly, James D. ; King, Adam C.

Background — 99m Tc-HL91 is a new hypoxia imaging agent that demonstrates increased uptake and retention in globally hypoxic myocardium in vitro. The purpose of this study was to determine whether 99m Tc-HL91 could detect regional ischemia in vivo by gamma camera imaging. Methods and Results —Eight open-chest dogs with left circumflex (LCx) stenoses were studied. Injection of 5 mCi of 99m Tc-HL91 and microspheres was followed by imaging over 4 hours. Heart slices were imaged, then stained with triphenyltetrazolium chloride (TTC), and tissues were well-counted. TTC staining demonstrated no injury. Mean LCx blood flow was 0.32±0.04 mL · min −1 · g −1 , and mean left anterior descending coronary artery (LAD) flow was 0.96±0.02 mL · min −1 · g −1 (ratio, 0.33). “Hot spots” were detected in 8 of 8 experiments in vivo within 60 minutes and improved over 4 hours. Region of interest analysis of LCx/LAD activity ratios demonstrated significant increases within 30 minutes (final ratio, 3.0; P <0.05). LCx and LAD washout curves demonstrated significant differences within 15 minutes. Washout curves were biexponential over 1 hour, followed by linear retention from 1 to 4 hours. Four-hour fractional retention was 0.12 for LAD and 0.44 for LCx ( P <0.01). Myocardial flow versus tracer uptake demonstrated 2 phases: phase 1 (flow, 0.05 to 0.7 mL · min −1 · g −1 ) had an inverse linear correlation ( r =−0.80); phase 2, (flow, >0.7 mL · min −1 · g −1 ) had no correlation. Ischemic heart/liver ratios remained near 1.0 for 4 hours. Conclusions — 99m Tc-HL91 positively identifies regional myocardial ischemia in a canine model using 99m Tc imaging. Quantitative techniques allowed identification of ischemic myocardium within 15 minutes of tracer administration.

100 项与 Tc-HL-91 相关的药物交易

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