99mTc-Glucarate for assessment of paclitaxel therapy in human ovarian cancer in mice

Document Type : Original Article


1 Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

2 Department of Anatomy, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran

3 Department of Radiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran


Objectives: The monitoring of cancer treatment response to chemotherapy is considered an essential strategy for follow-up of patients. The aim of this study was to evaluate the use of 99mTc-glucarate as a radiotracer for in vivo quantification and visualization of necrotic area and therapeutic effect of paclitaxel in ovarian cancer xenografted nude mice.
Materials and Methods: After implantation of human ovarian cancer (SKOV-3) in nude mice, tumor xenografted mice were enrolled in two groups as control and treatment (paclitaxel) groups. 99mTc-glucarate uptakes were quantified in tumors of control and treatment groups and also tumor imaging was performed with a gamma camera. The necrotic and viable areas of tumor and tumoral masses were evaluated through histopathological and macroscopic observations, respectively.
Results: 99mTc-glucarate uptake in tumor of treatment group was higher than control group.99mTc-glucarate uptake in ovarian tumor was clearly visualized with gamma imaging in both groups, but paclitaxel treated group showed higher radioactive uptake than control mice. The necrotic area in tumoral mass of mice treated with paclitaxel was confirmed by histopathological observations.
Conclusion: 99mTc-glucarate is an effective radiotracer for evaluation and monitoring of tumor necrosis caused by chemotherapy, and it may be helpful for therapy monitoring in patients with cancer.


Main Subjects

1. Tortolero-Luna G, Mitchell MF. The epidemiology of ovarian cancer. J Cell Biochem Suppl 1995; 23:200-207.
2. Baldwin LA, Huang B, Miller RW, Tucker T, Goodrich ST, Podzielinski I, et al. Ten-year relative survival for epithelial ovarian cancer. Obstet Gynecol 2012; 120:612-618.
3. Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000; 18:106-115.
4. Zhang D, Yang R, Wang S, Dong Z. Paclitaxel: new uses for an old drug. Drug Des Devel Ther 2014; 8:279-284.
5. Kampan NC, Madondo MT, McNally OM, Quinn M, Plebanski M. Paclitaxel and its evolving role in the management of ovarian cancer. Biomed Res Int 2015; 2015:413076.
6. Yeung TK, Germond C, Chen X, Wang Z. The mode of action of taxol: apoptosis at low concentration and necrosis at high concentration. Biochem Biophys Res Commun 1999; 263:398-404.
7. Mailloux A, Grenet K, Bruneel A, Beneteau-Burnat B, Vaubourdolle M, Baudin B. Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis. Eur J Cell Biol 2001; 80:442-449.
8. Wu Y, Chu Q, Tan S, Zhuang X, Bao Y, Wu T, et al. D-alpha-tocopherol polyethylene glycol succinate-based derivative nanoparticles as a novel carrier for paclitaxel delivery. Int J Nanomedicine 2015; 10:5219-5235.
9. Neesham D. Ovarian cancer screening. Aust Fam Physician 2007; 36:126-128.
10. Kumar S, Mahdi H, Bryant C, Shah JP, Garg G, Munkarah A. Clinical trials and progress with paclitaxel in ovarian cancer. Int J Womens Health 2010; 2:411-427.
11. Iyer VR, Lee SI. MRI, CT, and PET/CT for ovarian cancer detection and adnexal lesion characterization. AJR Am J Roentgenol 2010; 194:311-321.
12. Berger M, Gould MK, Barnett PG. The cost of positron emission tomography in six United States Veterans Affairs hospitals and two academic medical centers. AJR Am J Roentgenol 2003; 181:359-365.
13. Arteaga de Murphy C, Ferro-Flores G, Villanueva-Sanchez O, Murphy-Stack E, Pedraza-Lopez M, Melendez-Alafort L, et al. 99mTc-glucarate for detection of isoproterenol-induced myocardial infarction in rats. Int J Pharm 2002; 233:29-34.
14. Khaw B-A, Nakazawa A, O'donnell SM, Pak K-Y, Narula J. Avidity of technetium 99m glucarate for the necrotic myocardium: in vivo and in vitro assessment. J Nucl Cardiol 1997; 4:283-290.
15. Yaoita H, Uehara T, Brownell AL, Rabito CA, Ahmad M, Khaw BA, et al. Localization of technetium-99m-glucarate in zones of acute cerebral injury. J Nucl Med 1991; 32:272-278.
16. Petrov AD, Narula J, Nakazawa A, Pak KY, Khaw BA. Targeting human breast tumour in xeno-grafted SCID mice with 99Tcm-glucarate. Nucl Med Commun 1997; 18:241-251.
17. Gambini JP, Cabral P, Santander G, Canepa J, Andruskevicius P, Piuma L, et al. 99m Tc-Glucarate as a potential novel tracer of lung cancer lesions. Alasbimn J 2006; 9.
18. Gambini JP, Nuñez M, Cabral P, Lafferranderie M, Noble J, Corchs E, et al. Evaluation of patients with head and neck cancer by means of 99mTc-glucarate. J Nucl Med Technol 2009; 37:229-232.
19. Choudhury PS, Savio E, Solanki KK, Alonso O, Gupta A, Gambini JP, et al. 99mTc glucarate as a potential radiopharmaceutical agent for assessment of tumor viability: from bench to the bed side. World J Nucl Med 2012; 11:47-56.
20. Ballinger JR, Proulx A, Ruddy TD. Stable kit formulation of technetium-99m glucarate. Int J Radiat Appl Instrum A 1991; 42:405-406.
21. Babbar A, Sharma R. Formulation of lyophilized cold kit for instant preparation of 99mTc-glucarate and its scintigraphic evaluation in experimental models of infarction. Indian J Pharmacol 2003; 35:13-20.
22. Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 1989; 24:148-154.
23. Euhus DM, Hudd C, LaRegina MC, Johnson FE. Tumor measurement in the nude mouse. J Surg Oncol 1986; 31:229-234.
24. Prakash P, Cronin CG, Blake MA. Role of PET/CT in ovarian cancer. AJR Am J Roentgenol 2010; 194:W464-470.
25.  Abedi SM, Mardanshahi A, Shahhosseini R, Hosseinimehr SJ. Nuclear medicine for imaging of epithelial ovarian cancer. Future Oncol 2016; 12:1165-1177.
26. Munk Jensen M, Erichsen KD, Bjorkling F, Madsen J, Jensen PB, Sehested M,et al. Imaging of treatment response to the combination of carboplatin and paclitaxel in human ovarian cancer xenograft tumors in mice using FDG and FLT PET. PLoS One 2013; 8:e85126.
27. Ballinger JR, Hsue V, Rauth AM. Accumulation of technetium-99m glucarate: in vitro cell cultures and in vivo tumour models. Nucl Med Commun 2003; 24:597-606.
28. Pak K, Nedelman M, Daddona P. Visualization of experimental tumor model: application of a new Tc-99m-labeled compound. J Nucl Med 1989; 30:906.
29. Liu Z, Stevenson GD, Barrett HH, Kastis GA, Bettan M, Furenlid LR, et al. 99mTc glucarate high-resolution imaging of drug sensitive and drug resistant human breast cancer xenografts in SCID mice. Nucl Med Commun 2004; 25:711.
30. Perek N, Sabido O, Le Jeune N, Prevot N, Vergnon J-M, Clotagatide A, et al. Could 99mTc-glucarate be used to evaluate tumour necrosis? Eu J Nucl Med Mol Imaging 2008; 35:1290-1298.
31. Meng L, Xiu Y, Li Y, Xu X, Li S, Li X, et al. Investigations of 99mTc-labeled glucarate as a SPECT radiotracer for non-small cell lung cancer (NSCLC) and potential tumor uptake mechanism. Nucl Med Biol 2015; 42:608-613.
32. Narula J, Petrov A, Pak K-Y, Lister BC, Khaw B-A. Very early noninvasive detection of acute experimental nonreperfused myocardial infarction with 99mTc-labeled glucarate. Circulation 1997; 95:1577-1584.