Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2009  |  Volume : 5  |  Issue : 9  |  Page : 36-40

Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors


Cancer Research Department, Inserm, Universite de Nantes, U601, Nantes, France

Date of Web Publication21-Aug-2009

Correspondence Address:
Jean-Francois Chatal
GIP Arronax, 1, rue Aronnax, Nantes-Saint-Herblain 44818
France
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.55139

Rights and Permissions
 > Abstract 

Radioimmunotherapy (RIT) has been proven effective in the treatment of radiosensitive non-Hodgkin lymphoma but, for radioresistant solid tumors, new approaches are necessary to improve the clinical effectiveness. A real improvement has been the introduction of the pretargeting technology which appeared to be able to significantly increase tumor-to-normal organ uptake ratios.Another very promising approach consists in associating RIT with other treatment modalities. Finally the use of alpha particle-emitting radionuclides such as astatin-211 or bismuth-213 (alpha-RIT) should allow to efficiently eradicate disseminated microscopic clusters of tumor cells or isolated tumor cells which fit well with the short path length of alpha particles.

Keywords: Radioimmunotherapy, pretargeted radioimmunotherapy, alpha-immunotherapy


How to cite this article:
Chatal JF, Davodeau F, Cherel M, Barbet J. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors. J Can Res Ther 2009;5, Suppl S1:36-40

How to cite this URL:
Chatal JF, Davodeau F, Cherel M, Barbet J. Different ways to improve the clinical effectiveness of radioimmunotherapy in solid tumors. J Can Res Ther [serial online] 2009 [cited 2019 Jul 19];5:36-40. Available from: http://www.cancerjournal.net/text.asp?2009/5/9/36/55139


 > Introduction Top


Radioimmunotherapy (RIT) has been proven quite effective in the treatment of non-Hodgkin lymphoma (NHL) in combination with chemotherapy. [1] There is a consensus to consider that the best indication of RIT is the treatment of small microscopic tumors for which the highest tumor uptakes have been documented. [2] Consequently, it is likely that the best indication of RIT in NHL will be the adjuvant setting in consolidation of frontline chemotherapy associated with immunotherapy with naked anti-CD20 antibody. In contrast, RIT of solid tumors remains a difficult challenge because these tumors are more radioresistant than NHL and need higher absorbed doses to be killed. Up to now, with conventional RIT using 131 I- or 90 Y-labeled whole antibodies or F(ab') 2 fragments, the highest tumor absorbed doses were less than 30 Gy whereas it is likely that more than 80-100 Gy would be necessary for tumor eradication. It should be noted that the majority of these clinical RIT trials have included patients with bulky disease. In contrast, in small tumors, less than 1cm in diameter, a few studies have reported high doses, more than 100 or 150 Gy. [3]

Strategies to increase the targeting efficacy of the radioimmunoconjugates have been explored. Some biological modifiers, such as a-interferon, which have been reported to up-regulate antigen expression at the surface of tumor cells, have been tested in patients. A modest increase in the absorbed tumor doses has been observed when compared with conventional RIT without pretreatment with α-interferon. A real improvement in RIT effectiveness has been the introduction of the pretargeting technology, which appeared to be able to significantly increase tumor-to-normal organ uptake ratios with regard o conventional RIT using directly radiolabeled antibodies. Another improvement has been the introduction of combination approaches in which RIT is associated with other treatment modalities. Finally, the use of alpha-emitting radionuclides that can efficiently kill isolated cells, has been proposed for alpha-RIT of disseminated or residual disease. [4]


 > Pretargeting Top


The principle of this innovative technology consists in decoupling the phase of tumor targeting with an antitumor antibody and the phase of the delivery of the radionuclide. This separation allows the unlabeled antibody to bind to tumor targets over a few days and the small molecule of radiolabeled effector to reach the prelocalized antibody within a few hours. Consequently, this technology can deliver as much radioactivity to a tumor target as a conventionally radiolabeled antibody but with much less irradiation of bone marrow and more generally of all normal organs.

Several pretargeting methods have been developed and explored. One ingenious system is based on the high affinity between avidin or streptavidin and biotin. Two main configurations have been described and clinically evaluated. A first three-step approach, developed in the United States, consists of first an injection of a streptavidin-conjugated antibody followed, 1-2 days later, by the injection of a clearing agent and, 1 day later, by a third injection of 90 Y-labeled biotin. A second three-step approach has been developed in Italy and uses a biotin-conjugated antibody that is injected first followed by an injection of avidin and streptavidin acting as clearing and bridging agents. In the last step, 90 Y-labeled biotin is injected and diffused rapidly into the prelocalized streptavidin bound to the biotin-conjugated antibody. A lot of preclinical studies have been performed with these two different approaches and showed higher tumor-to-normal tissue ratios in a shorter period of time than conventionally radiolabeled antibody. These encouraging results have been confirmed by clinical studies. In a phase I trial enrolling 15 patients with B-cell NHL using a tetrameric single-chain anti-CD20-streptavidin fusion protein, the tumor-to-whole-body radiation dose ratio was 49:1, and two complete responses were observed without any significant hematologic toxicity. [5] In another clinical study conducted with the other approach using an intracranially injected biotin-conjugated anti-tenascin antibody in 31 patients with high-grade gliomas, the median survival was markedly longer (33 months) than that observed in a control historical group of 12 patients. [6]

In Nantes, France, we have been using, for the last 15 years, a different pretargeting system based on the use of a bispecific monoclonal antibody (bsmAb) with one arm directed to a tumor antigen (carcinoembryonic antigen, CEA) and the other arm directed to a metal complex (DTPA-indium). This bsmAb is injected first and, a few days later, at the time of maximum tumor accretion, a radiolabeled bivalent DTPA-indium hapten is injected and diffuses rapidly into the bsmAb prelocalized into the tumor where it cross-links with two adjacent bsmAb molecules at the surface of tumor cells.

This pretargeting system has been optimized and validated in numerous preclinical and clinical studies. Two types of cancer have been considered: Small cell lung cancer (SCLC) and medullary thyroid cancer (MTC). SCLC has been selected due to its high radiosensitivity, close to that of NHL, and to its dismal prognosis with an unmet need of new therapeutic options. However, only one-third of patients have CEA-expressing tumor cells, limiting the number of patients who could be treated. Fourteen patients with proven recurrence after previous chemotherapy have been treated between 1996 and 1998, with activities of 131 I-labeled bivalent hapten ranging from 1.48 to 6.66 GBq (40-180 mCi). [7] Toxicity was mainly hematological with only three cases of grade 3 or 4 thrombocytopenia. Two partial responses and one stabilization of more than 24 months were observed. Interestingly, these responses were observed near or at the maximal tolerated dose without hematological rescue that was established at 5.6 GBq (150 mCi). Consequently, there is no doubt that SCLC is a good indication for pretargeted RIT and should be taken into consideration for the next trials with optimized agents.

MTC has been selected because the tumors are well vascularized, allowing a favorable access of the bsmAb to the tumor cells and because high CEA expression by tumor cells allows high bsmAb tumor accretion. In a first clinical study aimed at assessing achievable tumor doses and performed in a limited number of patients, tumor doses as high as 174 cGy/mCi were calculated for small-size tumors. Consequently, it was extrapolated that an injected activity of 100 mCi could deliver a tumoricidal dose of more than 150 Gy. From 1996 to 2001, 35 patients with advanced progressing MTC were enrolled in two successive phase I clinical studies. Interestingly, 6 years after the first study (using a murine bsmAb) and 3 years after the second study (using a chimeric bsmAb) a long-term stabilization was observed in 19 patients (54%) [Figure 1].

To assess the impact of these stabilizations on overall survival, we had to consider that some patients with advanced progressing disease can benefit from long survival periods extending over several years and even decades in the absence of treatment. That is why we compared the survival data in this group of MTC patients with those obtained in a historical group of 65 untreated patients after initial surgery. In the latter group, it was shown that a long calcitonin doubling time (CtDT) was the best prognostic indicator of survival. [8] A high-risk group of patients, defined by a CtDT < 6 months, had a 10-year survival of 8%. An intermediate-risk group, defined by a CtDT > 6 months and < 2 years, had a 10-year survival of 37% and a low-risk group, defined by a CtDT > 2 years, had a long survival with all patients being alive at the end of the study. Consequently, the patients treated with pretargeted RIT were stratified in two groups: One high-risk group with a CtDT < 2 years and one low-risk group with a CtDT > 2 years. All patients enrolled in the clinical trials had progressing disease with a CtDT < 5 years. Overall survival in these treated groups was compared with that of a contemporaneous untreated group of 39 patients using the same stratification as for the treated group. [9] Overall survival was significantly longer in the high-risk treated group than in the high-risk untreated group, with a median survival of 110 versus 61 months ( P < 0.010). In the treated group, a biological response was arbitrarily defined as at least a 100% increase in the CtDT calculated before pretargeted radioimmunotherapy. With this definition, 47% of patients were biological responders and had a significantly longer survival than nonresponders (median of 159 vs. 109 months; P < 0.035) and untreated patients (median of 159 vs. 61 months; P < 0.010).

To our knowledge, these were the first clinical results documenting a survival benefit in patients with a solid tumor treated by RIT. This pretargeting technique based on bsmAb and radiolabeled bivalent hapten has been optimized using molecular engineering. A new technique designated "Dock and Lock" has recently been used to join two anti-CEA Fab arms together with a single anti-hapten Fab arm. [10] A new bivalent histamine-succinyl-glycine peptide hapten has been designed to allow radiolabeling with a variety of radionuclides. This new promising technique has been validated in preclinical studies [11] and should be evaluated shortly in a first phase I clinical study.

In summary, both pretargeting systems based on avidin-biotin and bispecific mAb-hapten have been clinically validated. We could then wonder which is the most effective. In the absence of a randomized study comparing these systems, it is not possible to answer. However, it appears that the preclinical and clinical results obtained with both methods are roughly comparable. One potential drawback of the avidin-biotin system is the immunogenicity of streptavidin that limits the possibilities of retreatment.


 > Combination Approaches Top


Currently, there is a consensus to claim that the best way to improve tumor response and survival in cancer patients consists in combining complementary treatment modalities. Radioimmunotherapy can be first combined with molecules capable of improving the distribution of the immunoconjugates and especially of increasing tumor activity uptake and consequently, tumor absorbed dose. Interferon has been shown to up-regulate antigen expression and thereby enhance tumor uptake. [12] A lot of vasoactive agents have been evaluated to affect vasculature and make easier radioantibody access to tumor cells. [13] Up to now this approach has not afforded a clear improvement on RIT effectiveness in terms of tumor response rate and overall survival.

More interesting and more promising is another approach consisting in associating RIT with other treatment modalities. DeNardo et al . have been the pioneers when they reported the results of a preclinical study in a nude mouse-human breast cancer model, combining a 90 Y-labeled mAb with paclitaxel. [14] After this first report, many other investigators have confirmed synergistic effects by combining RIT with chemotherapeutic agents in a variety of cancers. [14]


 > Alpha-Immunotherapy Top


Clearly, the efficiency of conventional, beta-emitting radionuclides to kill isolated cells is limited by the deposition of most of the beta particle energy far from the targeted cell. For disease such as leukemias and for residual disease, the use of alpha emitters that deliver large amounts of energy (several MeV) in an area of less than 100 µm has been proposed. [4] The availability of radionuclides with appropriate physical properties (half-life, radioactive decay pattern) has limited the development of this approach, but bismuth-213, available from an actinium-225/bismuth-213 generator or astatine-211 produced in cyclotrons are being considered. [16] These radionuclides have rather short half-lives, and pretargeting is also considered with alpha-emitting radionuclides. [17] In Nantes, a combination of alpha-radioimmunotherapy with several chemotherapeutic agents has been evaluated in multiple myeloma cell lines. The antibody was a murine IgG (BB4 mAb) that recognizes syndecan-1 (CD 138) antigen, which is expressed by the majority of plasma cells in the majority of patients with multiple myeloma. This cancer has a dismal prognosis and needs innovative therapeutic options. Radioimmunotherapy can be such an option. After initial chemotherapy, a high percentage of complete responses is observed before subsequent relapse. This clinical setting of residual disease with disseminated clusters of plasma cells fits well with the short path length of alpha particles. Thus BB4 Mab has been labeled with 213 Bi and incubated with three multiple myeloma cell lines [18] resulting in high, dose-dependent, cell mortality of myeloma cells, with all cells being killed by 30 kBq/10 5 cells. Up to 40% of the cells were found in an apoptotic state at a dose of 7.4 kBq/10 5 cells. Nonspecific mortality was low. Subsequently, 213 Bi-labeled BB4 Mab was combined with doxorubicin and paclitaxel and incubated with the three myeloma cell lines. [19] It was shown that the combination was more effective than drug alone or alpha-radioimmunotherapy alone. The killing effect was stronger when alpha-radioimmunotherapy was given 24h after doxorubicin or paclitaxel. The radiation enhancement ratio showed clearly that paclitaxel and doxorubicin were synergistic with alpha-radioimmunotherapy. Both cell cycle arrest in the G 2 -M phase and an increase in DNA double-strand breaks could lead to radiosensitization of cells by doxorubicin or paclitaxel but apoptosis was not involved in radiosensitization mechanisms. Another drug, gemcitabine, was combined with 213 Bi-labeled BB4 Mab but no radiosensitization was observed. [20]

In conclusion, there is a consensus to consider that radioimmunotherapy and pretargeted radioimmunotherapy, used alone, will probably not be capable of curing solid tumors, but curing solid tumors and other disseminated diseases should be possible using optimal combinations of pretargeted radioimmunotherapy and chemotherapy in the context of small tumor burden or residual disease. 2-Deoxy-D-glucose (2-DG) has shown to be a potent radiosensitizer by markedly enhancing the radiation-induced cell death of spheroids (which mimics the behavior of solid micrometastases). [21] Thus it should be interesting to combine pretargeted radioimmunotherapy and 2-DG aiming at increasing effectiveness.


 > Acknowledgement Top


This paper was presented at the Symposium on "Applications of 2-deoxy-D-glucose in the management of cancer," Institute of Nuclear Medicine and Allied Sciences, New Delhi, India, November 8-10, 2006.

 
 > References Top

1.Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, Leblanc M, et al . Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non- Hodgkin's lymphoma: Five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol 2006;24:4143-9.  Back to cited text no. 1
    
2.Goldenberg DM, Sharkey RM, Paganelli G, Barbet J, Chatal JF. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J Clin Oncol 2006;24:823-34.  Back to cited text no. 2
    
3.Bardies M, Bardet S, Faivre-Chauvet A, Peltier P, Douillard JY, Mahe M, et al . Bispecific antibody and iodine-131-labeled bivalent hapten dosimetry in patients with medullary thyroid or small-cell lung cancer. J Nucl Med 1996;37:1853-9.  Back to cited text no. 3
    
4.Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR, et al . Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233-9.  Back to cited text no. 4
    
5.Forero A, Weiden PL, Vose JM, Knox SJ, LoBuglio AF, Hankins J, et al . Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma. Blood 2004;104:227-36.  Back to cited text no. 5
    
6.Grana C, Chinol M, Robertson C, Mazzetta C, Bartolomei M, Cicco C, et al . Pretargeted adjuvant radioimmunotherapy with yttrium- 90-biotin in malignant glioma patients: A pilot study. Br J Cancer 2002;86:207-12.  Back to cited text no. 6
    
7.Vuillez JP, Kraeber-Bodere F, Moro D, Bardies M, Douillard JY, Gautherot E, et al . Radioimmunotherapy of small cell lung carcinoma with the two-step method using a bispecific anti-carcinoembryonic antigen/anti-diethylenetriaminepentaacetic acid (DTPA antibody and iodine- 131-di-DTPA hapten: Results of a phase I/II trial. Clin Cancer Res 1999;5:3259s-67s.  Back to cited text no. 7
    
8.Barbet J, Campion L, Kraeber-Bodere F, Chatal JF. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 2005;90:6077-84.  Back to cited text no. 8
    
9.Chatal JF, Campion L, Kraeber-Bodere F, Bardet S, Vuillez JP, Charbonnel B, et al . Survival Improvement in Patients With Medullary Thyroid Carcinoma Who Undergo Pretargeted Anti- Carcinoembryonic- Antigen Radioimmunotherapy: A Collaborative Study With the French Endocrine Tumor Group. J Clin Oncol 2006;24:1705-11.  Back to cited text no. 9
    
10.Rossi EA, Goldenberg DM, Cardillo TM, McBride WJ, Sharkey RM, Chang CH. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc Natl Acad Sci U S A 2006;103:6841-6.  Back to cited text no. 10
    
11.Sharkey RM, Cardillo TM, Rossi EA, Chang CH, Karacay H, McBride WJ, et al . Signal amplification in molecular imaging by pretargeting a multivalent, bispecific antibody. Nat Med 2005;11:1250-5.  Back to cited text no. 11
    
12.Meredith RF, Khazaeli MB, Macey DJ, Grizzle WE, Mayo M, Schlom J, et al . Phase II study study of interferon-enhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer. Clin Cancer Res 1999;5:3254s-8s.  Back to cited text no. 12
    
13.Pedley RB, El-Emir E, Flynn AA, Boxer GM, Dearling J, Raleigh JA, et al . Synergy between vascular targeting agents and antibody-directed therapy. Int J Radiat Oncol Biol Phys 2002;54:1524-31.  Back to cited text no. 13
    
14.DeNardo SJ, Kukis DL, Kroger LA, O'Donnell RT, Lamborn KR, Miers LA, et al . Synergy of Taxol and radioimmunotherapy with yttrium-90- labeled chimeric L6 antibody: Efficacy and toxicity in breast cancer xenografts. Poc Natl Acad Sci USA 1997;94:4000-4.  Back to cited text no. 14
    
15.Gold DV, Modrak DE, Schutsky K, Cardillo TM. Combined 90 yttrium- DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft. Int J Cancer 2004;109:618-26.  Back to cited text no. 15
    
16.Cherel M, Davodeau F, Kraeber-Bodere F, Chatal JF. Current status and perspectives in alpha radioimmunotherapy. Q J Nucl Med Mol Imaging 2006;50:322-9.   Back to cited text no. 16
    
17.Zhang M, Yao Z, Garmestani K, Axworthy DB, Zhang Z, Mallett RW, et al . Pretargeting radioimmunotherapy of a murine model of adult T-cell leukemia with the alpha-emitting radionuclide, bismuth 213. Blood 2002;100:208-16.  Back to cited text no. 17
    
18.Couturier O, Faivre-Chauvet A, Filippovich IV, Thιdrez P, Saο-Maurel C, Bardiθs M, et al . Validation of 213Bi-a-radioimmunotherapy for multiple myeloma. Clin Cancer Res 1999;5:3165s-70s.  Back to cited text no. 18
    
19.Supiot S, Gouard S, Charrier J, Apostolidis C, Chatal JF, Barbet J, et al . Mechanisms of cell sensitization to a radioimmunotherapy by doxorubicin or paclitaxel in multiple myeloma cell lines. Clin Cancer Res 2005;11:7047s-52s.  Back to cited text no. 19
    
20.Supiot S, Thillays F, Rio E, Gouard S, Morgenstern A, Bruchertseifer F, et al . Gemcitabine radiosensitizes multiple myeloma cells to low let, but not high let, irradiation. Radiother Oncol 2007;83:97-101.  Back to cited text no. 20
    
21.Khaitan D, Chandna S, Arva MB, Dwarakanath BS. Differential mechanisms of radiosensitization by 2-deoxy-D-glucose in the monolayers and multicellular spheroids of a human glioma cell line. Cancer Biol Ther 2006;5:1142-51.  Back to cited text no. 21
    


    Figures

  [Figure 1]


This article has been cited by
1 Emerging Trends for Radioimmunotherapy in Solid Tumors
Maneesh Jain,Suprit Gupta,Sukhwinder Kaur,Moorthy P. Ponnusamy,Surinder K. Batra
Cancer Biotherapy & Radiopharmaceuticals. 2013; 28(9): 639
[Pubmed] | [DOI]
2 Radiofrequency Ablation Before Intratumoral Injection of131I-chTNT Improves the Tumor-to-Normal Tissue Ratio in Solid VX2Tumor
Shu-Guang Zheng,Hui-Xiong Xu,Ming-De Lu,Dian-Chao Yue,Xiao-Yan Xie,Guang-Jian Liu
Cancer Biotherapy & Radiopharmaceuticals. 2013; 28(10): 725
[Pubmed] | [DOI]
3 Evaluation of strained alkynes for Cu-free click reaction in live mice
S.M. van den Bosch,R. Rossin,P. Renart Verkerk,W. ten Hoeve,H.M. Janssen,J. Lub,M.S. Robillard
Nuclear Medicine and Biology. 2013; 40(3): 415
[Pubmed] | [DOI]
4 Highly Reactivetrans-Cyclooctene Tags with Improved Stability for Diels–Alder Chemistry in Living Systems
Raffaella Rossin,Sandra M. van den Bosch,Wolter ten Hoeve,Marco Carvelli,Ron M. Versteegen,Johan Lub,Marc S. Robillard
Bioconjugate Chemistry. 2013; 24(7): 1210
[Pubmed] | [DOI]
5 Bispecific Her2 × cotinine antibody in combination with cotinine–(histidine)2–iodine for the pre-targeting of Her2-positive breast cancer xenografts
Soomin Yoon,Yun-Hee Kim,Se Hun Kang,Seok-Ki Kim,Hwa Kyoung Lee,Hyori Kim,Junho Chung,In-Hoo Kim
Journal of Cancer Research and Clinical Oncology. 2013;
[Pubmed] | [DOI]
6 Evolutionary dynamics of carcinogenesis and why targeted therapy does not work
Robert J. Gillies,Daniel Verduzco,Robert A. Gatenby
Nature Reviews Cancer. 2012; 12(7): 487
[Pubmed] | [DOI]
7 Evolutionary dynamics of carcinogenesis and why targeted therapy does not work
Gillies, R.J., Verduzco, D., Gatenby, R.A.
Nature Reviews Cancer. 2012; 12(7): 487-493
[Pubmed]
8 6th Annual European Antibody Congress 2010: November 29-December 1, 2010, Geneva, Switzerland
Beck, A., Wurch, T., Reichert, J.M.
mAbs. 2011; 3(2): 111-134
[Pubmed]
9 6thAnnual European Antibody Congress 2010
Alain Beck,Thierry Wurch
mAbs. 2011; 3(2): 111
[Pubmed] | [DOI]
10 Experimental study of radioimmunotherapy versus chemotherapy for colorectal cancer
G. M. de Jong, R. P. Bleichrodt, A. Eek, W. J. G. Oyen, O. C. Boerman, T. Hendriks
British Journal of Surgery. 2011; 98(3): 436
[VIEW] | [DOI]
11 A rapid microwave-assisted procedure for easy access to Npolydentate ligands for potential application in α-RIT
Mével, M., Bodio, E., Grosjean, S., Montavon, G., Meslin, J.-C., Julienne, K., Deniaud, D.
Synlett. 2010; 8(G04610ST): 1215-1218
[Pubmed]
12 New antibody conjugates in cancer therapy
Govindan, S.V., Goldenberg, D.M.
TheScientificWorldJournal. 2010; 10: 2070-2089
[Pubmed]
13 Brief intraperitoneal radioimmunotherapy of small peritoneal carcinomatosis using high activities of noninternalizing 125I-labeled monoclonal antibodies
Boudousq, V., Ricaud, S., Garambois, V., Bascoul-Mollevi, C., Boutaleb, S., Busson, M., Quenet, F., (...), Pouget, J.-P.
Journal of Nuclear Medicine. 2010; 51(11): 1748-1755
[Pubmed]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Pretargeting>Combination Appr...>Alpha-Immunotherapy>Acknowledgement>Article Figures
  In this article
>References

 Article Access Statistics
    Viewed4517    
    Printed237    
    Emailed2    
    PDF Downloaded526    
    Comments [Add]    
    Cited by others 13    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]