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ABSTRACT: Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases. In solid tumors, more resistant to radiations and less accessible to large molecules such as antibodies, clinical efficacy remains limited. However, radiolabeled antibodies used in minimal or small-size metastatic disease have shown promising clinical efficacy. In the adjuvant setting, ongoing clinical trials show impressive increase in survival in otherwise unmanageable tumors. New technologies are being developed over the years: recombinant antibodies and pretargeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. In several cases, clinical trials have confirmed preclinical studies. Finally, new radionuclides, such as lutetium-177, with better physical properties will further improve the safety of radioimmunotherapy. Alpha particle and Auger electron emitters offer the theoretical possibility to kill isolated tumor cells and microscopic clusters of tumor cells, opening the perspective of killing the last tumor cell, which is the ultimate challenge in cancer therapy. Preliminary preclinical and preliminary clinical results confirm the feasibility of this approach.
Methods in molecular biology (Clifton, N.J.) 01/2012; 907:681-97.
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ABSTRACT: Hyperthermic intraperitoneal chemotherapy is continuously under evaluation in ovarian cancer. The purpose of the present study was to evaluate the effect of chemotherapy, drug concentration and temperature.
A human ovarian carcinoma cell line was used. The effect of hyperthermia combined with chemotherapy was analyzed.
When hyperthermia was combined with chemotherapy, the 50% lethal dose (LD(50)) decreased with the duration of exposure. The effect of temperature was similar between 39 and 43 °C for a 30-min exposure. For a 60- to 90-min exposure, the LD(50) was equivalent between 38 and 43 °C. Beyond 40 °C, an increase in platinum salt concentration was necessary to obtain similar results according to the duration of exposure.
The cytotoxic effect of the combination seemed to be potentiated and limited at 40 °C.
European Surgical Research 03/2011; 46(3):139-47. · 0.93 Impact Factor
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Caroline Rousseau,
Anne Lise Ruellan,
Karine Bernardeau,
Françoise Kraeber-Bodéré,
Sebastien Gouard,
Delphine Loussouarn,
Catherine Saï-Maurel,
Alain Faivre-Chauvet,
John Wijdenes,
Jacques Barbet,
Joëlle Gaschet, Michel Chérel,
François Davodeau
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ABSTRACT: Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.
The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.
125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.
These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.
EJNMMI research. 01/2011; 1(1):20.
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European Journal of Nuclear Medicine 03/2010; 37(5):849-50. · 4.53 Impact Factor
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ABSTRACT: Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including carcinogenesis. In 2003, a single nucleotide polymorphism (-174G/C) of the IL-6 gene promoter has been linked to breast cancer prognosis in node-positive (N+) breast cancer patients. Since, different studies have led to conflicting conclusions about its role as a prognostic and/or diagnostic marker. The primary aim of our study was to investigate the link between -174G/C polymorphism and breast cancer risk on the one hand, and -174G/C polymorphism and prognosis in different groups of patients: sporadic N+breast cancers (n=138), sporadic N- breast cancers (n=95) and familial breast cancer (n=60) on the other hand. The variables of interest were disease-free survival and overall survival. The secondary aim of the study was to screen IL-6 gene promoter using direct sequencing to identify new polymorphisms in our French Caucasian breast cancer population. No association or trend of association between -174G/C polymorphism of IL-6 gene promoter gene and breast cancer diagnosis or prognosis was shown, even in meta-analyses. Furthermore, we have identified four novel polymorphic sites in the IL-6 gene promoter region: -764G-->A, -757C-->T, -233T-->A, 15C-->A.
Cytokine 07/2009; 47(3):214-23. · 3.02 Impact Factor
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ABSTRACT: A microdosimetric model for alpha-particle-emitting radiolabeled antibodies, based on an analytic method, was developed to be used for in vitro studies. The model took into consideration cell radii distributions or distributions of activity bound to cells, and calculated the single- and multihit distributions of specific energy within the target. The mean absorbed dose could then be derived from the specific energy spectra. The mean number of hits, the probability that no particle crossed the target, and the average lineal energy transfer at which the energy is deposited were also calculated. Many in vitro geometric configurations of cells (single cell, cellular monolayer, and cellular clusters) and many different distributions of radioactive sources observed in experiments (distribution on the cell surface or within the extracellular volume) could be modeled. To verify the implementation of our algorithm, a comparison was carried out for different sources and target configurations between our model and a general Monte Carlo code (MCNPX). A positive agreement was observed between the two approaches. By using the proposed model, computation speed was greatly improved, as compared with the Monte-Carlo approach. An example of the impact of some parameters (cell radii and activity distributions) on the dosimetric results is also given in this paper.
Cancer Biotherapy and Radiopharmaceuticals 07/2007; 22(3):387-92. · 1.79 Impact Factor
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ABSTRACT: The radiosensitizing properties of gemcitabine in relation to low Linear Energy Transfer (LET) particles (Cobalt 60) and high-LET particles (alpha-RIT (213)Bi-radiolabeled CHX-DTPA-B-B4) were analyzed. Three multiple myeloma cell lines (LP1, RPMI 8226, U266) were irradiated with or without 10 nM gemcitabine 24 h prior to radiation. Gemcitabine led to radiosensitization of LP1 and U266 cells with low-LET (Radiation Enhancement Ratio: 1.55 and 1.49, respectively) but did not radiosensitize any cell line when combined with high-LET.
Radiotherapy and Oncology 05/2007; 83(1):97-101. · 5.58 Impact Factor
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ABSTRACT: Peptide affinity for MHC molecules determines the number of MHC/peptide complexes stabilized at the cell surface in in vitro tests or in vaccination protocols. We isolated a high affinity monoclonal antibody specific for the HLA-A2/Mage3 complex that enables an equilibrium binding assay to be performed on T2 cell line loaded with a range of Mage3 peptides. Binding of Mage3 to the HLA-A2 molecule can be modeled by a standard receptor-ligand interaction characterized by an affinity constant. This model enables the measurement of the affinity of other immunogenic peptides for HLA-A2 by a competition test and the calculation of the density of complexes stabilized at the T2 cell surface for all peptide concentrations. Quantification of the HLA-A2/Mage3 complexes at target cell surfaces was used to estimate the number of complexes required to reach cytotoxicity ED50 of human T cell clones sorted from an unprimed repertoire. We confirm with this antibody the direct relationship between clone avidity and TCR affinity, and the moderate contribution of the CD8 co-receptor in the reinforcement of TCR-MHC/peptide contact. Nevertheless, CD8 plays a critical role in the amplification of the specific signal to establish an efficient T cell response at low specific complex densities found in physiological situations.
European Journal of Immunology 11/2005; 35(10):2864-75. · 5.10 Impact Factor
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ABSTRACT: Using a specific monoclonal antibody (MAb), B-B4, coupled to bismuth-213 ((213)Bi) by a chelating agent (CITC-DTPA), the feasibility of alpha-radioimmunotherapy (RIT) for multiple myeloma (MM) has been demonstrated previously.
In this study, the two MAbs tested, MA5 and B-B4, target the epithelial antigens Muc-1 and syndecan-1, respectively, which are both expressed by MM cell lines. Antibody characterization was evaluated by flow cytometric analysis of normal and tumoral hematopoeitic cells of MM patients as well as immunohistochemical tests of normal, nonhematopoetic tissues. Radiobiologic effects were evaluated for (213)Bi- and iodine-131 ((131)I)--labeled antibodies. We assessed in vitro mortality (thymidine incorporation, MTT, and clonogenic assays) and cell cycle modifications with propidium iodide staining. These tests were performed on MM cell lines until 120 hours postirradiation at several time points, using radiolabeled antibody concentrations ranging from 0.5 to 20 nM and specific activities ranging from 240 to 1200 MBq/mg of MAb.
MA5 stained all MM cells in only 50% of patients, whereas B-B4 recognized all MM cells in all patients. B-B4 principally showed hepatic, pulmonary, and duodenal staining, whereas MA5 marked renal and pulmonary tissues. RIT with (213)Bi-B-B4 induced specific mortality and G(2)/M phase cell cycle arrest, which depended on the concentrations and specific activity. For (213)Bi-MA5, this arrest appeared at concentrations above 10 nM, an amount fivefold higher than that required with B-B4. This difference was also found in thymidine incorporation assays. Furthermore, with (213)Bi-B-B4, the arrest at the G(2)/M phase appeared quickly, within 24 hours after irradiation, and affected up to 60% of the cells (for 20 nM of (213)Bi-B-B4 at 1,200 MBq/mg). Conversly, (131)I-B-B4 had a very limited effect on cell mortality and did not induce any cell cycle arrest.
The results of this study show that B-B4 might be the more effective therapeutic antibody and suggest that alpha-RIT might be more suitable than beta-RIT for treating single-cell tumor models. Thus, these findings set the stage for the beginning of clinical trials using alpha-emitter--radiolabeled B-B4, with special attention paid to hepatic, pulmonary, and intestinal side effects.
Cancer 03/2002; 94(4 Suppl):1202-9. · 4.77 Impact Factor
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Stephane Supiot M.D,
Alain Faivre-Chauvet Ph.D,
Olivier Couturier M.D,
Ph.D. Marie Françoise Heymann M.D,
Nelly Robillard,
Ph.D. Françoise Kraeber-Bodéré M.D,
Laurence Morandeau Ph.D,
Ph.D. Marc Andrè Mahé M.D,
Michel Chérel Ph.D,
Stephane Supiot,
Alain Faivre‐Chauvet,
Olivier Couturier,
Marie Françoise Heymann,
Françoise Kraeber‐Bodéré,
Laurence Morandeau,
Marc Andrè Mahé, Michel Chérel
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ABSTRACT: BACKGROUND
Using a specific monoclonal antibody (MAb), B-B4, coupled to bismuth-213 (213Bi) by a chelating agent (CITC-DTPA), the feasibility of alpha-radioimmunotherapy (RIT) for multiple myeloma (MM) has been demonstrated previously.METHODS
In this study, the two MAbs tested, MA5 and B-B4, target the epithelial antigens Muc-1 and syndecan-1, respectively, which are both expressed by MM cell lines. Antibody characterization was evaluated by flow cytometric analysis of normal and tumoral hematopoeitic cells of MM patients as well as immunohistochemical tests of normal, nonhematopoetic tissues. Radiobiologic effects were evaluated for 213Bi- and iodine-131 (131I)–labeled antibodies. We assessed in vitro mortality (thymidine incorporation, MTT, and clonogenic assays) and cell cycle modifications with propidium iodide staining. These tests were performed on MM cell lines until 120 hours postirradiation at several time points, using radiolabeled antibody concentrations ranging from 0.5 to 20 nM and specific activities ranging from 240 to 1200 MBq/mg of MAb.RESULTSMA5 stained all MM cells in only 50% of patients, whereas B-B4 recognized all MM cells in all patients. B-B4 principally showed hepatic, pulmonary, and duodenal staining, whereas MA5 marked renal and pulmonary tissues. RIT with 213Bi-B-B4 induced specific mortality and G2/M phase cell cycle arrest, which depended on the concentrations and specific activity. For 213Bi-MA5, this arrest appeared at concentrations above 10 nM, an amount fivefold higher than that required with B-B4. This difference was also found in thymidine incorporation assays. Furthermore, with 213Bi-B-B4, the arrest at the G2/M phase appeared quickly, within 24 hours after irradiation, and affected up to 60% of the cells (for 20 nM of 213Bi-B-B4 at 1,200 MBq/mg). Conversly, 131I-B-B4 had a very limited effect on cell mortality and did not induce any cell cycle arrest.CONCLUSIONS
The results of this study show that B-B4 might be the more effective therapeutic antibody and suggest that alpha-RIT might be more suitable than beta-RIT for treating single-cell tumor models. Thus, these findings set the stage for the beginning of clinical trials using alpha-emitter–radiolabeled B-B4, with special attention paid to hepatic, pulmonary, and intestinal side effects. Cancer 2002;94:1202–9. © 2002 American Cancer Society.DOI 10.1002/cncr.10286
Cancer 02/2002; 94(S4):1202 - 1209. · 4.77 Impact Factor
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ABSTRACT: A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P < 0.02). The change in serum calcitonin levels paralleled those in tumor volume. Analysis of dose-response curves at days 20 and 40 showed additivity between RIT and paclitaxel, and analysis at day 60 suggested a synergistic effect. In conclusion, addition of doxorubicin did not improve RIT efficacy, whereas paclitaxel improved RIT efficacy significantly without increasing toxicity.
Molecular Cancer Therapeutics 02/2002; 1(4):267-74. · 5.23 Impact Factor
