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Murviel-lès-Montpellier, France

Chevreau C.,Institute Claudius Regaud | Ravaud A.,Center Hospitalier University Saint Andre | Escudier B.,Institute Gustave Roussy | Amela E.,Center Oscar Lambret | And 8 more authors.
Clinical Genitourinary Cancer | Year: 2014

Background The expanded access program and anecdotal cases suggested sunitinib is safe in RCC patients with BM and might have worthwhile activity. Patients and Methods In a phase II trial, patients with untreated BM received the standard regimen of sunitinib. The primary end point was objective response (OR) rate in BM after 2 cycles. An OR rate of 35% was prospectively defined as the minimum needed to warrant further investigation. According to Simon's optimal 2-stage design, at least 3 of the initial 15 patients had to have an OR for accrual to continue. Results Among 16 evaluable patients, 1 had a complete response outside the central nervous system (CNS). CNS disease was stabilized in 5 (31%). However, no BM showed an OR. Therefore, no further accrual took place. Median time to progression was 2.3 months and overall survival was 6.3 months. There was 1 toxic death, from peritonitis with gastric perforation. Three patients experienced at least 1 treatment-related grade 3 or greater toxicity but no neurological adverse events were attributable to sunitinib. Conclusion Although tolerability was acceptable in RCC patients with previously untreated BM, sunitinib has limited efficacy in this setting. © 2014 Elsevier Inc. All rights reserved.

Piron B.,Institute Of Recherche En Cancerologie Of Montpellier | Piron B.,French Institute of Health and Medical Research | Piron B.,Montpellier University | Piron B.,Institute Regional Of Cancerologie Of Montpellier | And 22 more authors.
Nuclear Medicine and Biology | Year: 2014

Introduction: Low dose-rate radioimmunotherapy (RIT) using 125I-labelled monoclonal antibodies (125I-mAbs) is associated with unexpected high cytotoxicity per Gy. Methods: We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53-/- and p53+/+ HCT116 cells exposed to increasing activities of internalizing anti-HER1 125I-mAbs or non-internalizing anti-CEA 125I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. Results: Cell hypersensitivity to low absorbed doses of anti-CEA 125I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4°C during exposure but were repaired under standard RIT conditions (37°C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei. Conclusion: Hypersensitivity to non-internalizing 125I-mAbs is not due to lack of detection of DNA damage after low absorbed dose-rates. However, DNA double strand breaks accumulate in cells exposed both to internalizing and non-internalizing 125I-mAbs and lead to micronuclei formation. These results suggest impairment in DNA double strand breaks repair after low absorbed doses of 125I-mAbs. © 2014 Elsevier Inc.

Elgqvist J.,Institute Of Recherche En Cancerologie Of Montpellier | Elgqvist J.,French Institute of Health and Medical Research | Elgqvist J.,Montpellier University | Elgqvist J.,Institute Regional Of Cancerologie Of Montpellier | And 6 more authors.
Frontiers in Oncology | Year: 2014

This article presents a general discussion on what has been achieved so far and on the possible future developments of targeted alpha (a)-particle therapy (TAT). Clinical applications and potential benefits of TAT are addressed as well as the drawbacks, such as the limited availability of relevant radionuclides. Alpha-particles have a particular advantage in targeted therapy because of their high potency and specificity. These features are due to their densely ionizing track structure and short path length. The most important consequence, and the major difference compared with the more widely used ß--particle emitters, is that single targeted cancer cells can be killed by self-irradiation with a-particles. Several clinical trials on TAT have been reported, completed, or are on-going: four using 213Bi, two with 211At, two with 225Ac, and one with 212Pb/212Bi. Important and conceptual proof-of-principle of the therapeutic advantages of a-particle therapy has come from clinical studies with 223Ra-dichloride therapy, showing clear benefits in castration-resistant prostate cancer. © 2014 Elgqvist, Frost, Pouget and Albertsson.

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