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Potentiation of high-LET radiation by gemcitabine: targeting HER2 with trastuzumab to treat disseminated peritoneal disease.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2007 Mar 15; Vol. 13 (6), pp. 1926-35. - Publication Year :
- 2007
-
Abstract
- Purpose: Recent studies from this laboratory with (212)Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb as an in vivo generator of (212)Bi. The objective of the studies presented here was improvement of the efficacy of alpha-particle radioimmunotherapy using a chemotherapeutic agent.<br />Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by (212)Pb radioimmunotherapy.<br />Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 muCi (212)Pb-trastuzumab. Improvement in median survival was observed at 5 microCi (212)Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 microCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single (212)Pb radioimmunotherapy (10 microCi) administration was then evaluated. Mice received three doses of gemcitabine: one before (212)Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to (212)Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 microCi (212)Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 microCi (212)Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before (212)Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before (212)Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because (212)Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine).<br />Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized
Antineoplastic Agents therapeutic use
Carcinoma mortality
Carcinoma secondary
Deoxycytidine therapeutic use
Female
Humans
Lead Radioisotopes therapeutic use
Linear Energy Transfer drug effects
Mice
Mice, Nude
Peritoneal Neoplasms mortality
Peritoneal Neoplasms secondary
Survival Analysis
Trastuzumab
Treatment Outcome
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Gemcitabine
Antibodies, Monoclonal therapeutic use
Carcinoma radiotherapy
Deoxycytidine analogs & derivatives
Peritoneal Neoplasms radiotherapy
Radiation-Sensitizing Agents therapeutic use
Radioimmunotherapy methods
Receptor, ErbB-2 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 13
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 17363549
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-06-2300