title: Potentiation of high-LET radiation by gemcitabine: targeting HER2 with trastuzumab to treat disseminated peritoneal disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  CONCLUSIONS
  Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch and Biometric Research Branch, National Cancer Institute, Bethesda, MD 20892, USA. dm71q@nih.gov
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Erik D
authors.initials: ED
authors.lastname: Brady
authors.forename: Paul S
authors.initials: PS
authors.lastname: Albert
authors.forename: Alia
authors.initials: A
authors.lastname: Abdulla
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000627:therapeutic use; D018499:Linear Energy Transfer / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D007856:Lead Radioisotopes; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine