Targeting of HER2 antigen for the treatment of disseminated peritoneal disease.
The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of (213)Bi-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 muCi, respectively. The therapeutic effectiveness of (213)Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P = 0.001).
Milenic
Diane E
DE
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, and Biometric Research Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Garmestani
Kayhan
K
Brady
Erik D
ED
Albert
Paul S
PS
Ma
Dangshe
D
Abdulla
Alia
A
Brechbiel
Martin W
MW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D003110:Colonic Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017879:Isothiocyanates / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D010532:Peritoneal Diseases / Q000378:metabolism / Q000532:radiotherapy*; D010865:Pilot Projects; D016499:Radioimmunotherapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D015996:Survival Rate; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007205:Indium Radioisotopes; D017879:Isothiocyanates; D004369:Pentetic Acid; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C085678:N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N',N',N'',N''-pentaacetic acid