title: Evaluation of platinum chemotherapy in combination with HER2-targeted α-particle radiation.
abstract: The studies described herein assess the potential of combining platinum-based chemotherapy with high-linear energy transfer (LET) α-particle-targeted radiation therapy using trastuzumab as the delivery vehicle. An initial study explored the combination of cisplatin with (213)Bi-trastuzumab in the LS-174T i.p. xenograft model. This initial study determined the administration sequence of cisplatin and (213)Bi-trastuzumab. Cisplatin coinjected with (213)Bi-trastuzumab increased the median survival (MS) to 90 days versus 65 days for (213)Bi-trastuzumab alone. Toxicity was observed with a weight loss of 17.6% in some of the combined treatment groups. Carboplatin proved to be better tolerated. Maximal therapeutic benefit, that is, a 5.1-fold increase in MS, was obtained in the group injected with (213)Bi-trastuzumab, followed by carboplatin 24 hours later. This was further improved by administration of multiple weekly doses of carboplatin. The MS achieved with administration of 3 doses of carboplatin was 180 days versus 60 days with (213)Bi-trastuzumab alone. The combination of carboplatin with (212)Pb radioimmunotherapy was also evaluated. The therapeutic efficacy of (212)Pb-trastuzumab (58-day MS) increased when the mice were pretreated with carboplatin 24 hours prior (157-day MS). These results again demonstrate the necessity of empirically determining the administration sequence when combining therapeutic modalities.
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. dm71q@nih.gov
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Shih
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Wong
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001729:Bismuth / Q000008:administration & dosage; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003110:Colonic Neoplasms / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007856:Lead Radioisotopes / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001729:Bismuth; D007856:Lead Radioisotopes; D009944:Organoplatinum Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab