title: Combination therapy with Pretarget CC49 radioimmunotherapy and gemcitabine prolongs tumor doubling time in a murine xenograft model of colon cancer more effectively than either monotherapy.
abstract: Pretarget radioimmunotherapy (RIT) is a multistep strategy for cancer therapy designed to reduce nontarget organ exposure by uncoupling the tumor targeting moiety from the radioactive ligand. Using this approach, we and others have demonstrated objective responses to therapy among patients with non-Hodgkin's lymphoma, with less hematological toxicity than is typically seen at equivalent doses of conventional RIT in the same patient population. In the present study, we show that combination therapy with gemcitabine (200 mg/kg on days -1 and +1) and Pretarget RIT (400 micro Ci (90)Y-labeled DOTA-biotin on day +1) is superior to Pretarget monotherapy (400 or 800 micro Ci (90)Y) as well as to gemcitabine monotherapy in nude mice bearing established human LS174T colon cancer xenografts. For the targeting moiety, we used a murine anti-TAG-72 (CC49) single-chain Fv-streptavidin (scFvSA) fusion protein that has been shown to be safe and well-tolerated in humans. The median number of days to tumor volume doubling in the gemcitabine-only studies (200 mg/kg) was 10.4 +/- 5.5 days; in the Pretarget 400 micro Ci dose-only studies, tumor doubling time was 6.7 +/- 4.9 days; and in combination therapy studies, it was 23.9 +/- 7.2 days (P </= 0.0001 versus Pretarget or gemcitabine monotherapy). There were no consistently significant differences among the two monotherapy regimens and the combination therapy regimen with respect to peripheral blood cell counts, nor were there significant differences in bone marrow colony-forming activity among the three treatment groups. These data indicate that gemcitabine can be combined with Pretarget RIT to increase antitumor response, without increasing hematological toxicity, in a murine xenograft model.
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D003110:Colonic Neoplasms / Q000628:therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D000093542:Gemcitabine
chemical_list: D000912:Antibodies, Neoplasm; D000964:Antimetabolites, Antineoplastic; C091202:B72.3 antibody; D008024:Ligands; D011993:Recombinant Fusion Proteins; D003841:Deoxycytidine; D001973:Bromodeoxyuridine; D000093542:Gemcitabine