Avidin chase can reduce myelotoxicity associated with radioimmunotherapy of experimental liver micrometastases in mice.
Myelotoxicity is the main factor which decides the maximum tolerated dose (MTD) in radioimmunotherapy (RIT). Since bone marrow is mostly irradiated from blood radioactivity, enhancing the clearance of unbound circulating radiolabeled antibody is important to reduce myelotoxicity and to increase the MTD. We applied the avidin chase method, which was devised to obtain high tumor-to-background ratios in tumor-targeting, to RIT of experimental liver micrometastases and evaluated its influence on the side effects and therapeutic outcome. Seven days after intrasplenic injection of human colon cancer LS174T cells, nude mice were intravenously injected with biotinylated (131)I-labeled anti-CEA monoclonal antibody (MAb) (24 - 38 microg, 11.1 MBq). Mice of the chase group then received an intravenous injection of avidin twice (24 and 30 h, 72 - 115 microg each). Biodistribution, side effects (white blood cell counts and body weight change), and short- and long-term therapeutic effects were determined. Avidin chase markedly accelerated the clearance of radiolabeled MAb from the blood (P < 0.0001) and normal tissues, resulting in milder leukocytopenia and body weight loss, both of which recovered earlier than in the non-chase group (P < 0.01). The tumor uptake of radiolabeled MAb was also decreased by avidin chase, but the metastases-to-background ratios were increased. Avidin chase gave the therapeutic gain ratio of 1.89. Treated groups with and without avidin chase showed significant therapeutic effects compared to the non-treated group. There was no significant difference in the therapeutic effects between the two treated groups. Avidin chase effectively reduced the side effects of RIT and should increase the MTD.
Sato
N
N
Department of Nuclear Medicine and Diagnostic Imaging, Kyoto University Graduate School of Medicine, Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. nsat@kuhp.kyoto-u.ac.jp.
Saga
T
T
Sakahara
H
H
Nakamoto
Y
Y
Zhao
S
S
Kuroki
M
M
Iida
Y
Y
Endo
K
K
Konishi
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001360:Avidin / Q000494:pharmacology*; D019921:Biotinylation; D001835:Body Weight / Q000187:drug effects; D002272:Carcinoembryonic Antigen / Q000276:immunology; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007958:Leukocyte Count / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000209:etiology; D016499:Radioimmunotherapy / Q000009:adverse effects* / Q000379:methods; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D001360:Avidin