Selection of radioimmunoconjugates for the therapy of well-established or micrometastatic colon carcinoma.
In order to optimize radioimmunotherapy (RAIT) as a cancer-treatment modality, it is necessary to select the appropriate radionuclide and antibody carrier. We evaluated the therapeutic potential of a single cycle of Mu-9 anti-CSAp monoclonal antibody (MAb) labeled with 3 different radionuclides, 131I, 90Y and 188Re. Intact antibodies and bivalent fragments with different blood clearance kinetics, normal organ distribution and varying tumor accretion and retention are also evaluated. Efficacy of treatment for large and small tumor burden was assessed in nude mice bearing s.c. GW-39 human colonic-carcinoma xenografts or intrapulmonary micrometastatic GW-39 colonies at the maximal tolerated dose of each agent. The magnitude and duration of myelosuppression associated with each radioantibody was considered by monitoring peripheral blood counts, marrow colony-forming unit activity and hematopoietic tissue weight. Radiation-dose estimates were calculated based on the kinetics of antibody accretion and elimination from tumor and normal tissues, and the results were correlated with tumoricidal activity and dose-limiting toxicity results. These studies, therefore, represent a detailed analysis, in a well-defined experimental tumor system, of several parameters (antibody form, radioisotope, tumor size) influencing the overall outcome of RAIT using equitoxic doses. It was found that myelosuppression is the primary dose-limiting toxicity for all radioantibodies except 90Y-F(ab')2, even though the different agents showed varied organ distribution. In a single-cycle treatment schedule of Mu-9 MAb, the 131I-labeled IgG is the radioimmunoconjugate of choice for the treatment of s.c. and intrapulmonary growth of the GW-39 human colonic-carcinoma xenograft in nude mice.
Sharkey
R M
RM
Garden State Cancer Center, Belleville, NJ 07109, USA.
Blumenthal
R D
RD
Behr
T M
TM
Wong
G Y
GY
Haywood
L
L
Forman
D
D
Griffiths
G L
GL
Goldenberg
D M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics; D000951:Antigens, Neoplasm / Q000276:immunology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D007457:Iodine Radioisotopes; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011868:Radioisotopes; D011879:Radiotherapy Dosage; D012211:Rhenium; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007140:Immunoglobulin Fab Fragments; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D015021:Yttrium Radioisotopes; C030139:colon-specific antigen; D012211:Rhenium