Enhanced antitumor activity of combination radioimmunotherapy (131I-labeled monoclonal antibody A33) with chemotherapy (fluorouracil).
Monoclonal antibody (mAb) A33 reacts with an antigen expressed by >95% of colon cancer and normal colon epithelial cells. An earlier Phase I trial of 131I-labeled mAb A33 (131I-mAb A33) demonstrated bone marrow suppression as the dose-limiting toxicity, and although modest antitumor effects were seen, no normal colon toxicity was observed. In this study, a nude mouse model was used to test whether combinations of low-dose 131I-mAb A33 (0.1 mCi) and chemotherapy [5-fluorouracil (5-FU) or 5-FU + leucovorin, doxorubicin, or carmustine] enhance the antitumor effects, compared to 131I-mAb A33 alone or either drug regimen alone. 5-FU was administered either at 30 mg/kg/day for 5 days or at 75 mg/kg/day on days 1 and 5. In assessing the reduction in tumor volumes over the first 28 days of the experiment, 5-FU treatment (with or without leucovorin) in combination with 131I-mAb A33 showed a statistically significant additive antitumor effect compared to 131I-mAb A33 alone or to chemotherapy alone. When long-term survival was used as an end point, 38% of the mice treated with 5-FU and 131I-mAb A33 were disease free at 276 days compared to none from any other group, suggesting a synergistic effect. These data indicate that Phase II clinical trials combining radiolabeled antibody therapy with 5-FU-based treatments are warranted.
Tschmelitsch
J
J
New York Branch, Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Barendswaard
E
E
Williams
C
C
Yao
T J
TJ
Cohen
A M
AM
Old
L J
LJ
Welt
S
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000951:Antigens, Neoplasm / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002330:Carmustine / Q000008:administration & dosage; D003106:Colon / Q000276:immunology; D003110:Colonic Neoplasms / Q000628:therapy*; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D002955:Leucovorin / Q000008:administration & dosage; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy / Q000379:methods*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; C104258:GPA33 protein, human; C504395:Gpa33 protein, mouse; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D004317:Doxorubicin; D002955:Leucovorin; D005472:Fluorouracil; D002330:Carmustine