Comparison of equitoxic radioimmunotherapy and chemotherapy in the treatment of human colonic cancer xenografts.
The therapeutic efficacy of 5-fluorouracil (5-FUra; 0.6 mg/day x 5 days) + leucovorin (LV; 1.8 mg/day x 5 days) and of 131I-labeled MN-14 anticarcinoembryonic antigen IgG (275 microCi single dose) was evaluated in size-matched (0.3-0.7 cm3) s.c. LoVo, HT-29, DLD-1, HCT-15, LS174T, and MOSER, GW-39, and WidR human colonic tumors. These lines express varying amounts of carcinoembryonic antigen and exhibit varying degrees of in vitro responsiveness to 5-FUra. Unlike radioimmunotherapy (RAIT), multiple cycles of chemotherapy were feasible over a 3-week period. However, no therapeutic advantage to a second cycle of 5-FUra/LV administration was found. Therefore, it is reasonable to compare single cycles of both treatment modalities. RAIT was statistically more effective in 5 of 8 tumor lines (LoVo, LS174T, MOSER, WidR, and GW-39). In 1 other line (DLD-1), RAIT was marginally more efficacious, but tumors responded well to both therapies. The lack of a statistical difference between the 2 modalities of treatment may indicate that the efficacy of the 2 treatments is equivalent, or the relatively large variability within the treatment groups may have prevented significance given the number of animals evaluated. RAIT and 5-FUra/LV were equally efficacious in the HT-29 and the HCT-15 tumor lines. Of the 5 xenografts that responded better to RAIT, 3 lines (LS174T, GW-39, and WidR) demonstrated a greater percentage of tumors responding over a 5- to 6-week period. The other 3 lines (LoVo, MOSER, and DLD-1) exhibited a similar percent of tumors responding to both therapies, but a greater growth inhibition in those RAIT-treated tumors that responded. In vitro responsiveness to 5-FUra/LV did not directly correlate with in vivo responsiveness (r2 = -0.664), since LS174T and LoVo tumors, with rapid growth rates (0.05-0.36 cm3/day), were not highly responsive to therapy. Growth inhibition from RAIT also did not correlate with total tumor carcinoembryonic antigen content (r2 = 0.003), an observation that may be due to additional variables, such as accessibility of antigen and innate radiosensitivity of the tumor. RAIT was most effective in the fastest growing tumor lines (LS174T, GW-39, MOSER, WidR, and LoVo). These preclinical results suggest an advantage to radioantibody therapy over one of the most commonly used forms of chemotherapy to treat colorectal cancer. These studies also highlight the need to establish criteria that will enable the selection of therapeutic modalities in patients.
Blumenthal
R D
RD
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, New Jersey 07103.
Sharkey
R M
RM
Natale
A M
AM
Kashi
R
R
Wong
G
G
Goldenberg
D M
DM
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy / Q000379:methods*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D002955:Leucovorin; D005472:Fluorouracil