Combination therapy using gemcitabine and radioimmunotherapy in nude mice with small peritoneal metastases of colonic origin.
BACKGROUND
Gemcitabine has been shown to exert a radiosensitizing effect in various epithelial cancers. The aim of the present studies was to investigate whether the efficacy of radioimmunotherapy (RIT) using the (131)I-labeled anti-CEA monoclonal antibody (MAb) MN-14 could be enhanced by coadministration of gemcitabine in nude mice with small (1-3 mm) peritoneal metastases of colonic origin.


METHODS
Firstly, the maximum tolerated dose (MTD) of gemcitabine was determined, when administered intraperitoneally at two different dosing schedules (0.11-3.0 mg/mouse/administration on days 0, 3, 6, and 9, or 0.022-0.60 mg/mouse/administration on days 0, 1, 2, 3, and 4). In two separate therapy studies in which these two administration regimens were applied, the efficacy of gemcitabine monotherapy was compared to that of RIT alone (125 muCi (131)I-MN-14/mouse) or RIT combined with gemcitabine.


RESULTS
When administered every 3rd day for a total of 4 administrations, or daily for 5 consecutive days, the gemcitabine was considered safe at 0.33 mg/mouse/administration and 0.066 mg/mouse/administration, respectively. In the first therapy study, median survival of the control mice was 39 days. Gemcitabine monotherapy at 0.11 mg or 0.33 mg/mouse/administration every 3rd day (total, 4 administrations) resulted in a median survival of 52 and 57 days, respectively (p = 0.0003, compared to controls). RIT alone resulted in a median survival of 66 days (p < 0.0001, compared to controls). The combination of RIT and gemcitabine coadministration resulted in a median survival of 73 and 94 days, respectively (p = 0.12, for trend). In the second therapy study, median survival of the control mice was 48 days, which was similar to the median survival of the mice treated with daily administrations of gemcitabine monotherapy at 0.022 mg/mouse/administration on 5 consecutive days (49 days; p = 0.17). RIT alone resulted in a significantly improved median survival of 66 days (p= = 0.0010, compared to controls). Combination therapy using RIT and gemcitabine resulted in a median survival of 64 days, which did not differ significantly from the survival of the mice treated with RIT alone (p = 0.43).


CONCLUSIONS
At the dose regimens employed, gemcitabine did not enhance the efficacy of RIT of experimental small-volume peritoneal carcinomatosis of colonic origin.
Koppe
Manuel J
MJ
Department of Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. m.koppe@chir.umcn.nl
Oyen
Wim J G
WJ
Bleichrodt
Robert P
RP
Verhofstad
Albert A
AA
Goldenberg
David M
DM
Boerman
Otto C
OC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004334:Drug Administration Schedule; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000556:secondary* / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000633:toxicity; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D002272:Carcinoembryonic Antigen; D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine