Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft.
A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P < 0.02). The change in serum calcitonin levels paralleled those in tumor volume. Analysis of dose-response curves at days 20 and 40 showed additivity between RIT and paclitaxel, and analysis at day 60 suggested a synergistic effect. In conclusion, addition of doxorubicin did not improve RIT efficacy, whereas paclitaxel improved RIT efficacy significantly without increasing toxicity.
Kraeber-Bodéré
Françoise
F
Institut National de la Santé et de la Recherche Médicale Research Unit 463, CEA L. R. C. 18V, Regional Cancer Center, 44093 Nantes, France.
Saï-Maurel
Catherine
C
Campion
Loïc
L
Faivre-Chauvet
Alain
A
Mirallié
Eric
E
Chérel
Michel
M
Supiot
Stéphane
S
Barbet
Jacques
J
Chatal
Jean-François
JF
Thédrez
Philippe
P
D000818:Animals; D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen / Q000276:immunology; D018276:Carcinoma, Medullary / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000627:therapeutic use*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D013964:Thyroid Neoplasms / Q000473:pathology / Q000628:therapy*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D002272:Carcinoembryonic Antigen; C069971:DTPA-IgG complex; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D011838:Radiation-Sensitizing Agents; D004369:Pentetic Acid; D004317:Doxorubicin; D017239:Paclitaxel