Combined 90Yttrium-DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft.
We have examined the application of (90)Y-DOTA-cPAM4, anti-MUC1 IgG, in combination with the front-line drug gemcitabine as a potential therapeutic for pancreatic cancer. Athymic nude mice bearing CaPan1 human pancreatic cancer xenografts were administered 2 mg of gemcitabine on days 0, 3, 6, 9 and 12 with concurrent (90)Y-DOTA-cPAM4 (100 microCi) provided on day 0. A second group of mice received a second cycle of treatment 5 weeks after the start of the first cycle. Control groups of mice included those that received either treatment arm alone, the combined modality treatment employing a nontargeting control antibody (hLL2, anti-B-cell lymphoma) and a final group that was left untreated. Gemcitabine administered as a single agent provided no antitumor effect. A single cycle of the combined (90)Y-DOTA-cPAM4 and gemcitabine treatment provided greater inhibition of tumor growth than was observed for any of the other treatment procedures. Tumor growth was delayed for a period of 7 weeks. Two cycles of gemcitabine with concomitant (90)Y-DOTA-cPAM4 yielded significant tumor regression and increased median survival to 21 weeks vs. 12 weeks for mice receiving a single cycle of therapy (p<0.024). Median tumor volume doubling-times were 18 weeks in mice treated with 2-cycles of therapy vs. 7 weeks in mice given only 1-cycle (p<0.001), and 3.5 weeks for the group that received 2-cycles of gemcitabine concomitant with equitoxic nontargeting (90)Y-DOTA-hLL2 (p<0.001). These data suggest that addition of (90)Y-DOTA-cPAM4 RAIT to a gemcitabine treatment regimen may provide enhanced antitumor efficacy for the treatment of pancreatic cancer.
Gold
David V
DV
Garden State Cancer Center, Center for Molecular Medicine and Immunology Belleville, NJ 07109, USA. dvgold@gscancer.org
Modrak
David E
DE
Schutsky
Keith
K
Cardillo
Thomas M
TM
D000230:Adenocarcinoma / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001835:Body Weight; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016499:Radioimmunotherapy; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D011838:Radiation-Sensitizing Agents; D015021:Yttrium Radioisotopes; C113625:yttrium(III)-1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; D003841:Deoxycytidine; D000093542:Gemcitabine