Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease

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Abstract
Purpose: Recent studies from this laboratory with 212Pb-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using 212Pb as an in vivo generator of 212Bi. The objective of the studies presented here was improvement of the efficacy of α-particle radioimmunotherapy using a chemotherapeutic agent. Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by 212Pb radioimmunotherapy. Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 μCi 212Pb-trastuzumab. Improvement in median survival was observed at 5 μCi 212Pb-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 μCi versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single 212Pb radioimmunotherapy (10 μCi) administration was then evaluated. Mice received three doses of gemcitabine: one before 212Pb-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioimmunotherapy (P < 0.001), specifically attributable to 212Pb-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 μCi 212Pb radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 μCi 212Pb-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before 212Pb radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before 212Pb-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because 212Pb-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine). Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients.