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

Authors' Affiliations: ¹ Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch and ² Biometric Research Branch, National Cancer Institute, Bethesda, Maryland and ³ Walter Reed Medical Center, Washington, District of Columbia

Requests for reprints: Diane E. Milenic, NIH, 10 Center Drive, MSC-1002, Building 10, Room 1B40, Bethesda, MD 20892. Phone: 301-496-9086; Fax: 301-402-1923; E-mail: dm71q{at}nih.gov.

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 -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.

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				D. E. Milenic, K. Garmestani, E. D. Brady, K. E. Baidoo, P. S. Albert, K. J. Wong, J. Flynn, and M. W. Brechbiel Multimodality Therapy: Potentiation of High Linear Energy Transfer Radiation with Paclitaxel for the Treatment of Disseminated Peritoneal Disease Clin. Cancer Res., August 15, 2008; 14(16): 5108 - 5115. [Abstract] [Full Text] [PDF]