Antitumor Efficacy of Capecitabine and Celecoxib in Irradiated and Lead-Shielded, Contralateral Human BxPC-3 Pancreatic Cancer Xenografts: Clinical Implications of Abscopal Effects

Abstract

Purpose: X-ray therapy (XRT) remains one of the major modalities used to treat patients diagnosed with locally advanced pancreatic adenocarcinoma. However, the effect of XRT on metastatic tumors outside the field of irradiation (abscopal effect) remains largely unknown. In the current study, we examined the effect of XRT alone and in combination with capecitabine and/or celecoxib in both irradiated and lead-shielded contralateral BxPC-3 pancreatic cancer xenografts. This chemoradiation regimen was chosen based on our molecular analysis of pancreatic adenocarcinoma. Experimental Design: Athymic mice were injected bilaterally with BxPC-3 cells and treatment was initiated 28 days postimplant. During XRT (2 Gy for 5 consecutive days, administered on days 0 and 24), one flank was irradiated whereas the rest of the body (including the contralateral tumor) was lead shielded. Capecitabine (350 mg/kg) was administered on days 0 to 13 and 24 to 37. Celecoxib was initiated in the diet at 100 ppm (equivalent to 20 mg/kg/d p.o.) and administered throughout the study. Results: In irradiated xenografts, capecitabine and XRT showed synergistic anitiumor efficacy (P = 0.008), which was further improved with the addition of celecoxib (P < 0.001). In contralateral shielded xenografts, abscopal effects were observed. Whereas monotherapy with XRT showed significant reduction in tumor area in irradiated xenografts, growth was promoted by 23% (P < 0.001) in contralateral lead-shielded tumors in the same animals relative to untreated tumors. Interestingly, synergistic antiproliferative efficacy occurred in these contralateral tumors when capecitabine was administered (P < 0.001), despite being outside the irradiated field. The addition of celecoxib further inhibited tumor growth (P < 0.001). This trimodal combination most effectively stabilized disease in both shielded and irradiated tumors; however, tumor eradication was not observed. There were no significant changes in thymidine phosphorylase, dihydropyrimidine dehydrogenase, or cyclooxygenase-2 mRNA levels in irradiated or lead-shielded tumors, suggesting that efficacy cannot be predicted solely from these previously identified indicators of response. Immunohistochemistry examining the proliferation marker Ki-67 showed concordance with tumor response in both irradiated and contralateral shielded xenografts. Conclusions:These results have implications in the rational design of treatment paradigms for pancreatic cancer where metastatic disease remains the primary cause of patient morbidity and abscopal effects in tumors outside the field of irradiation may affect tumor response.Pancreatic cancer, the fourth leading cause of cancer mortality in the United States (1, 2), is characterized by an unusual resistance to both radiation [X-ray therapy (XRT)] and chemotherapy. Despite highly aggressive therapeutic approaches, the overall median survival of 3 to 5 months and a 5-year survival rate of 0.4% to 3% have not appreciably changed in the last 80 years (3). Surgery remains the ...

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“…Expression levels were determined using an ABI 7900 Sequence Detection System as previously described (26). The real-time quantitative PCR primers and fluorophore-labeled probe (Hs00234753_m1) were purchased from Applied Biosystems (Foster City, CA).…”

“…The real-time quantitative PCR primers and fluorophore-labeled probe (Hs00234753_m1) were purchased from Applied Biosystems (Foster City, CA). The sequence for the primers and probes for human S9 ribosomal have been described previously (26). Expression levels were calculated using the relative standard curve method (26).…”

“…The sequence for the primers and probes for human S9 ribosomal have been described previously (26). Expression levels were calculated using the relative standard curve method (26). All reactions were run in triplicate, and standard curves with correlation coefficients <0.98 were repeated.…”

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