Antitumor efficacy of capecitabine and celecoxib in irradiated and lead-shielded, contralateral human BxPC-3 pancreatic cancer xenografts: clinical implications of abscopal effects.
OBJECTIVE
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.


METHODS
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.
Blanquicett
Carmelo
C
Division of Clinical Pharmacology, Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Saif
M Wasif
MW
Buchsbaum
Donald J
DJ
Eloubeidi
Mohamad
M
Vickers
Selwyn M
SM
Chhieng
David C
DC
Carpenter
Mark D
MD
Sellers
Jeffrey C
JC
Russo
Suzanne
S
Diasio
Robert B
RB
Johnson
Martin R
MR
D015720:5'-Nucleotidase / Q000032:analysis / Q000235:genetics; D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000201:enzymology; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis / Q000235:genetics; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000201:enzymology; D019394:Ki-67 Antigen / Q000032:analysis; D007854:Lead; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D011720:Pyrazoles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D016861:Cyclooxygenase Inhibitors; D019394:Ki-67 Antigen; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; D003841:Deoxycytidine; D007854:Lead; D000069287:Capecitabine; D051546:Cyclooxygenase 2; D042943:Dihydrouracil Dehydrogenase (NADP); D015720:5'-Nucleotidase; D000068579:Celecoxib; D005472:Fluorouracil