Development of an orthotopic canine prostate cancer model expressing human GRPr

作者：Tweedle Michael F; Ding Haiming; Drost William T; Dowell Joshua; Spain James; Joseph Mathew; Elshafae Said M; Menendez Maria Isabela; Gong Li; Kothandaraman Shankaran; Dirksen Wessel P; Wright Chadwick L; Bahnson Robert; Knopp Michael V; Rosol Thomas J

来源：Prostate, 2018, 78(14): 1111-1121.

DOI：10.1002/pros.23686

• bombesin
• canine prostate cancer
• GRP

BackgroundAce-1 canine prostate cancer cells grow orthotopically in cyclosporine immunosuppressed laboratory beagles. We previously transfected (human Gastrin-Releasing Peptide Receptor, huGRPr) into Ace-1 cells and demonstrated receptor-targeted NIRF imaging with IR800-G-Abz4-t-BBN, an agonist to huGRPr. Herein, we used the new cell line to develop the first canine prostate cancer model expressing a human growth factor receptor.
MethodsDogs were immunosuppressed with cyclosporine, azathioprine, prednisolone, and methylprednisolone. Their prostate glands were implanted with Ace-1(huGRPr) cells. The implantation wounds were sealed with a cyanoacrylic adhesive to prevent extraprostatic tumor growth. Intraprostatic tumors grew in 4-5 week. A lobar prostatic artery was then catheterized via the carotid artery and 25-100nmol IR800-Abz4-t-BBN was infused in 2mL followed by euthanasia in dogs 1-2, and recovery for 24h before euthanasia in dogs 3-6. Excised tissues were imaged optically imaged, and histopathology performed.
ResultsDog1 grew no tumors with cyclosporine alone. Using the four drug protocol, Dogs 2-6 grew abundant 1-2mm intracapsular and 1-2cm intraglandular tumors. Tumors grew >5cm when the prostate cancer cells became extracapsular. Dogs 4-6 with sealed prostatic capsule implantation sites had growth of intracapsular and intraglandular tumors and LN metastases at 5 weeks. High tumor to background BPH signal in the NIRF images of sectioned prostate glands resulted from the 100nmol dose (approximate to 8nmol/kg) in dogs 2-4 and 50nmol dose in dog 5, but not from the 25nmol dose in Dog 6. Imaging of mouse Ace-1(huGRPr) tumors required an intravenous dose of 500nmol/kg body wt. A lymph node that drained the prostate gland was detectable in Dog 4. Histologic findings confirmed the imaging data.
ConclusionAce-1(huGRPr) cells created viable, huGRPr-expressing tumors when implanted orthotopically into immune-suppressed dogs. Local delivery of an imaging agent through the prostatic artery allowed a very low imaging dose, suggesting that therapeutic agents could be used safely for treatment of early localized intraglandular prostate cancer as adjuvant therapy for active surveillance or focal ablation therapies, or for treating multifocal intraglandular disease where focal ablation therapies are not indicated or ineffective.

• 出版日期2018-10-1