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
Deptartment of Radiology, The Wright Center for Innovation in Biomolecular Imaging, The Ohio State University, Columbus, Ohio.
Deptartment of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio.
Prostate. 2018 Jul 11. doi: 10.1002/pros.23686.
Ace-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.
Dogs were immunosuppressed with cyclosporine, azathioprine, prednisolone, and methylprednisolone. Their prostate glands were implanted with Ace-1 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 25-100 nmol IR800-Abz4-t-BBN was infused in 2 mL followed by euthanasia in dogs 1-2, and recovery for 24 h before euthanasia in dogs 3-6. Excised tissues were imaged optically imaged, and histopathology performed.
Dog1 grew no tumors with cyclosporine alone. Using the four drug protocol, Dogs 2-6 grew abundant 1-2 mm intracapsular and 1-2 cm intraglandular tumors. Tumors grew >5 cm 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 100 nmol dose (∼8 nmol/kg) in dogs 2-4 and 50 nmol dose in dog 5, but not from the 25 nmol dose in Dog 6. Imaging of mouse Ace-1 tumors required an intravenous dose of 500 nmol/kg body wt. A lymph node that drained the prostate gland was detectable in Dog 4. Histologic findings confirmed the imaging data.
Ace-1 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.
Ace-1犬前列腺癌细胞可在环孢素免疫抑制的实验比格犬体内原位生长。我们之前将（人胃泌素释放肽受体，huGRPr）转染到Ace-1细胞中，并用IR800-G-Abz4-t-BBN（huGRPr的一种激动剂）证明了受体靶向的近红外荧光成像。在此，我们使用新的细胞系建立了首个表达人类生长因子受体的犬前列腺癌模型。
用环孢素、硫唑嘌呤、泼尼松龙和甲泼尼龙对犬进行免疫抑制。将Ace-1细胞植入它们的前列腺。用氰基丙烯酸粘合剂封闭植入伤口以防止前列腺外肿瘤生长。前列腺内肿瘤在4-5周内生长。然后通过颈动脉对一条叶状前列腺动脉进行插管，将25-100 nmol的IR800-Abz4-t-BBN注入2 mL中，随后对犬1-2实施安乐死，对犬3-6在安乐死前恢复24小时。对切除的组织进行光学成像，并进行组织病理学检查。
仅用环孢素时，犬1未长出肿瘤。使用四种药物方案，犬2-6长出了大量1-2毫米的被膜内肿瘤和1-2厘米的腺内肿瘤。当前列腺癌细胞突破被膜时，肿瘤生长超过5厘米。在前列腺被膜植入部位密封的犬4-6在5周时出现了被膜内和腺内肿瘤生长以及淋巴结转移。在犬2-4的100 nmol剂量（约8 nmol/kg）和犬5的50 nmol剂量下，切片前列腺的近红外荧光图像中肿瘤与背景良性前列腺增生信号比很高，但犬6的25 nmol剂量未出现这种情况。对小鼠Ace-1肿瘤进行成像需要静脉注射500 nmol/kg体重的剂量。在犬4中可检测到引流前列腺的淋巴结。组织学结果证实了成像数据。
当将Ace-1细胞原位植入免疫抑制的犬体内时，可形成有活力的、表达huGRPr的肿瘤。通过前列腺动脉局部递送成像剂所需的成像剂量非常低，这表明治疗剂可安全用于治疗早期局限性腺内前列腺癌，作为主动监测或聚焦消融治疗的辅助治疗，或用于治疗不适合或无效的聚焦消融治疗的多灶性腺内疾病。
