Laboratori de Recerca Translacional, Institut Català d'Oncologia, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, 08908, Spain.
BMC Cancer. 2013 Aug 10;13:382. doi: 10.1186/1471-2407-13-382.
Cisplatin (CDDP) resistance in testicular germ cell tumors (GCTs) is still a clinical challenge, and one associated with poor prognosis. The purpose of this work was to test pazopanib, an anti-tumoral and anti-angiogenic multikinase inhibitor, and its combination with lapatinib (an anti-ErbB inhibitor) in mouse orthotopic models of human testicular GCTs.
We used two different models of human testicular GCTs orthotopically grown in nude mice; a CDDP-sensitive choriocarcinoma (TGT38) and a new orthotopic model generated from a metastatic GCT refractory to first-line CDDP chemotherapy (TGT44). Nude mice implanted with these orthotopic tumors were treated with the inhibitors and the effect on tumoral growth and angiogenesis was evaluated.
TGT44 refractory tumor had an immunohistochemical profile similar to the original metastasis, with characteristics of yolk sac tumor. TGT44 did not respond when treated with cisplatin. In contrast, pazopanib had an anti-angiogenic effect and anti-tumor efficacy in this model. Pazopanib in combination with lapatinib in TGT38, an orthotopic model of choriocarcinoma had an additive effect blocking tumor growth.
We present pazopanib as a possible agent for the alternative treatment of CDDP-sensitive and CDDP-refractory GCT patients, alone or in combination with anti-ErbB therapies.
顺铂（CDDP）耐药性在睾丸生殖细胞肿瘤（GCTs）中仍然是一个临床挑战，与预后不良有关。本研究旨在测试帕唑帕尼，一种抗肿瘤和抗血管生成的多激酶抑制剂，及其与拉帕替尼（一种抗-ErbB 抑制剂）联合应用于裸鼠原位人睾丸 GCTs 模型中的疗效。
我们使用两种不同的人睾丸 GCTs 原位生长的裸鼠模型；一种是顺铂敏感的绒毛膜癌（TGT38），另一种是从一线 CDDP 化疗耐药的转移性 GCT 中生成的新的原位模型（TGT44）。将这些原位肿瘤植入裸鼠后，用抑制剂进行治疗，并评估对肿瘤生长和血管生成的影响。
TGT44 耐药性肿瘤的免疫组织化学特征与原始转移灶相似，具有卵黄囊肿瘤的特征。TGT44 对顺铂治疗无反应。相比之下，帕唑帕尼对该模型具有抗血管生成作用和抗肿瘤疗效。帕唑帕尼联合拉帕替尼在 TGT38（绒毛膜癌的原位模型）中具有协同作用，可阻断肿瘤生长。
我们提出帕唑帕尼作为 CDDP 敏感和 CDDP 耐药性 GCT 患者的替代治疗药物，单独或联合抗-ErbB 治疗。
