Angelova Assia L, Aprahamian Marc, Grekova Svitlana P, Hajri Amor, Leuchs Barbara, Giese Nathalia A, Dinsart Christiane, Herrmann Alexia, Balboni Ginette, Rommelaere Jean, Raykov Zahari
Infection and Cancer Programme F010 and INSERM U701, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
Clin Cancer Res. 2009 Jan 15;15(2):511-9. doi: 10.1158/1078-0432.CCR-08-1088.
Pancreatic carcinoma is a gastrointestinal malignancy with poor prognosis. Treatment with gemcitabine, the most potent chemotherapeutic against this cancer up to date, is not curative, and resistance may appear. Complementary treatment with an oncolytic virus, such as the rat parvovirus H-1PV, which is infectious but nonpathogenic in humans, emerges as an innovative option.
To prove that combining gemcitabine and H-1PV in a model of pancreatic carcinoma may reduce the dosage of the toxic drug and/or improve the overall anticancer effect.
Pancreatic tumors were implanted orthotopically in Lewis rats or subcutaneously in nude mice and treated with gemcitabine, H-1PV, or both according to different regimens. Tumor size was monitored by micro-computed tomography, whereas bone marrow, liver, and kidney functions were monitored by measuring clinically relevant markers. Human pancreatic cell lines and gemcitabine-resistant derivatives were tested in vitro for sensitivity to H-1PV infection with or without gemcitabine.
In vitro studies proved that combining gemcitabine with H-1PV resulted in synergistic cytotoxic effects and achieved an up to 15-fold reduction in the 50% effective concentration of the drug, with drug-resistant cells remaining sensitive to virus killing. Toxicologic screening showed that H-1PV had an excellent safety profile when applied alone or in combination with gemcitabine. The benefits of applying H-1PV as a second-line treatment after gemcitabine included reduction of tumor growth, prolonged survival of the animals, and absence of metastases on CT-scans.
In addition to their potential use as monotherapy for pancreatic cancer, parvoviruses can be best combined with gemcitabine in a two-step protocol.
胰腺癌是一种预后较差的胃肠道恶性肿瘤。吉西他滨是目前针对这种癌症最有效的化疗药物，但治疗并非根治性的，且可能会出现耐药性。用溶瘤病毒进行辅助治疗，如大鼠细小病毒H-1PV，它对人类具有感染性但无致病性，成为一种创新选择。
证明在胰腺癌模型中联合使用吉西他滨和H-1PV可降低毒性药物的剂量和/或提高总体抗癌效果。
将胰腺肿瘤原位植入Lewis大鼠或皮下植入裸鼠，并根据不同方案用吉西他滨、H-1PV或两者进行治疗。通过微型计算机断层扫描监测肿瘤大小，而通过测量临床相关标志物监测骨髓、肝脏和肾脏功能。对人胰腺细胞系和吉西他滨耐药衍生物在体外测试有无吉西他滨时对H-1PV感染的敏感性。
体外研究证明，吉西他滨与H-1PV联合产生协同细胞毒性作用，药物的50%有效浓度降低达15倍，耐药细胞对病毒杀伤仍敏感。毒理学筛查表明，单独使用或与吉西他滨联合使用时，H-1PV具有良好的安全性。在吉西他滨后将H-1PV作为二线治疗的益处包括肿瘤生长减缓、动物存活期延长以及CT扫描无转移。
细小病毒除了有可能作为胰腺癌的单一疗法外，还可以在两步方案中与吉西他滨最佳联合使用。
