Gorlick Richard G, Abramson David H, Sowers Rebecca, Mazza Beth Anne, Dunkel Ira J
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Pediatr Blood Cancer. 2008 Mar;50(3):573-6. doi: 10.1002/pbc.21266.
Many patients with retinoblastoma have a genetic predisposition to cancer and external beam radiation therapy and alkylating agent chemotherapy may increase their risk of secondary malignancy. Identification of effective chemotherapy agents for retinoblastoma that are not associated with an elevated risk of secondary malignancy would be beneficial.
Twenty-six specimens of fresh retinoblastoma tumor cells were studied in vitro with a PT430 competitive displacement assay. Differential displacement of the PT430 by methotrexate and not trimetrexate was considered indicative of a defect in reduced folate carrier (RFC)-mediated transport. Elevations in the accumulation of PT430 were considered indicative of dihydrofolate reductase (DHFR) amplification.
In 9 of the 26 (35%) samples, displacement by methotrexate was less than half the displacement by trimetrexate indicative of a defect in the RFC. In 5 of the 26 (19%) samples, trimetrexate did not displace the PT430. In 7 of 26 (27%) samples, the peak PT430 accumulation was suggestive of DHFR overexpression. Overall 9 of 26 (35%) samples had no evidence of a transport defect or DHFR overexpression and would be anticipated to be potentially sensitive to methotrexate. In 15 of the 26 (58%), no defects existed in trimetrexate displacement or DHFR overexpression and would be anticipated to be potentially sensitive to trimetrexate.
These results would support consideration of a phase II study to determine the effectiveness of trimetrexate for recurrent intra-ocular retinoblastoma.
许多视网膜母细胞瘤患者具有癌症遗传易感性，而外照射放疗和烷化剂化疗可能会增加他们发生继发性恶性肿瘤的风险。鉴定出与继发性恶性肿瘤风险升高无关的视网膜母细胞瘤有效化疗药物将大有裨益。
采用PT430竞争性置换试验对26份新鲜视网膜母细胞瘤肿瘤细胞标本进行体外研究。甲氨蝶呤而非三甲曲沙对PT430的差异置换被认为指示了还原型叶酸载体（RFC）介导转运的缺陷。PT430积累的升高被认为指示了二氢叶酸还原酶（DHFR）扩增。
在26份样本中的9份（占35%）中，甲氨蝶呤的置换量不到三甲曲沙置换量的一半，指示存在RFC缺陷。在26份样本中的5份（占19%）中，三甲曲沙未置换PT430。在26份样本中的7份（占27%）中，PT430积累峰值提示DHFR过表达。总体而言，26份样本中的9份（占35%）没有转运缺陷或DHFR过表达的证据，预计可能对甲氨蝶呤敏感。在26份样本中的15份（占58%）中，三甲曲沙置换或DHFR过表达不存在缺陷，预计可能对三甲曲沙敏感。
这些结果支持考虑开展一项II期研究，以确定三甲曲沙对复发性眼内视网膜母细胞瘤的有效性。
