Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression.
PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.
Wang
Eunice S
ES
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021-6306, USA.
O'Connor
Owen
O
She
Yuhong
Y
Zelenetz
Andrew D
AD
Sirotnak
F M
FM
Moore
Malcolm A S
MA
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D005493:Folic Acid Antagonists / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D008727:Methotrexate / Q000627:therapeutic use / Q000633:toxicity*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D000630:Aminopterin; D008727:Methotrexate