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 Journal Article

Authors: Wang, E. S.; O'connor, O.; She, Y.; Zelenetz, A. D.; Sirotnak, F. M.; Moore, M. A. S.
Article Title: 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
Abstract: 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.
Keywords: controlled study; unclassified drug; human cell; drug efficacy; nonhuman; methotrexate; mouse; animals; mice; animal tissue; cell survival; reverse transcription polymerase chain reaction; apoptosis; gene expression; animal experiment; in vivo study; antineoplastic activity; in vitro study; tumor xenograft; mice, scid; tumor cells, cultured; prediction; hodgkin disease; cancer inhibition; b cell lymphoma; cancer regression; nonhodgkin lymphoma; breast carcinoma; drug response; lymphoma; tumor cell; transplantation, heterologous; lung carcinoma; large cell lymphoma; maximum tolerated dose; drug cytotoxicity; mice, inbred nod; folic acid antagonist; ic 50; folic acid antagonists; drug sensitivity; membrane transport; follicular lymphoma; sodium chloride; burkitt lymphoma; scid mouse; aminopterin; drug exposure; folate metabolism; 10 propargyl 10 deazaaminopterin; non-hodgkin's; humans; human; priority journal; article; anti-folate; murine xenografts
Journal Title: Leukemia and Lymphoma
Volume: 44
Issue: 6
ISSN: 1042-8194
Publisher: Taylor & Francis Group  
Date Published: 2003-06-01
Start Page: 1027
End Page: 1035
Language: English
DOI: 10.1080/1042819031000077124
PUBMED: 12854905
PROVIDER: scopus
Notes: Export Date: 12 September 2014 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Eunice S Wang
    13 Wang
  2. Yuhong She
    31 She
  3. Andrew D Zelenetz
    556 Zelenetz
  4. Malcolm A S Moore
    427 Moore
  5. Francis M Sirotnak
    120 Sirotnak