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Distinct Mechanistic Activity Prowle of Pralatrexate in Comparison to Other Antifolates in in Vitro and in Vivo Models of Human Cancers

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Distinct Mechanistic Activity Prowle of Pralatrexate in Comparison to Other Antifolates in in Vitro and in Vivo Models of Human Cancers Cancer Chemother Pharmacol (2009) 64:993–999 DOI 10.1007/s00280-009-0954-4 ORIGINAL ARTICLE Distinct mechanistic activity proWle of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers E. Izbicka · A. Diaz · R. Streeper · M. Wick · D. Campos · R. SteVen · M. Saunders Received: 22 July 2008 / Accepted: 26 December 2008 / Published online: 17 February 2009 © The Author(s) 2009. This article is published with open access at Springerlink.com Abstract both NSCLC models, with more eVective dose-dependent Purpose This study evaluated mechanistic diVerences of TGI in the more rapidly growing NCI-H460 xenografts. pralatrexate, methotrexate, and pemetrexed. Conclusions Pralatrexate demonstrated a distinct mecha- Methods Inhibition of dihydrofolate reductase (DHFR) nistic and anti-tumor activity proWle relative to methotrex- was quantiWed using recombinant human DHFR. Cellular ate and pemetrexed. Pralatrexate exhibited enhanced uptake and folylpolyglutamate synthetase (FPGS) activity cellular uptake and increased polyglutamylation, which were determined using radiolabeled pralatrexate, metho- correlated with increased TGI in NSCLC xenograft models. trexate, and pemetrexed in NCI-H460 non-small cell lung cancer (NSCLC) cells. The tumor growth inhibition (TGI) Keywords Pralatrexate · Antifolates · Polyglutamylation · was assessed using MV522 and NCI-H460 human NSCLC Non-small cell lung cancer · Xenograft · xenografts. Dihydrofolate reductase (DHFR) Results Apparent Ki values for DHFR inhibition were 45, 26, and >200 nM for pralatrexate, methotrexate, and pemetrexed, respectively. A signiWcantly greater percent- Introduction age of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed. Folate plays a key role in the one-carbon metabolic pro- In vivo, pralatrexate showed superior anti-tumor activity in cesses essential for deoxyribonucleic acid (DNA) replica- tion. Antifolates are divalent anions which cross the cell membrane predominantly via the reduced folate carrier Preliminary reports of these studies were presented at the following (RFC-1). RFC-1 is an oncofetoprotein found predominantly meetings: Izbicka E, Diaz A, Campos D, Wick M, SteVen R, Saunders M (2007) DiVerential activity and potential mechanism of action of in the membranes of fetal and tumor cells [1]. Upon entry pralatrexate (PDX), methotrexate and pemetrexed (Alimta) in human in the cell, antifolates are polyglutamylated by folylpolyg- cancer models in vivo and in vitro. Proc AACR-NCI-EORTC lutamate synthetase (FPGS), and the polyglutamylated International Conference 108:A135, San Francisco, CA, October products tend to be retained within the cell. Polyglutamyla- 2007. tion is a time- and concentration-dependent process that Campos DR, Diaz A, Wick M, SteVen R, Saunders M, Izbicka E occurs in tumor cells and to a lesser extent in normal tis- (2007) Distinct activity of pralatrexate in human cancer models in vivo sues. The longer intracellular half-life of these polygluta- and in vitro. Proc AACR Centennial Conference 49:B15, Singapore, mylated conjugates extends product action in malignant November 4–9, 2007. cells through more eVective dihydrofolate reductase E. Izbicka · A. Diaz · R. Streeper · M. Wick · (DHFR) inhibition [2, 3]. Because the intracellular concen- D. Campos tration of antifolates is critical for their pharmacological CTRC IDD, San Antonio, TX, USA activity, polyglutamylation is a key determinant of antifo- late-mediated cytotoxicity [4]. R. SteVen · M. Saunders (&) Allos Therapeutics, Inc., Westminster, CO, USA Methotrexate was designed nearly 60 years ago and e-mail: [email protected] functions to block the activity of DHFR. Methotrexate is 123 994 Cancer Chemother Pharmacol (2009) 64:993–999 approved for use in the treatment of gestational choriocarci- O OH noma, chorioadenoma destruens and hydatidiform mole. In O acute lymphocytic leukemia, methotrexate is approved for OH NH 2 N the prophylaxis of meningeal leukemia and is used in main- H N O tenance therapy in combination with other chemotherapeu- N tic agents. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast can- H2N N N cer, head and neck cancer, bladder cancer, advanced myco- H sis fungoides, and lung cancer, particularly squamous cell Pralatrexate (PDX) and small cell types. Methotrexate is also used in combina- tion with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas. More recently O OH O investigated antifolates include raltitrexed (Tomudex®) and ® OH pemetrexed (Alimta ) which target thymidylate synthase NH 2 N H (TS) and glycinamide ribonucleotide formyl transferase N O (GARFT). Alimta® is approved for the treatment of non- N N small cell lung cancer (NSCLC) and malignant pleural H N N N mesothelioma. Methotrexate has also been used extensively 2 for treatment of certain autoimmune disorders, primarily Methotrexate (MTX) rheumatoid arthritis [5–7]. Fig. 1 Pralatrexate and methotrexate structures Pralatrexate [PDX (RS)-10-propargyl-10-deazaaminop- terin], is a 10-deazaaminopterin analog of methotrexate, and is a small-molecule inhibitor of DHFR (Fig. 1). Pralat- ongoing studies have shown responses in 14 of 26 (54%) rexate diVers from methotrexate at position 10 where a car- evaluable patients with T cell lymphoma, of which nine bon with a propargyl side chain is substituted for the were complete responses (CR) [15]. nitrogen with a methyl substituent. Pralatrexate was ratio- nally designed for improved cellular transport via RFC-1, and to have greater intracellular drug retention through the Materials and methods enhanced formation of polyglutamylated conjugates [2, 3]. The relative diVerence in polyglutamate formation in nor- Reagents mal versus malignant cells may account for the enhanced pharmacodynamic activity of pralatrexate. Pralatrexate is Drugs used included [14C]-pralatrexate, 28.4 mCi/mmol, thought to exert its pharmacological eVect primarily 4.58 M (Clauson-Kaas A/S, Farum, Denmark); [3H]- through inhibition of DHFR, having an IC50 in the picomo- methotrexate, 49.6 Ci/mmol, 20.16 M (Moravek, Brea, lar range [8]. CA); [14C]-pemetrexed, 51.7 mCi/mmol, 5.55 M (Eagl- This study investigated the potential mechanistic diVer- ePicher Pharmaceutical Services, LLC, Lenexa, KA); pra- ences between pralatrexate and other antifolates, speciW- latrexate (Pharmaceutical Service, University of Iowa, cally methotrexate and pemetrexed. Despite being Iowa City, IA), methotrexate (Sigma-Aldrich, St Louis, introduced over 40 years ago, methotrexate is still used MO), and pemetrexed (Eli Lilly, Indianapolis, IN). today in the treatment of several tumor types; however, few methotrexate analogues have been developed. In compari- In vitro studies son to methotrexate, pralatrexate has demonstrated superior in vitro and in vivo anti-tumor activity in breast and lung NCI-H460 human NSCLC cells obtained from the Ameri- cancer cell lines and in xenograft models of lymphoma [9, can Type Cell Collection, Manassas, VA, were propagated 10], human mammary carcinoma, and NSCLC [8]. Pralat- in vitro as described [16]. MV522 human metastatic human rexate has been studied in three completed [11–13] and two NSCLC cells were obtained from Dr. M.J. Kelner (Univer- ongoing clinical trials in NSCLC, and one completed study sity of California, San Diego) and propagated as described in mesothelioma [14]. In a Phase 2 study in NSCLC, the [16]. median time to progression of disease for patients who achieved stable disease and for those with a partial response Enzyme activity assays (PR) was ¸10.5 months. The median duration of survival was 13 months [13]. Furthermore, four clinical trials are DHFR activity was determined using a spectrophotometric ongoing in lymphoma. Preliminary data from one of the assay that measured the decrease of absorbance at 340 nm 123 Cancer Chemother Pharmacol (2009) 64:993–999 995 characteristic of dihydrofolate as it is reduced to tetrahydro- approximately 100 mm3 in size, animals were paired by folate (THF) [17] using a DHFR activity assay kit (Sigma- tumor size into treatment and control groups; each group Aldrich, St Louis, MO). The experiments were repeated at contained nine mice. The antifolates were administered as least twice. Apparent inhibition constants (Ki app) were single agents via intraperitoneal (IP) injection. Pralatrexate determined using the INTERCEPT function (Microsoft was dosed at 1 and 2 mg/kg [every day (QD) £ 5, for two Excel). To measure folylpolyglutamyl synthetase (FPGS) cycles of 5 days each]. Other treatments included pemetr- activity, we Wrst optimized a conventional FPGS assay that exed (150 mg/kg; QD £ 5, for two cycles) and methotrex- 14 used [ C]-L-glutamic acid as a substrate for glutamylation ate (1 and 2 mg/kg; QD £ 5, for two cycles). Equivalent [18] using archived tumor tissue xenografts from the in doses of the two antifolates were chosen as there were no vivo study. Tumor tissue was processed as described [19]. previous data available in this murine model. SigniWcant FPGS activity was assayed at 37°C for 60 min in the pres- endpoints included mean tumor growth inhibition (TGI), ence of 1 mM L-glutamate, 5 mM MgATP, and 500 M weight loss, and treatment toxicity determined as described aminopterin. The reaction was terminated by boiling the [19]. Principles of laboratory animal care per NIH publica- samples for 3 min. The samples were chilled on ice and tion
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